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Logo of cegDove Medical PressThis ArticleSubscribeSubmit a ManuscriptSearchFollowDovepressClinical and Experimental Gastroenterology
Clin Exp Gastroenterol. 2011; 4: 75–119.
Published online 2011 May 3. doi:  10.2147/CEG.S17114
PMCID: PMC3132853

Molecular and cellular pathways associated with chromosome 1p deletions during colon carcinogenesis


Chromosomal instability is a major pathway of sporadic colon carcinogenesis. Chromosome arm 1p appears to be one of the “hot spots” in the non-neoplastic mucosa that, when deleted, is associated with the initiation of carcinogenesis. Chromosome arm 1p contains genes associated with DNA repair, spindle checkpoint function, apoptosis, multiple microRNAs, the Wnt signaling pathway, tumor suppression, antioxidant activities, and defense against environmental toxins. Loss of 1p is dangerous since it would likely contribute to genomic instability leading to tumorigenesis. The 1p deletion-associated colon carcinogenesis pathways are reviewed at the molecular and cellular levels. Sporadic colon cancer is strongly linked to a high-fat/low-vegetable/low-micronutrient, Western-style diet. We also consider how selected dietary-related compounds (eg, excess hydrophobic bile acids, and low levels of folic acid, niacin, plant-derived antioxidants, and other modulatory compounds) might affect processes leading to chromosomal deletions, and to the molecular and cellular pathways specifically altered by chromosome 1p loss.

Keywords: chromosome 1p, colon carcinogenesis, molecular pathways, cellular pathways


Chromosomal instability is a major feature of sporadic colon carcinogenesis.111 Eighty-five percent of colorectal cancers are aneuploid, the remaining 15% being diploid.5 Chromosome 1p deletions in colon tumors have been reported by laboratories from at least 15 countries around the world.1249 Chromosome 1p deletions occur at an early stage of colon carcinogenesis,21,24,2628,30,31,33,37,39,4145 and are strongly linked to karyotypic evolution during colon cancer development.43

Many reports in the literature indicate that the macroscopically normal mucosa proximal or distal to a colon cancer exhibit aneuploidy (loss or gain of chromosomes or parts of chromosomes). Relevant to this review, Cianciulla et al44 reported that deletions of chromosome 1p were simultaneously found in both the distant normal-appearing mucosa of 76% of patients who also harbored 1p deletions in their cancer. These findings indicate that the loss of chromosome 1p may be one of the “hot spots” among the numerous defects in the non-neoplastic mucosa associated with the possible initiation of colon carcinogenesis.5070

The pioneering work of Paraskeva et al7175 indicated the likely involvement of chromosome 1p loss in in vitro immortalization72,74 and in the progression of adenomas to carcinomas.75 The functional importance of loss of distal 1p in colon tumorigenesis was demonstrated in 1993 by Tanaka et al76 who introduced chromosomal band 1p36 into colon carcinoma cells and found that their tumorigenicity was suppressed.

Chromosome 1p deletions can affect distinct pathways of sporadic colon carcinogenesis, including both chromosomal instability and chromosomal instability-negative pathways. The underlying mechanisms associated with the loss of chromosome 1p that may contribute to genomic instabilty and drive colon carcinogenesis are loss of genes associated with DNA repair, spindle checkpoint function, apoptosis, multiple microRNAs (miRNAs), the Wnt signaling pathway, tumor suppression, antioxidant activities, and defense against environmental toxins.77,78 Since centromeric instability and resulting telomeric fusions have been proposed as a mechanism for the loss of chromosome 1p,79 the loss of genes located on chromosome 1p that function to ensure centromeric stability and telomere integrity, in turn, can exacerbate chromosomal instability throughout the genome. These 1p deletion-associated pathways that may lead to colon carcinogenesis will be reviewed at the molecular and cellular levels, and dietary factors that affect these pathways (eg, excess hydrophobic bile acids, and low levels of folic acid, niacin, plant-derived antioxidants, and other modulatory compounds) will be explored. It is likely that certain dietary factors prevent, initiate, or exacerbate genomic instability in colon epithelial cells and thus have importance for colon carcinogenesis.

Mechanisms of carcinogenesis associated with the loss of key genes on chromosome 1p

Chromosome 1, the longest human chromosome, is gene-dense with 3141 genes.80 The genes located on chromosome 1 were identified with the assistance of the Weizmann Institute of Science websites:

GeneLoc ( and GeneCards – The Human Gene Compendium ( Genes located on the p arm of chromosome 1 that are associated with protection against oxidative stress, DNA damage, mitotic perturbations, excessive cellular proliferation, development of apoptosis resistance, aberrant colonic cell differentiation, and environmental toxicity have been tabulated and the function of the gene products described (Tables 18). Since many of these genes have tumor suppressive capabilities, the simultaneous loss caused by a 1p deletion could initiate the formation of neoplastic clones and enhance tumorigenesis through Darwinian selection.8

Table 1
DNA repair and DNA damage response genes
Table 8
Genes associated with protection against environmental and metabolic toxicity

Mechanisms protective against genomic instability

Cells with DNA damage, spindle damage, and dysfunctional telomeres signal DNA damage responses.8184 These DNA damage responses include the activation of numerous checkpoints that arrest the damaged cells in the G1, S, G2, or M-phase of the cell cycle, depending upon the nature of the damage or dysfunction and the stage of the cell cycle of the target cell. DNA-damage checkpoints are activated following direct damage to DNA.8591 Spindle assembly checkpoints are activated following damage to the mitotic machinery,85,9298 or as a result of DNA damage during mitosis.99 Telomere checkpoints are activated by defective telomeres.100106 These checkpoints prevent the damaged cell from completing DNA replication and mitosis until all damage is repaired (Figure 1), and thus prevent 1) mutations that could be formed by replicating a damaged DNA template, 2) aneuploidy that could result from chromosome mis-segregation, and 3) telomere fusions that result in anaphase bridges, broken chromosomes, and translocations as a consequence of the well-known breakage–fusion–bridge cycles.107114

Figure 1
The damaging effects of dietary factors and inflammatory conditions on the colonic epithelium. Damage to DNA, the mitotic spindle, and to telomeres is mediated through the generation of ROS (reactive oxygen species) and/or RNS (reactive nitrogen species). ...

However, cells with excessive direct DNA damage,115122 massive chromosome loss or chromosomal imbalances,123 prolonged activation or inhibition of the spindle checkpoint pathways,122127 or excessively shortened or dysfunctional telomeres,128140 initiate a cascade of molecular events that ultimately leads to either caspase-dependent cell death,141143 caspase-independent cell death,144 or a special form of apoptosis referred to as mitotic catastrophe145148 (Figure 2). (Brightfield micrographs are shown in Figure 3 illustrating the cellular alterations that accompany apoptosis [Figure 3A], mitotic perturbation [Figure 3B], mitotic catastrophe [Figure 3C], and micronuclei formation [associated with aneuploidy] [Figure 3D]). The cell-destructive and cell-protective pathways are downstream of a common signal transduction network that responds to DNA damage.149 The repair/survival and non-repair/cell death pathways are probably activated simultaneously.149 The repair, checkpoint, and cell death response to DNA damage are, however, well co-ordinated,150 the interplay of positive and negative regulatory loops resulting in a delayed death response to DNA damage.149

Figure 2
Excessive spindle damage, dysfunctional telomeres, or DNA damage can result in a prolonged cell cycle arrest which activates pro-cell death pathways. This activation of pro-cell death pathways leads to removal of cells with unrepaired damage to the mitotic ...
Figure 3
Examples of cellular alterations that accompany apoptosis (A), mitotic perturbation during anaphase (B), mitotic catastrophe with complete chromosome/spindle disruption (C), and abundant micronuclei formation associated with aneuploidy (D). Panels A, ...

DNA repair and the DNA damage response (DDR) (Table 1)

The genes on chromosome 1p associated with DNA repair or the DNA damage response (DDR) include CLSN, DCL-RE1B (APOLLO), DDI2, GADD45α, MSH4, MUTYH, RAD54L, and TP73. The functions of these gene products are described in Table 1. The pathways that lead to the prevention of genomic instability are diagrammatically shown in Figure 4. DNA damage elicits a well orchestrated and highly interactive series of events called the DDR, which causes cells to undergo growth arrest so that DNA damage can be adequately repaired. Although p53 mutation or loss of heterozygosity (LOH) is a late event in colon carcinogenesis,151 the loss of p73 (found on chromosome 1p) through chromosomal deletion events may act early in colon carcinogenesis. P73 is an important isoform of the p53 family, since it performs many of the transcriptional functions of p53, and may even target the same genes as p53 during the DDR. In addition, TP73 has distinct transcriptional targets and harmonizes with p53 and p63 to maintain genomic stability.152158 In addition to its role in growth arrest after DNA damage to allow DNA repair to take place, p73 plays an active role in spindle dynamics, mitotic exit and chromosomal stability. The PSRC1 (proline/serine-rich coiled-coil 1) gene found on chromosome 1p (see Table 2) encodes a protein which is a direct transcriptional target of both p53 and p73.159 PSRC1 functions as a microtubule destabilizing protein that controls spindle dynamics and mitotic progression by recruiting and regulating microtubule depolymerases.160 Through its transcriptional activity, p73 is important for the M-to-G1 transition during mitosis.161 Functional knock-out of p73 gene expression by small interfering RNAs alters mitotic progression, resulting in an increase of ana-telophase cells, the accumulation of aberrant late mitotic figures, and the appearance of abnormalities in the subsequent interphase.161 This novel pathway involves the p73-mediated transcription of Kip2/p57, a cyclin-dependent kinase inhibitor, and the coordination of mitotic exit and transition to G1.161,162 Like p53, p73 has been confirmed to be a tumor suppressor.163167 Therefore, a loss of p73 should have a major impact in the development of genomic instability during carcinogenesis.

Figure 4
DNA damage causes several downstream molecular and cellular events. The DNA damage response involves several DNA repair proteins and transcription factors that allow the cell cycle to be arrested at several points to enhance genomic stability. All of ...
Table 2
Mitosis-related and spindle checkpoint genes

Since base excision repair (BER) removes damage that would otherwise be mutagenic in mammalian cells,168170 BER is one of the most important DNA repair pathways in the gastrointestinal tract. BER ameliorates environmentally induced DNA damage in addition to the alkylation, oxidation, and deamination events that occur during normal metabolic processes.171,172 A critical enzyme in the base excision repair pathway is MUTYH (MutY homolog or A/G-specific adenine DNA glycosylase), whose germline mutation is a known cause of MAP (MutYH-associated polyposis), a recently described autosomal recessive colorectal adenoma predisposition syndrome with a very high risk of colorectal cancer.173 Myh deficiency enhances intestinal tumorigenesis in multiple intestinal neoplasia (ApcMin/+) mice.174 Interestingly, Myh deficiency in mice has a larger effect on tumor initiation than on progression in the small bowel.174 Since 1p deletions are observed in the human non-neoplastic mucosa of patients with colon cancer,44 it is possible that Myh-deficient field defects may initiate the process of colon carcinogenesis in humans as it does in the mouse model. Since MUTYH-null mouse embryonic stem cells exhibit a mutator phenotype,175 the loss of MUTYH can affect multiple pathways associated with colon carcinogenesis. The role of MUTYH in the repair of oxidative DNA damage begins with the formation of 8-oxo-guanine (8-oxoG) (see Figure 4), which then causes a mispairing of the oxidized guanine base with adenine upon DNA replication. Mismatch repair processes are activated and MUTYH excises adenine leaving an apurinic (AP) site resulting, after AP endonuclease action, in a DNA single strand (ss) break.176180 The activity of MUTYH, in conjunction with other glycosylases and the spontaneous generation of AP sites, may be quite extensive, since about 9000 AP sites/cell occur daily.168 The AP site is then correctly repaired by the sequential action of several enzymes which catalyze template-directed insertion of one or a few nucleotides at the previously damaged site.172

In addition to their role in DNA repair or the DDR, MUTYH and p73 play important roles in the death of cells that experience either excessive oxidative DNA damage or chromosomal instability. The MUTYH-mediated cell death pathway is described in the next section followed by a section on the p73-mediated cell death pathway, which utilizes part of the MUTYH pathway in its mediation of cell death in response to excessive mitotic perturbation.

MUTYH/PARP/AIF pathway of cell death

MUTYH-mediated cell death has, as a central player, the activation of PARP-1 [poly(ADP-ribose) polymerase-1] (Figure 5). Excessive DNA ss breaks caused by the action of MUTYH and AP endonuclease in the nucleus results in the activation of PARP-1, which attaches polymers of ADP-ribose to proteins, thereby opening up the chromatin to allow access of DNA repair proteins.181,182 PARP initially serves as a survival protein facilitating the rapid repair of DNA strand breaks, and also prevents DNA degradation, in part, by inhibiting the activity of deoxyribonucleases through the process of poly(ADP) ribosylation.183 Since the synthesis of ADP-ribose polymers consumes nicotinamide adenine dinucleotide (NAD+),184 and NAD+ is largely found in mitochondria where it participates in the production of ATP (bottom right side of Figure 5), sustained PARP activation will consume energy reserves, resulting in cell death, usually through the process of necrosis.185188 A marked deficiency in energy reserves may cause the ATP-dependent Na+/K+ transport proteins, which maintain ionic balance, to fail, resulting in cell swelling and lysis of the cell,189 one of the hallmarks of necrosis.190

Figure 5
The mechanisms by which excessive activity of MUTYH and AP endonucleases can lead to cell death through the activation of PARP and the generation of toxic poly(ADP)ribose (PAR) polymers and mitochondrial DNA (mtDNA) damage (see text for detailed description). ...

In addition to the above energy catastrophe caused by excessive PARP activity in the nucleus, persistent single-stranded gaps in newly replicated DNA initiated by the action of MUTYH in mitochondria can result in the fragmentation and depletion of mitochondrial DNA (mtDNA)191,192 accompanied by the loss of mitochondrial function culminating in cell death191,193 (bottom right side of Figure 5). Dysfunctional mitochondria can release Ca++ into the cytosol which can activate calpains, causing Bax activation, lysosomal rupture, and the release of cathepsins into the cytosol191,194 resulting in a caspase-independent mode of cell death. Calpain activation can also result in Bax activation, followed by Bax oligomerization and mitochondrial damage, resulting in the loss of the mitochondrial membrane potential.

There is another unique mechanism that can lead to PARP-mediated cell death after excessive MUTYH activity, in addition to the fragmentation of mtDNA, energy catastrophe and calpain/lysosomal rupture/cathepsin pathways of mitochondrial failure described above. The main product of PARP-1 activity is the generation of polymers of ADP-ribose (PAR). Although these polymers are usually covalently bound to proteins, free PAR polymers are themselves toxic195197 and function as a death signal.197199 The PAR polymers bind to mitochondria and induce the release of tAIF (truncated apoptosis-inducing factor) from the mitochondria into the cytosol199 (lower left side of Figure 5). tAIF is then translocated to the nucleus where it binds to DNA,200202 causes DNA condensation203 and recruits DNA degrading factors (eg, endogenous endo- and exo-nucleases) resulting in DNA degradation198,204 (upper left side of Figure 5). This series of events is part of an intricate program of caspase-independent cell death,203213 and is currently an active area of research.

Several mechanisms have been proposed to explain how tAIF is released from the mitochondria into the cytosol.210,214 Prior to truncation, AIF is embedded in the inner mitochondrial membrane,215 and the release of AIF requires its cleavage215,216 from a 62 kDa AIF mitochondrial form to a truncated 57 kDa soluble AIF form (tAIF).217,218 Calpain-I, which is activated by Ca++,219 and Ca++-independent cathepsins B, L, and S218,220 can cleave intramitochondrial AIF.221223 The calpains and cathepsins can truncate AIF in the same position at Gly102/Leu103.218 Calpain-I, however, appears to be the critical enzyme regulating AIF processing in which the AIF pathway is important for cell death.219 Oxidative modifcation of AIF markedly increases the susceptibility of AIF to calpain-I-mediated processing, most probably through the exposure of a normally hidden calpain cleavage site.219 Since the PAR polymer is a highly negatively charged molecule, it could depolarize mitochondria leading to opening of the mitochondrial membrane permeability transition pore (MPTP) followed by the release of tAIF.197,199 PAR polymers of increasing complexity and molecular weight are more toxic than simple PAR polymers of low molecular weight.197 The PAR polymer could also bind to PAR polymer binding proteins associated with mitochondria, which then release AIF.199,224226 This results in AIF cleavage producing a tAIF, which is soluble and enters the cytosol. The release of tAIF may also be caused by a significant but not excessive decrease in NAD+ (as a result of PARP activity), ATP, and the mitochondrial membrane potential, resulting in the opening of the MPTP (mitochondrial permeability transition pore).186,196,211 The release of tAIF may also be caused by other caspase-independent pathways involving molecules that are often found in the downstream execution phase of apoptosis, such as tBid (truncated Bid),227229 Bax oligomers (formed after activation of Bax by Ca++-dependent calpains),211,217 Bak,230 and Bim-EL.231,232 The activation of PARP also activates other stress-response pathways such as the RIP/TRAF2/JNK pathway,233235 which may be responsible, in part, for generation of tBid228 and the phosphorylation of Bim-EL. The phosphorylation of Bim-EL releases Bim-EL from sequestration by the microtubular dynein motor complex,236 allowing it to bind to bcl-2,231 thereby enhancing the cell death process.

Mechanisms that interfere with tAIF release include the 1) degradation of the PAR polymer by PARG (PAR glycohydrolase),237 2) inhibition of tAIF translocation to the nucleus by Bcl-2, Bcl-xl, HSP70, or Iduna, and 3) interference of transcription of the AIF gene by BNIP3.238 PARG, Bcl-2, Bcl-xl, HSP70, Iduna, and BNIP3 have been shown to be upregulated during carcinogenesis, consistent with the development of tumor cell resistance to cell death. In addition, pro-cell death molecules involved in this MUTYH/PARP/AIF pathway, such as AIF, Bid, Bax, Bak, and Bim-EL, have been reported to be downregulated during carcinogenesis. Thus, overall, MUTYH likely has an important role in the death of cells exposed to excessive reactive oxygen species/reactive nitrogen species (ROS/RNS)-induced DNA damage, and interference with the MUTYH cell death pathway is associated with carcinogenesis.

P73 and caspase-dependent cell death

Like p53, p73 is responsible for the induction of apoptosis in response to excessive DNA damage that cannot be repaired.239 P73 has the ability to upregulate the transcription of numerous classic apoptosis-related genes such as caspases 3, 6, and 8, Bcl-2 family members, and death receptors (Figure 6). In order for p73 to function as a transcription factor, it must be phosphorylated. The c-Abl kinase, activated by DNA damage, phosphorylates and activates p73 on tyrosine 99.240 The stress-induced mitogen-activated protein kinase, p38 MAPK, phosphorylates and activates p73 on threonine residues.239 The degradation of p73 by the E3 ubiquitin-like protein, Itch, is prevented by the Yes-associated protein, YAP. E2F1, p53, and c-jun (located on chromosome 1p; Figures 4 and and6)6) may also have a role in p73 activation in different cell types.241,242 One mechanism by which p73 induces apoptosis includes the transcription of PUMA (p53 upregulated modulator of apoptosis), which in turn causes Bax translocation to the mitochondria with the release of cytochrome c.243 A second mechanism involves the transcription of scotin, which causes endoplasmic reticulum (ER) stress and subsequent apoptosis.244,245 Unlike p53, a direct role of p73 in the apoptotic process (eg, mitochondrial translocation and perturbation) has not been verified. The role of p73 in the regulation of the miRNA processing complex will be discussed in the section “MiRNAs and miRNA processing”. As noted above, loss of p73 through chromosome 1p deletion occurs early in colon carcinogenesis, contrary to the loss of p53 which is a late event.

Figure 6
The possible mechanisms by which p73 transcription and activation can lead to cell death through classic apoptotic mechanisms. Definitions of proteins not included in the main text: PERP (p53 apoptosis effector related to PMP22; tetraspan membrane protein ...

Mitosis-related and spindle checkpoint function (Table 2)

There are 24 genes on chromosome 1p whose gene products affect many different aspects of the mitotic process, and include kinases, phosphatases, centromere proteins, centrosome proteins, cyclins, regulatory mitotic proteins, motor spindle proteins, regulators of chromosomal condensation, a mitosis-related transcription factor, a deacetylase, and a major spindle checkpoint protein (Table 2). The large number of mitosis-related genes that are lost if there is a chromosome 1p deletion could potentially be responsible for colon cancer initiation and progression, since cancer epidemiology studies show that abnormal expression of mitosis-related genes is frequent in different tumor types.246,247 Mitotic checkpoints, and specifically the spindle assembly checkpoint, are major targets for tumor-associated alterations.247 The mitotic spindle assembly checkpoint is essential for ensuring that all chromosomes are properly aligned on the metaphase plate, with every chromosome attached to a spindle microtubule by its kinetochore to prevent aneuploidy.97 If these processes fail to occur and the cell undergoes a prolonged mitotic arrest (Figure 2), the cell may be eliminated through caspase-dependent or caspase-independent cell death mechanisms147 to ensure genomic stability (Figure 7).

Figure 7
The different cellular fate following spindle, telomere and DNA damage during mitosis. Cells with excessive genomic damage can undergo caspase-dependent cell death (CDMCD) or caspase-independent mitotic cell death (CIMCD). DNA-damaged cells may, however, ...

Oxidative stress is a major factor that can induce disturbances in spindle organization,248,249 induce centrosome amplification, cause proteolysis of the anaphase inhibitor securin and mitotic cyclins,250 affect components of the anaphase-promoting complex,251 and override the spindle checkpoint,250 thereby affecting chromosomal stability. During the process of mitosis, direct oxidative damage to chromosomes resulting in double-strand breaks, or oxidative damage to telomeres can activate p53 (Figure 7) or p73 (Figure 6), major DNA damage response proteins that elicit apoptosis through multiple caspase-dependent mechanisms. In addition, caspase-independent mitotic cell death can also occur during a mitotic catastrophe (Figure 3C, Figure 7), which is a prestage to distinct modes of cell death that may be caspase-dependent or caspase-independent.148

The length of time that a spindle is destabilized may determine the mode and timing of cell death after mitotic exit.123,124,126 It has been suggested that prolonged mitotic delay can lead to the decay of anti-apoptotic messenger RNAs (mRNAs)252,253 and/or the gradual accumulation of pro-apoptotic signals.252,254 Of the 24 mitosis-related genes (Table 2), the products of 7 genes have dual-role mitosis/pro-apoptotic functions. These dual-role mitosis/pro-apoptotic genes include APITD1, CCNL2, CDC2L2, CDC42, E2F2, KIF1B, and PLK3 (Table 2). Cells may become genomically unstable if they evade mitotic checkpoints through a process referred to as mitotic slippage, mitotic arrest slippage, or mitotic checkpoint slippage255263 (Figure 7). With mitotic slippage, the cell exits mitosis prematurely, carrying broken chromosomes, abnormal numbers of chromosomes, and unrepaired DNA damage into the daughter cells. In addition to loss of pro-apoptotic proteins, it has been reported that the gradual loss of the checkpoint effector, cyclin B, releases the mitotic arrest induced by spindle disruptive agents, despite the continued presence of spindle damage and upstream checkpoint proteins.14,258,260 In order for a DNA-damaged cell to survive after mitotic slippage, it must evade both apoptosis in the subsequent G1 phase of the cell cycle124 (Figure 7) and reproductive cell death that can follow centrosome amplification and the generation of tetraploid cells264 (Figure 7).

Thus, a decrease in pro-apoptotic mitotic/cell cycle-related genes located on chromosome 1p (APITD1, CCNL2, CDC2L2, CDC42, E2F2, KIF1B, PLK3) (Table 2) may result in resistance to cell death, a critical event that drives tumorigenesis.52,54,265267

Apoptosis-related genes (Table 3)

Table 3
Apoptosis-related genes

Seven genes associated with apoptosis are located on chromosome 1p. Bcl-10 and Bcl2L15 are Bcl-2 family members, THAP3 is a zinc-coordinating DNA-binding protein, DNA fragmentation factor A (DFFA) and B (DFFB) are the two subunits of DFF, caspase-9 is a major initiator caspase in the apoptotic proteolytic cascade, and TNFRSF25 is a death domain-containing receptor related to TNFR-1 and CD95 (Apo-1/Fas). The deletion of 3 of these genes would have important implications for carcinogenesis through the increase in apoptosis resistance, and will be discussed in some detail.

DFF is a heterodimeric protein composed of a catalytically active 40 kD subunit, DFFB (CAD [caspase-activated DNase]), and an inhibitory 45 kD subunit, DFFA (ICAD [inhibitor of CAD]).268,269 When bound to DFFB, DFFA inhibits the nuclease activity of DFFB.268,269 During apoptosis, caspase-3 cleaves DFFA at amino acids 117 and 224 and dissociates it from DFFB, thereby releasing the inhibition of DFFB.270 DFFB activity results in chromatin condensation271 and the formation of the typical crescents and margination of chromatin that are characteristic of classic apoptotic cells at the ultrastructural level.190,266,272276 Characteristic ultrastructural features of apoptotic cells treated with a ROS-generating and DNA-damaging agent are shown in Figure 8. At the molecular level, the action of DFF on DNA results in the initial cleavage of DNA into 50- to 300-kb long fragments,277,278 representing the dismemberment of the higher order organization of chromatin into chromosomal loop domains, and the fragmentation of DNA into oligonucleosomal sized fragments that form a “ladder” on agarose gel electrophoresis.279 The importance of DFF in suppressing tumorigenesis280 was demonstrated by Yan et al281 using DFF40-null mice. DFF-deficient cells exhibit significant increases in mutation, chromosomal instability, and survival compared with wild-type control cells.281 This is probably a result of the inhibition of cell death of DNA-damaged cells resulting from the failure to undergo DNA fragmentation.282,283 DFF is reported to avoid chromosome instability in a p53-independent manner.284 Irradiation of cells with a caspase-resistant form of DFFA led to increased clonogenic survival of cells with increased chromosomal aberrations and aneuploidy.284 The ability of DFF to maintain chromsosomal stability appears to be the result of the DNA fragmentation-induced death of cells with excessive DNA damage.284 Although DFFB has intrinsic DNAse activity, both DFFA and DFFB are required to generate DNase activity,140,269 and must be co-expressed.280 DFFA has been postulated to stabilize the synthesis of DFFB,270,271 or mediate the correct folding and chromatin localization of DFFB.271 The absence of DFF results in an increased frequency of cell transformation and enhanced susceptibility to radiation-induced carcinogenesis, indicating that DFF is a tumor suppressor.280 Recently, it has been reported that the expression of DFFA protein, but not DFFA mRNA, is regulated by a specific miRNA, miR-145, suggesting a mechanism of translational regulation.285 The regulation of DFFB by miRNA has not been investigated, and, so far, none of the miRNAs found on chromosome 1p (Table 4) have been determined to have DFFA or DFFB as target mRNAs for translational regulation.

Figure 8
Transmission electron micrographs of HCT-116 cells reacted with 0.5 mM sodium deoxycholate for 2 hours. A) Normal cell (arrow 1) with prominent nucleolus and dispersed chromatin; arrow 2 points to a cell in early apoptosis, showing margination of chromatin, ...
Table 4
MicroRNAs (miRNAs) and components of the miRNA processing complex

Caspase-9 is a member of the family of cysteine-aspartic acid-specific proteases (caspases), and is also referred to as Apaf-3 (apoptotic protease-activating factor 3). In the presence of cytochrome c and dATP, Apaf-1 binds to procaspase-9286 via a CARD (caspase activation recruitment domain),287 forming a complex referred to as the apoptosome.286,288,289 The cellular oxidative state can affect apoptosome formation by promoting an interaction between caspase-9 and Apaf-1 via disulfide formation.290 In the apoptosome, caspase-9 is activated to process other downstream caspases, including caspase-3 and caspase-2.291 Caspase-9 plays an important role in apoptosis induced by genotoxic stress.292,293 The caspase-9-induced apoptotic pathway can result from mitochondrial membrane depolarization, formation of the apoptosome, and the activation of multiple caspases, including caspase-3 and caspase-2.294 Loss of caspase-9 is therefore important to carcinogenesis, since it can result in apoptosis resistance and the propagation of DNA-damaged cells.295 If caspase-9 is lost, caspase-3 cannot be activated, and thus cannot cleave many substrates including DFFA, an essential endonuclease in apoptosis (see previous page). Similarly, if caspase-9 is lost, caspase-2 may not be activated. Caspase-2 plays a specific role in genotoxic stress-induced apoptosis in some cell types.296,297 (However, there is another pathway for activation of caspase-2. Activation of p53 by DNA damage can result in the p53-mediated transcription of the death domain protein PIDD [p53-induced protein with a death domain], which, together with RAIDD or RIP1, can form a multiprotein complex called the PIDDosome298300 which then activates caspase-2298). DNA damage can also activate caspase-2 through the activation of c-Abl.301 C-Abl binds directly to caspase-9, phosphorylates it on Tyr-153, which then results in the autocleavage and activation of caspase-9 resulting in the apoptosis of excessively DNA-damaged cells.301 Caspase-9 also mediates apoptosis caused by ER stress.302 ER stress first activates caspase-12,302 which is located on the outer membrane of the ER;303 caspase 12 then activates caspase-9 through a cytochrome c-independent mechanism.302 In some cells, ER stress can result in caspase-8 activation, formation of tBid, mitochondrial damage, release of cytochrome c and the activation of caspase-9 through the formation of the apoptosome.304 Therefore, ER stress can activate caspase-9 through both mitochondrial-independent and -dependent mechanisms.

MiRNAs and miRNA processing (Table 4)

miRNAs are evolutionarily conserved, endogenous, small (21 to 24 nucleotides) non-coding RNAs cleaved from 70 to 100 nucleotide hairpin-shaped precursors that reduce translation and stability of target mRNAs through RISC (RNA interference effector complex)-mediated mRNA degradation and translational suppression via sequence-recognition interactions with the 3′ untranslated region of their targeted mRNAs.305315 The diverse cellular functions affected by miRNAs306,316,317 is underscored by the prediction that thousands of genes are potential miRNA targets.318320 At least 800 different miRNAs predicted by computational scanning in the human genome have been documented ( Individual miRNAs have the potential to downregulate large numbers of target mRNAs with seed region complementary sites in their 3′ untranslated regions.321323 It has been speculated that miRNAs could regulate ~30% of the human genome.306 MiRNAs function in proliferation, cell cycle control, the prevention of replicative stress, differentiation, and apoptosis.324333 More than half of the known human miRNAs are located at fragile sites, as well as at sites of LOH, amplification, and common breakpoint regions, which are particular genomic regions that are prone to alteration in cancer cells.327 The overexpression or underexpression of miRNAs as a result of chromosomal additions or deletions, respectively, in individual cells can have dramatic effect on hundreds to thousands of target genes. It is, therefore, not surprising that aberrant expression of miRNAs is associated with cancerous tissues,334340 and that characteristic miRNA expression profiles are features of certain human cancers.341350 Impaired miRNA processing enhances cellular transformation and tumorigenesis,351,352 and certain miRNAs are even classified as tumor suppressors and oncogenes.353355 Alterations in a series of specific miRNAs have been associated with the age of onset of colon cancer, the growth of colon cancer cells, and certain stages of colon carcinogenesis.344,356369 Human colon cancer profiles from 80 colon tumors and 28 samples of normal mucosa show differential miRNA expression depending on mismatch repair status and are characteristic of undifferentiated proliferative states.367 Examination of the genomic regions containing differentially expressed miRNAs revealed that they were also differentially methylated in colon cancer at a far greater rate than would be expected by chance.367 MiRNA profiles could accurately predict microsatellite status in a set of 39 colon cancer studied by Lanza and colleagues.370 This is probably a reflection of the presence or near absence of chromosomal instabilty in the respective microsatellite stable vs unstable cancers.371

There are 20 miRNAs and 3 components of the miRNA processing complex (Argonaute proteins 1,3,4) encoded on chromosome 1p (Table 4). One of the 20 miRNAs, miR-34a, is known to be regulated by p53.309,330,372376 Tarasov et al375 evaluated the differential regulation of 74 miRNAs by p53; 50 miRNAs were either positively or negatively regulated by p53, miR-34a showing the highest fold increase (33.4 fold). Although the 20 miRNAs found on chromosome 1p can have pleiotropic effects on cells, miR-34a is the most well studied for its role in cell cycle arrest and apoptosis in response to DNA damage.309,330,374,377,378 The miR-34 family of miRNAs is one of only 18 mammalian miRNA families379 that are present in flies and worms.309 It is probable that links between p53 and the miRNA-34 family may have arisen early in the evolution of the stress-related p53 network.309 Because of its central role in preventing carcinogenesis, miR-34a has been classified as a tumor suppressor.372,377 MiR-34a has numerous downstream targets, including bcl-2 (major anti-apoptotic protein), NOTCH1, Delta1 (ligand for NOTCH1), NOTCH2 (found on chromosome 1p), CDK4, CDK6, Cyclin D1, Cyclin E2, c-Met, MYCN, SIRT1 and E2F3.319,362,374,375,377,380384 The inhibition of NOTCH1 by miR-34a would enhance apoptosis since NOTCH1 is known to inhibit p53 activity385,386 and to have an anti-apoptotic role387,388 in tumorigenesis. The inhibition of SIRT1 by miR-34a contributes to p53-dependent apoptosis389 through deacetylating and stabilizing p53 leading to an increase in p21 and PUMA.384 The E2F3 transcription factor is not known to have a role in apoptosis; however, it is a novel repressor of the ARF/p53 pathway390 and a potent transcriptional inducer of cell-cycle progression.377 Therefore, the downregulation of E2F3 by miRNA-34a would have a growth inhibitory effect.362,374 MYCN has important roles in both cell proliferation and apoptosis, and MYCN amplification is almost always associated with the loss of chromosome 1p36.382 It is probable that the effects of miR-34a on cellular molecular pathways is widespread, since enforced expression of 34A shows a dramatically altered gene expression profile with upregulation of 532 mRNA transcripts and downregulation of 681 mRNA transcripts highly enriched for those genes that regulate cell-cycle progression, apoptosis (BCL2, BIRC3 [baculoviral IAP repeat-containing 3], DcR3 [decoy receptor 3]), DNA repair, and angiogenesis.330 In conclusion, although p53 is a late event in colon carcinogenesis, the deletion of a major downstream target of p53, miR-34a, as a result of chromosomal 1p deletion, could have dramatic effects on colon tumorigenesis.

MiR-101 is a miRNA that, like 34a, is pro-apoptotic391 and considered to be a tumor suppressor.391,392 The nomenclature of miR-101-1 (Table 4) and miR-101-2 is based on the fact that miR-101-1 is produced from a genomic locus on chromosome 1p31 and miR-101-2 from a genomic locus on chromosome 9p24.392 Loss of heterozygosity at both 1p and 9p are known to be associated with cancer.392 The mechanism by which miR-101 induces apoptosis is by targeting and decreasing the expression of the multifaceted anti-apoptotic protein Mcl-1 (myeloid cell leukemia sequence 1).391 Mcl-1 undergoes rapid turnover which may serve as a convergence point for signals that affect global translation, thereby coupling translation to cell survival and the apoptotic machinery.393 (The DNA damage response can also result in Mcl-1 destruction and the initiation of apoptosis.394,395) Mcl-1 specifically inhibits apoptosis, in part, by sequestering the pro-apoptotic Bim, Bak, tBid, and Noxa, in an inactive state. Since Mcl-1 can interact with tBid and inhibit its induction of cytochrome c release, it plays an important role in resistance to TRAIL and TNFα-induced apoptosis.396,397 Therefore, Mcl-1 can inhibit apoptosis induced by both the death receptor (extrinsic) and mitochondrial (intrinsic) pathways. Mcl-1 is targeted for proteasome-mediated degradation by the E3 ubiquitin ligase MULE398 and is rapidly degraded with a half-life of 30 minutes to 3 hours.393 Its short half-life relates to the presence of a long proline-, glutamic acid-, serine-, and threonine-rich (PEST) region upstream of the Bcl-2 homology domains.398 The inhibition of translation with cycloheximide can cause the rapid degradation of Mcl-1 within 30 minutes, thereby triggering the apoptotic machinery through the release of Bim and the activation of Bak and Bax.393 Although full-length Mcl-1 does not interact with Bax, the caspase-mediated cleavage of Mcl-1 at Asp127 generates a fragment that induces apoptosis through direct interaction with Bax.399 Phosphorylation of Mcl-1 can affect its function and degradation.400 The phosphorylation of Mcl-1 is prominent in cells that accumulate in the G2/M phase of the cell cycle as a result of exposure to microtubule disrupting agents, and in synchronized cells passing through this phase.401 This phosphorylation, especially at serine 64, enhances the anti-apoptotic function of Mcl-1,400 thereby allowing cells to properly align their chromosomes prior to anaphase. In colorectal mucosa, the Mcl-1 protein is found in the apical cells of the crypt,402,403 whereas the distribution is more diffuse in the malignant cells.403

In addition to the development of apoptosis resistance, the loss of miR-101 also leads to cancer progression through the overexpression of histone methytransferase EZH2 (enhancer of zeste homolog 2), a polycomb group member, with concomitant dysregulation of epigenetic pathways.392,404 MiR-101 also represses the expression of FOS (v-fos FBJ murine osteosarcoma viral oncogene homolog) oncogene, a key component of the AP-1 (activator protein-1) transcription factor, MYCN (a gene amplified in many tumors), and COX-2, an enzyme involved in the production of prostaglandins from the metabolism of arachidonic acid.405 Enhanced expression of miRNA-101 also has an effect on the late stages of cancer, since it inhibits invasion and migration.

The p53/p63/p73 family of tumor suppressors are known to regulate the major components of the miRNA processing complex,164,406 which include Drosha-DGCR8, Dicer-TRBP2, and Argonaute proteins. Drosha (RNASEN) is an RNAse III endonuclease; DGCR8 is a double stranded RNA binding protein; DICER contains an RNA helicase motif required for the formation of RISC (RNA induced silencing complex); TRBP2 (trans-activation-responsive RNA binding protein 2) is a component of the miRNA loading complex (composed of DICER1, AGO2, and TRBP2) required for the formation of RISC. Argonaute proteins are endonucleases that aid in the maturation of pre-miRNAs of 60 to 70 nucleotides to mature miRNAs of 21 to 24 nucleotides; the tethering to mRNA mimics the miRNA-mediated repression of protein synthesis.164,407,408 There are 8 members of the Argonaute family in the human genome;409 4 belong to the PIWI subfamily and are expressed mainly in the testis, whereas the other 4 belong to the elF2C/AGO subfamily and are expressed in a variety of adult tissues. Ago1 and Ago2 (catalytic engine of RISC) reside in 3 complexes with distinct DICER and RNA-induced proteins involved in RNA metabolism.410 Three of the 4 members of the elF2C/AGO subfamily are found in a tandem cluster of closely related Argonaute non-nucleolytic proteins,411 Ago1, Ag3, and Ago4 on chromosome 1p (Table 4). Therefore, loss of chromosome 1p should have a major impact on the process of miRNA processing in the affected cells.

A family of miRNAs on chromosome 1p of particular interest to colon carcinogenesis is the miR-200 family, which includes miR-200a, -200b, and -429 (Table 4). These 3 family members are all encoded on a 7.5-kb polycistronic primary miRNA transcript and help determine the epithelial phenotype of cancer cells through the regulation of the Wnt/β-catenin signaling pathway.412,413 Wnt growth factors activate a cascade of intracellular events, known as the canonical Wnt pathway, which ultimately leads to a coordinated proliferation, differentiation, and sorting of the epithelial cell population that forms the colonic crypts.414 In colorectal cancer, epithelial cells that acquire mutations in the Wnt/β-catenin signaling pathway gain inappropriate proliferative capabilities mimicking the effect of a permanent Wnt stimulation.414 Beta-catenin is a transcription factor that translocates to the nucleus and activates target genes involved in stimulation of the cell cycle and inhibition of apoptosis. E-cadherin binds directly to β-catenin in the cytoplasm, which restricts the movement of β-catenin to the nucleus. ZEB1 and ZEB2 are proteins that repress the transcription of E-cadherin. Members of the miR-200 family were found to directly target the mRNA of ZEB1 and ZEB2,412,415418 upregulate E-cadherin expression in cancer cell lines, and reduce cellular motility.412 Conversely, downregulation of one miR-200 family member that was tested, miR-200a, was shown to promote tumor growth by reducing E-cadherin and activating the Wnt/β-catenin signaling pathway.413 Cancer progression has some similarities with embryonic development and wound healing, in which a process of epithelial-to-mesenchymal transition (EMT) occurs.419 Although the EMT normally occurs as a process of stem cell differentiation, the EMT that occurs during carcinogenesis involves a change from a differentiated tumor to a more invasive dedifferentiated tumor.412,419,420

The loss of the miR-200 family of miRNAs, coupled with the loss of 4 proteins associated with the Wnt/β-catenin signaling pathway (Table 5 below), and the loss of the pro-apoptotic miR-34a and the miRNA transcriptional protein, p73, should have a significant impact on the initiation and progression of colon cancer.

Table 5
Genes associated with the Wnt signaling pathway

Wnt/β-catenin signaling pathway (Table 5)

The Wnt signaling pathway is critical for the differentiation and sorting of the epithelial cell population necessary for the organization of the colonic crypts and for the regulation of crypt cell renewal and homeostasis.414,421 Wnt signaling is initiated by the binding of extracellular Wnt factors to receptors on the cell surface, which triggers a signaling cascade that leads to the accumulation of β-catenin.414,422 In the absence of Wnt signals, β-catenin is degraded by a multicomplex complex composed, in part, of APC (adenomatous polyposis coli), GSK3β (glycogen synthase kinase-3-beta), and the scaffold proteins Axin1 and Axin2/conductin,423425 forming the β-catenin destruction box. This destruction box is responsible for the GSK3β-mediated phosphorylation of β-catenin and its subsequent degradation by the ubiquitin-proteasome pathway. The Wnt signals block this phosphorylation and degradation, resulting in the accumulation of β-catenin. Cytoplasmic β-catenin accumulation and translocation to the nucleus allows β-catenin to associate with TCF/LEF (T cell factor/lymphocyte enhancer factor) transcription factors which target genes that enhance cell survival and proliferation (ie, c-myc, cyclin D1).426428 Mutations in APC, β-catenin, Axin1, or ICAT (inhibitor of beta-catenin and Tcf-interacting protein) result in the deregulated accumulation of β-catenin and the constitutive activation of Wnt signaling,429431 a major cause of cancer, including colorectal cancer.418,424,425,432

There are 4 genes located on chromosome 1p that are directly involved in the Wnt signaling pathway (CTNNBIP1, DVL1, WNT2B, and WNT4) (Table 5). WNT2B and WNT4 are secreted signaling factors and Dvl1 is a cytoplasmic molecule that associates with Frat-1 to activate the Wnt signaling pathway. The loss of these positive regulators of the Wnt signaling pathway as a result of a chromosomal 1p deletion may contribute to the dysregulation of crypt organization that could initiate the carcinogenic process.433 CTNNBIP1/ICAT (Table 5), on the other hand, is a negative protein regulator of the Wnt signaling pathway. ICAT disrupts β-catenin–TCF interactions,434436 thereby downregulating gene expression associated with proliferation and cell survival. The crystallographic structure of ICAT indicates the mechanism by which ICAT interferes with β-catenin function. The NH2-terminal domain of ICAT binds to armadillo repeats 10–12 of β-catenin, whereas the COOH-terminal domain of ICAT binds to the groove formed by armadillo repeats 5–9.435,437 The armadillo repeats 5–9 are crucial for the binding of β-catenin to both TCF and E-cadherin.438 The importance of ICAT in the prevention of carcinogenesis is underscored by the fact that ICAT is a multipotent inhibitor of β-catenin438 by interfering with the binding of β-catenin to TCF, cadherins, and APC, with consequences for transcription, cell adhesion, and cytoskeletal function.438440 The cytoplasmic and nuclear location of ICAT, using an immunohistochemical approach, is consistent with a broader role for ICAT than previously reported.440

In addition to the effects on transcription and cell adhesion, ICAT can function as a pro-cell death molecule in certain situations. Overexpression of ICAT in colorectal tumor cells results in growth arrest and cell death, and serves to eliminate cells with a constitutively activated Wnt signaling pathway.441 Using flow cytometry, the cell death was evidenced by a sub-G1 peak of the cell cycle, and the forced entry of cells into an illegitimate DNA synthetic phase without having undergone a prior mitosis (enhanced trypan exclusion of >4N cells).441 Transgenic mice expressing ICAT also make activated T cells (dependent on β-catenin–TCF signaling for survival442,443) highly susceptible to apoptosis (using annexin V staining), by reducing the expression of BclxL below a critical threshold.436 The mechanism by which ICAT reduces BclxL expression is not known at the present time.

Since chromosomal instability is a major feature of colon carcinogenesis, it is appropriate to consider the role of the Wnt signaling pathway in mitotic control and aberrant Wnt signaling in the generation of chromosomal aberrations. A precedent for exploring the role of aberrant Wnt signaling in chromosomal instability are the findings that 1) multiple signaling pathways converge to orient the mitotic spindle in Caenorhabditis elegans embryos;444 2) APC and EB1 (a microtubule-associated protein) have the ability to maintain proper spindle positioning in the developing nervous system of Drosophila;445,446 3) binding of APC protein to microtubules increases microtubule stability and is regulated by GSK3β;447 4) APC has a role in chromosome segregation;448 5) β-catenin is a component of the mammalian mitotic spindle and functions to ensure proper centrosome separation and subsequent establishment of a bipolar spindle;449 6) GSK3β has a role in mitotic spindle dynamics and chromosome alignment,450 and localizes to the centrosome and specialized cytoskeletal structures;451 7) dishevelled genes are involved in mitotic progression in cooperation with polo-like kinase 1;452 and 8) conductin/axin2 and Wnt signaling regulates centrosome cohesion.453 It is now well established that aberrant Wnt/β-catenin signaling can induce chromosomal instability in cancer, including colon cancer.454458 An understanding of the mechanisms by which specific components of the Wnt signaling pathway affect mitosis, mitotic slippage and other aspects of the cell cycle, including interaction with spindle checkpoint proteins, needs to be experimentally determined.

Tumor suppressors (Table 6)

Table 6
Tumor suppressor genes

Experiments involving somatic cell fusion and chromosome segregation established the concept that certain genes are capable of suppressing tumorigenesis.459,460 Tumor suppressors are genes whose miRNA or protein products reduce the formation of tumors and prevent malignant progression by decreasing proliferation, regulating the cell cycle, maintaining chromosome integrity, enhancing DNA repair, inducing apoptosis, and, by reducing angiogenesis, invasion, migration, and cell adhesion. Classic tumor suppressor genes that, when deleted or mutated, contribute to tumorigenesis in many types of tumors include p53, RB, INK4a (p16), and ARF.461 In colorectal cancer, mutations and LOH of the tumor suppressor, APC, can affect both the initiation and progression of cancer, whereas the loss of p53 is a late event. Therefore, when the loss of chromosome 1p became associated with many types of cancer, including colon cancer, several groups began the quest to identify the specific tumor suppressor gene or genes located on 1p.462467 Several genomic loci were identified as “hot spots” for tumor suppressor genes, which included 1p36 and 1p34. It became evident that many genes, both inside and outside of these “hot spots”, could be classified as tumor suppressors; 26 tumor suppressor genes, their genomic loci, and the function of their gene products are listed in Table 6. (Note: 11 genes classified as tumor suppressors in Table 6 are not listed in other tables [Tables 15 and and77]).

Table 7
Genes associated with antioxidant function

Several tumor suppressors are haploinsufficient,468 and cell cycle regulatory tumor suppressor genes seem especially dosage-sensitive.469 These findings indicate that the loss of only one copy of a gene in a diploid cell could have a biologic effect.469 Such a loss could contribute to cellular transformation, with the process of selection driving clonal expansion of pre-neoplastic cells.8

Certain tumor suppressors play a more prominent role in tumorigenesis than others in particular tissue types. However, it is probable that the loss of numerous tumor suppressor genes as a result of a chromosomal deletion probably plays a prominent role in the initiation and progression of cancer through a “combination” of different and/or complementary adverse cellular and molecular events.461,467

Antioxidants (Table 7)

Four genes on chromosome 1p are associated with defense against oxidative stress (Table 7). Two of these (peroxiredoxin 1 [PRDX1] and endoplasmic reticulum protein ERP19 [TXNDC12]) utilize reducing equivalents provided through the thioredoxin system, and 2 (glutamate-cysteine ligase [modifier subunit] or GCLM and glutathione peroxidase 7 [GPX7]) utilize glutathione. One of the most important genes associated with oxidative stress is glutamate-cysteine ligase (GCL) (also called gamma-glutamylcysteine synthetase), the first rate limiting enzyme of glutathione synthesis.470,471 This enzyme requires coupled ATP hydrolysis to form an amide bond between the γ-carboxyl group of glutamate and the amino group of cysteine to form γ-glutamylcysteine. The enzyme consists of a heavy catalytic subunit (73 kDa) and a light (31 kDa) regulatory subunit (GCLM); the light chain or modifier subunit is found on chromosome 1p. It has been known for the past 2 decades that the ultimate formation of glutathione is required for intestinal function.472 The long-term ingestion of reduced glutathione has recently been shown to suppress the accelerating effect of a beef tallow diet on colon carcinogenesis in rats.473 The specific importance of GCLM to protection against oxidative stress is underscored in GCLM (−/−) knock-out mice, which are severely compromised in the oxidative stress response.474

GCL can be increased by oxidative stress or glutathione depletion475,476 through the inhibition of SHP-1477 and the activation of jun N-terminal kinase (JNK).477,478 The increase in GCL can protect against mitochondrial injury and numerous cellular processes that are depend on the generation of glutathione, such as cell cycle progression, inhibition of caspases (protection against apoptosis), activity of detoxification enzymes (see GSTM genes in Table 8; discussed below), and DNA repair.479482 Recent studies indicate that a reduced state of proteins in the nucleus is an important environment that induces heterochromatin formation482 and the regulation of histones and PARP activities.483

Defense against environmental and metabolic toxicity (Table 8)

Chromosome 1p contains 19 genes associated with protection against toxins/carcinogens derived from the environment, dietary/cooking-derived components, and metabolism (Table 8). These genes consist of 2 arylacetamide deacetylase-like enzymes, 4 members of the aldo-keto reductase family, 6 members of the cytochrome P450 family of polypeptides, all 5 members of the mu class of glutathione-S-transferases (GSTs), and 2 metal response element binding transcription factors. A compilation of the 10 most significant transcripton factors capable of targeting the 5′-upstream promoter regions of these 19 genes (GeneCards [SABiosciences’ database; UCSC Genome Browser]) indicates the possible involvement of 95 distinct transcription factors that control their expression. In addition, the Wnt/beta-catenin signaling pathway has been shown to activate various P450 family and GST mu class enzymes in mouse models.484 Since transcription factors respond to different cellular demands and stresses, the presence of these genes on chromosome 1p indicates that the loss of this chromosome arm could compromise the cell’s ability to respond to a variety of environmental toxins/carcinogens that could damage DNA.

It is of interest that all 5 genes of the mu class of GSTs are located on chromosome 1p. The 5 genes are arranged in tandem in the physical order 5′-M4-M2-M1-M5-M3-3′.485,486 The M4-M2-M1-M5 sequence in the gene cluster is oriented in a head-to-tail orientation, whereas the M3 gene is oriented tail-to-tail with respect to the adjacent M5 gene, and is therefore transcribed in the reverse orientation relevant to the other 4 GST mu genes.485 This GST mu gene cluster functions in the detoxification of electrophilic compounds by conjugating glutathione to a wide number of endogenous and exogenous toxins/carcinogens.487 Genetic polymorphisms in GSTM1 increase susceptibility to gastric and colorectal adenocarcinomas.488 In addition, about 70% of human loci is deleted for GSTM1 and 50% of the human population is homozygous deleted for GSTM1.485 This deletion is a result of unequal crossing-over between the two 2.3 kb repeated regions in the intergenic regions that flank the GSTM1 gene. Homozygous deletion of GSTM1 results in increased baseline chromosomal aberrations in lymphocytes among smokers, indicating the role of epoxides and other reactive metabolites of polycyclic aromatic hydrocarbons in inducing genomic instability in these compromised cells.489 All 5 GSTM genes have distinct promoter regions that respond to a different array of transcription factors. Therefore, the loss of chromosome 1p would compromise cellular defenses against toxins/carcinogens, especially in individuals harboring the GSTM1 deletion or other specific polymorphisms.

Development of resistance to cell death and the propagation of cells with DNA damage and chromosomal defects (summary)

We have described in this review how the combination of the persistent damage to a cell’s genome with the inability of that cell to adequately repair the damage or die in response to the excessive damage, is a dangerous situation which can result in clonal selection and the development of colon carcinogenesis. The molecular and cellular mechanisms that are associated with the death of cells are most complex, and include both caspase-dependent and caspase-independent processes. Listed in Tables 17 are 27 pro-apoptotic/pro-cell death genes found on chromosome 1p, whose simultaneous loss caused by a chromosome 1p deletion could have a major impact on the development of resistance to cell death. In Table 9, we extract from those tables the specific genes whose products contribute to cell death. Caspase-9 and both subunits of DNA fragmentation factor are on the downstream execution phase of apoptosis, and the consequences of their loss are obvious. However, the loss of other gene products (eg, TP73, miR-34a) can have pleiotropic effects on cell death pathways because of multiple transcriptional or translational targets. In addition, TP73, KIF1B, and E2F2 are classified as haploinsufficient genes, with loss of function implied with the presence of only 1 allele.490 Some gene products have dual DNA repair/pro-cell death functions (eg, MUTYH) and dual mitosis/pro-cell death functions (KIF1B). One can see (Table 9) that, in addition to classic pro-apoptotic genes, there are dual role cell survival/pro-cell death genes, DNA damage-response genes, various tumor suppressor genes, genes associated with mitosis, miR-NAs, Wnt signaling, and protection against the generation of peroxides. The mechanism of action of these 27 genes in the control of cell fate is an active area of investigation and beyond the scope of this review. This detailed study of the implications of the loss of chromosome 1p serve as an example of how specific chromosomal deletions can have a major impact on carcinogenesis.

Table 9
Summary of pro-cell death genes on chromosome 1p

Role of dietary factors in colon carcinogenesis (Table 10491538)

Table 10
Preventive effects of dietary factors on processes and signaling pathways associated with genes located on chromosome 1p

In this section we first address what alteration in specific dietary factors can lead to the loss of chromosome segments or entire chromosome arms in general to produce loss of heterozygosity. Second, we will consider how the consequences of the loss of genes located on chromosome 1p might be affected by pro-carcinogenic and anti-carcinogenic dietary factors. Our approach is to show how specific dietary factors may influence the molecular and cellular processes affected by chromosome 1p loss that were described in previous sections. Links of diet to any of the specific genes lost by the 1p deletion (see Tables 18) are listed in Table 10.

Diets high in fat,473,539547 but low in fiber,540,548551 low in vegetable intake,552555 and micronutrient deficient556560 induce oxidative stress and DNA damage and adversely affect many molecular pathways that prevent genomic instability and apoptosis resistance, 2 major processes that, together, enhance the development of sporadic colon cancer.

The effects of diet likely occur early in the carcinogenesis process, since an altered vegetable intake is known to affect pivotal carcinogenesis pathways in the colonic mucosa from adenoma patients and controls.561 Although 2 alleles are associated with each gene, and the loss of 1 allele may be compensated for by the other, many genes are reported to be haploinsufficient, including those associated with the mitotic checkpoint.562 It is relevant that TP73, KIF1B, and E2F2, found on chromosome 1p, have also been reported to be haploinsufficient,490,563,564 and could have dramatic consequences for colon tumorigenesis if only 1 allele is expressed in colonic epithelial cells. It is possible that many other genes may be found to be haploinsufficient in the future, since a map of 1079 probable haploinsufficient genes has been compiled by systematic identification of genes unambiguously and repeatedly compromised by copy number variation among 8458 apparently healthy individuals.565 Those genes with a high probability of exhibiting haploinsufficiency were enriched among genes implicated in human dominant diseases and among genes causing abnormal phenotypes in heterozygous knockout mice.565 In addition, the loss of several genes on the same chromosome arm that affect a particular molecular pathway (see Tables 18) may together have a significant effect on that pathway, although the loss of a single gene may have little effect. Specific dietary factors may decrease the protein levels of certain genes through post-translational mechanisms (eg, proteasomal degradation), thereby inducing a functional pseudo-biallelic loss of a gene, one through a physical loss of the chromosomal segment harboring that gene, and the other an actual degradation of the gene product.

Although dietary factors may affect many processes associated with carcinogenesis, we will evaluate specific factors associated with oxidative stress/inflammation, since these genotoxic processes are known to have major effects on the initiation and progression of cancer, including colon cancer.566578 Direct damage to DNA, assessed by immunohistochemical staining of 8-oxoG, correlates with poor survival in colorectal cancer.579 ROS can cause excessive DNA double strand breaks, resulting in the loss of chromosome segments or entire arms, depending on the location of the break. In addition, several DNA repair proteins are degraded through an oxidative mechanism,580,581 thereby affecting DNA repair and increasing susceptibility to cancer.582 Oxidative stress can affect spindle organization, induce centrosome amplification, cause proteolysis of components of the anaphase-promoting complex, and override the spindle checkpoint, thereby affecting chromosomal stability. Therefore, oxidative stress can induce a mutator phenotype in affected cells.583 The big question is what dietary factors contribute directly to oxidative DNA damage and aneuploidy (alteration in the number of whole chromosomes or chromosomal segments). We now address several dietary factors that may be associated with these forms of genomic instability. Although the literature on dietary factors associated with genomic instability is substantial, we have chosen to discuss the effects of a high-fat diet, folate deficiency, and niacin deficiency, since the molecular and cellular mechanisms associated with the overabundance or deficiency of these factors have been especially well studied.

A high-fat diet derived from beef tallow or corn oil (eg, linoleic acid, palmitic acid) is one of the major causes of sporadic colon cancer. Long-chain nonesterified (“free”) fatty acids (FFA) and some of their derivatives and metabolites can modify the intracellular production of ROS, in particular superoxide anions and hydrogen peroxide, in part, through their interference with the mitochondrial electron transport chain.584 FFA can also interfere with the glutathione system and stimulate the generation of superoxide anions from phagocytic NADPH oxidases.584 Chronic exposure of cells to FFA (eg, palmitic acid) can also alter miRNA expression (eg, miR-34a, miR-146).585

The genotoxicity associated with a high-fat diet is also caused, in part, by high concentrations of hydrophobic bile acids released into the gastrointestinal tract in response to high-fat meals where they act as detergents to aid in the digestion of fats. Our research group showed that deoxycholic acid (a major hydrophobic bile acid in the human colon) induces ROS586589 in vitro, and oxidative DNA damage,590 sessile adenomas,591 and colon cancer592 in dietary-related mouse models. In addition to the bile acid-induced formation of 8-oxoG in guanine bases of DNA and the induction of DNA strand breaks (activation of γ-H2AX593 and PARP594), we have shown that deoxycholic acid affects genomic instability at the chromosomal level.595 Evidence indicating the induction of chromosomal damage by deoxycholic acid include the formation of micronuclei and aberrant mitoses, attenuation of activation of the nocodazole-induced spindle checkpoint, and decrease in protein expression of major spindle checkpoint proteins (eg, Mad2, BubR1, securin). The dramatic effect of deoxycholic acid on the process of mitosis is underscored by the finding that deoxycholic acid modulates 71 mitosis-related genes at the mRNA and/or protein levels in vitro and in vivo using mouse models.8 The induction by hydrophobic bile acids of both DNA and chromosomal damage indicates that hydrophobic bile acids are endogenous carcinogens that, at high pathophysiologic concentrations, are capable of contributing to the initiation and progression of colon cancer.8,189,595597 In addition to causing genomic instability, deoxycholic acid can activate survival pathways (eg, NF-κB594 and autophagy598), which allow for the survival and selection of cells with genomic instability.8,599

Coffee drinkers have a lower incidence of cancer, including that of the colon and rectum.600603 One coffee compound that we found to prevent the formation of bile acid-induced proximal colon cancer in a mouse model is chlorogenic acid (CGA), the ester of caffeic acid with quinic acid.592 CGA is one of the most abundant polyphenols in the human diet, with coffee, fruits (eg, blueberry, strawberry, raspberry, apple), and vegetables (eg, eggplants, potato, carrot, tomato) as its major sources.493,604 CGA and its metabolites are likely responsible, in part, for the lower risk of rectal cancer associated with the consumption of decaffeinated coffee in 2 large prospective cohort studies.603 One possible mechanism by which polyphenols can reduce colon cancer in this model is through the reduction in deoxycholic acid levels.605 In this study, Han et al605 report that when rats on a high-fat diet (30% beef tallow) received dietary curcumin (component of the Indian spice turmeric) or caffeic acid (metabolite of CGA), the fecal concentration of deoxycholic acid was substantially reduced. In addition, dietary supplementation of this high-fat diet with caffeic acid, catechin (plant polyphenol), rutin (citrus flavonoid glycoside), and ellagic acid (plant polyphenol) significantly reduced the levels of fecal lithocholic acid, a second major hydrophobic bile acid and risk factor for colon cancer.605

The induction of double-strand breaks is a major cause of the production of chromosomal fragments and the deletion of hundreds to thousands of genes. An important DNA repair protein in preventing large chromosomal deletions is Parp-1606 (Figure 5). DNA strand breakage is directly caused by ROS (which would be enhanced due to the loss of genes encoding antioxidant proteins in the chromosome 1p deletion [Table 7]) or as a result of the activity of base excision repair enzymes (see Figure 5). Strand breakage activates Parp-1, which is involved with opening up chromatin and allowing DNA repair processes to occur, including base excision repair, single-strand and double-strand repair (Figure 5). Shibata et al606 carried out mutation analysis using Parp-1 knockout (Parp−/−) mice, and found that PARP deficiency enhanced deletion mutations, especially >1 kbp. A dietary micronutrient whose deficiency has a major effect on PARP activity is niacin (vitamin B3) obtained from meat and corn. The term niacin refers to nicotinic acid and nicotinamide, which are both used by humans to form NAD+. PARP-1 utilizes NAD+ to make poly(ADP-ribose) needed for poly(ADP-ribosyl)ation of proteins. In keeping with the protective effect of PARP, we determined that pre-treatment of cells in vitro with nicotinic acid and nicotinamide protected against bile acid-induced apoptosis,607 presumably by enhancing PARP-mediated DNA repair of bile acid-induced DNA damage and replenishing the NAD+ levels in mitochondria. In addition, we showed that pre-treatment of cells with nicotinic acid and nicotinamide upregulated the mRNA levels of the glycolytic enzymes, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glucose-6-phosphate dehydrogenase (G6PD).608 GAPDH and G6PD may protect against oxidative stress, in part through the generation of the reduced pyridine nucleotides, NADH and NADPH, respectively, from NAD+.608 Niacin supplementation was even reported to improve pellagra (severe niacin deficiency) in a patient with Crohn’s disease,609 a pre-cancerous inflammatory condition610 associated with oxidative DNA damage.611 Pellagra most probably developed in these Crohn’s disease patients through a combination of intestinal malabsorption of niacin/nicotinic acid612,613 and the high demand for NAD+ that accompanies DNA damage-induced PARP-1 activity (see Figure 5). Work from our laboratory indicated that CGA and its metabolites, caffeic acid, m-coumaric acid, and 3-(m-hydroxyphenyl) propionic acid, increased PARP-1 protein expression.493 The modulation of PARP-1 protein levels by CGA may explain, in part, the colon cancer preventive properties of CGA when added as a supplement to the bile acid-induced colon cancer mouse model.592

The mechanisms by which chromosome segments are deleted and translocated can be most complex. Deletions and translocations can arise from centromeric instability and telomeric instability.7,614 and have been proposed as possible mechanisms for chromosomal aberrations associated with chromosome 1.615617 Centromeric instability can result from hypomethylation or acetylation of pericentromeric heterochromatin, resulting in decondensation/uncoiling/disruption of the centromere618620 and loss of the affected chromosome arms. Telomeric instability is characterized by telomeric fusions, formation of anaphase bridges during mitosis, broken chromosomes upon the stress of cell division, and fusion of chromosomal fragments to chromosome ends. This cycle of chromosomal abberations is referred to as breakage–fusion–bridge cycles.107114,621 Six genes found on chromosome 1p (APITD1, CCDC28B, CDCA8, HDAC1, KIF2C, RCC2) are associated with centomeres (see Table 2), and whose loss would affect centromeric instability. A deficiency of HDAC1, for example, has been reported to disrupt pericentromeric heterochromatin.622 In addition to its role in the repair of interstrand cross-links,623 APOLLO (aka DCLRE1B [DNA cross-link repair 1 B]) is also involved in the protection of telomeres (see Table 1). APOLLO is stabilized when bound to the telomere-binding protein TRF2, and protects human telomeres in S phase624 (Figure 4). A reduced level of APOLLO results in an increased number of telomere-induced DNA damage foci and telomeric fusions in S-phase,624 suggesting that APOLLO contributes to a processing step associated with the replication of chromosome ends. Hydrophobic bile acids, probably through the generation of oxidative stress, can modulate 71 genes associated with mitosis8 and decrease the protein expression of 3 major spindle checkpoint proteins (eg, Mad2, BubR1, securin).8 These alterations in gene expression, coupled with direct oxidative damage to components of the mitotic apparatus, may be responsible, in part, for the observed bile acid-induced mitotic aberrations.595 It is, therefore, possible that bile acids may contribute to the loss of chromosome 1p through its effects on centromere instability and telomeric fusions.

Another mechanism by which large chromosomal deletions can occur is through folic acid deficiency.625,626 Folic acid can attenuate the loss of heterozygosity of the DCC tumor suppressor gene in the colonic mucosa of patients with colorectal adenomas,625 indicating that folic acid deficiency can affect allelic deletion and associated micronuclei formation.627,628 Folates are a group of water-soluble B vitamins (obtained from leafy, green vegetables, the whole grain quinoa, and lentils) whose deficiency contributes to colon cancer.629633 Folates maintain DNA stability through their ability to donate one-carbon units for cellular metabolism and particularly for DNA biosynthesis, repair, and methylation.629,633 Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in one-carbon metabolism. MTHFR catalyzes a unidirectional reaction that determines the balance between cellular availability of 5,10-methylenetetrahydrofolate, used for thymidylate and purine synthesis, and methyltetrahydrofolate used for biological methylation.629 Folate deficiency, therefore, enhances carcinogenesis by impairing normal methylation and nucleotide synthesis, and creates an imbalance between the partitioning of cellular folates into these two pathways. Inhibition of folate metabolism results in excessive uracil misincorporation into DNA633,634 with approximately 4 million uracil bases/cell.559 The repair of 2 adjacent uracil residues on opposite strands of DNA can result in a double-strand break, leading to chromosomal breakage and aneuploidy.558,629,634 Folate deficiency also induces hypomethylation and inhibits DNA excision repair in immortalized normal human colon epithelial cells633 and in the rat colon.635

Recent studies have implicated folate deficiency in the modulation of miRNA expression.497,636 Using microarrays of 385 known human miRNAs, it was determined that folate deficiency in vitro in cultured cells induced a statistically significant fold-change in 24 miRNAs.636 One of these miRNAs was miR-34a, which is found on chromosome 1p and involved in p53-mediated signaling (see Table 4 and the section on MiRNA and MiRNA Processing). MiRNAs were also determined to be altered in patients on a folate-deficient diet.636 In addition to folate deficiency, polymorphisms of MTHFR and altered folate levels are associated with colon cancer risk.637640 The fact that MTHFR is located on chromosome 1p at 1p36.22 indicates that the loss of this chromosome arm, coupled with folate deficiency, can have major effects on genomic instability.

In this section we have considered how dietary factors such as niacin, folic acid, and a low-fat diet associated with low bile acid levels, together with antioxidants that protect against oxidative DNA damage (Table 10), might affect the processes relevant to carcinogenesis that are altered by chromosome 1p loss. In addition to a deficiency in dietary factors that prevent oxidative DNA damage, a deficiency of certain dietary factors that modulate DNA repair proteins, miRNA expression, antioxidant enzymes, defenses against environmental toxicity, and the Wnt signaling pathway (Table 10) can exacerbate the effects of the loss of chromosome 1p. An understanding of the complex molecular and cellular pathways that are affected by dietary factors is an enormous undertaking, but one that has become a focus of colon cancer prevention.


This work was supported in part by NIH 5 R01 CA119087, Arizona Biomedical Research Commission Grant #0803, VA Merit Review Grant 0142 of the Southern Arizona Veterans Affairs Health Care System and Biomedical Diagnostics and Research, Inc., Tucson, Arizona.



The authors declare no conflicts of interest.


1. Steinbeck RG. Chromosome division figures reveal genomic instability in tumorigenesis of human colon mucosa. Br J Cancer. 1998;77:1027–1033. [PMC free article] [PubMed]
2. Hermsen M, Postma C, Baak J, et al. Colorectal adenoma to carcinoma progression follows multiple pathways of chromosomal instability. Gastroenterology. 2002;123:1109–1119. [PubMed]
3. Ribas M, Masramon L, Aiza G, Capella G, Miro R, Peinado MA. The structural nature of chromosomal instability in colon cancer cells. FASEB J. 2003;17:289–291. [PubMed]
4. Richter H, Slezak P, Walch A, et al. Distinct chromosomal imbalances in nonpolypoid and polypoid colorectal adenomas indicate different genetic pathways in the development of colorectal neoplasms. Am J Pathol. 2003;163:287–294. [PubMed]
5. Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C. The significance of unstable chromosomes in colorectal cancer. Nat Rev Cancer. 2003;3:695–701. [PubMed]
6. Postma C, Hermsen MA, Coffa J, et al. Chromosomal instability in flat adenomas and carcinomas of the colon. J Pathol. 2005;205:514–521. [PubMed]
7. Stewenius Y, Gorunova L, Jonson T, et al. Structural and numerical chromosome changes in colon cancer develop through telomere-mediated anaphase bridges, not through mitotic multipolarity. Proc Natl Acad Sci U S A. 2005;102:5541–5546. [PubMed]
8. Payne CM, Bernstein C, Dvorak K, Bernstein H. Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis. Clin Exp Gastroenterol. 2008;1:19–47. [PMC free article] [PubMed]
9. Ashktorab H, Schaffer AA, Daremipouran M, Smoot DT, Lee E, Brim H. Distinct genetic alterations in colorectal cancer. PloS One. 2010;5:e8879. [PMC free article] [PubMed]
10. Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology. 2010;138:2059–2072. [PubMed]
11. Bacolod MD, Barany F. Gene dysregulations driven by somatic copy number aberrations-biological and clinical implications in colon tumors: A paper from the 2009 William Beaumont Hospital Symposium on Molecular Pathology. J Mol Diagn. 12:552–561. [PubMed]
12. Reichmann A, Martin P, Levin B. Chromosomes in human large bowel tumors. A study of chromosome 1. Cancer Genet Cytogenet. 1984;12:295–301. [PubMed]
13. Muleris M, Salmon RJ, Dutrillaux B, et al. Characteristic chromosomal imbalances in 18 near-diploid colorectal tumors. Cancer Genet Cytogenet. 1987;29:289–301. [PubMed]
14. Muleris M, Salmon RJ, Dutrillaux B. Existence of two distinct processes of chromosomal evolution in near-diploid colorectal tumors. Cancer Genet Cytogenet. 1988;32:43–50. [PubMed]
15. Leister I, Weith A, Bruderlein S, et al. Human colorectal cancer: High frequency of deletions at chromosome 1p35. Cancer Res. 1990;50:7232–7235. [PubMed]
16. Bravard A, Luccioni C, Muleris M, Lefrancois D, Dutrillaux B. Relationships between UMPK and PGD activities and deletions of chromosome 1p in colorectal cancers. Cancer Genet Cytogenet. 1991;56:45–56. [PubMed]
17. Couturier-Turpin MH, Esnous C, Louvel A, Poirier Y, Couturier D. Chromosome 1 in human colorectal tumors. Cytogenetic research on structural changes and their significance. Hum Genet. 1992;88:431–438. [PubMed]
18. Bardi G, Johansson B, Pandis N, et al. Cytogenetic aberrations in colorectal adenocarcinomas and their correlation with clinicopathologic features. Cancer. 1993;71:306–314. [PubMed]
19. Bardi G, Pandis N, Fenger C, Kronborg O, Bomme L, Heim S. Deletion of 1p36 as a primary chromosomal aberration in intestinal tumorigenesis. Cancer Res. 1993;53:1895–189. [PubMed]
20. Bardi G, Johansson B, Pandis N, et al. Cytogenetic analysis of 52 colorectal carcinomas – non-random aberration pattern and correlation with pathologic parameters. Int J Cancer. 1993;55:422–428. [PubMed]
21. Bomme L, Bardi G, Pandis N, Fenger C, Kronborg O, Heim S. Clonal karyotypic abnormalities in colorectal adenomas: Clues to the early genetic events in the adenoma-carcinoma sequence. Genes Chromosomes Cancer. 1994;10:190–196. [PubMed]
22. Bardi G, Sukhikh T, Pandis N, Fenger C, Kronborg O, Heim S. Karyotypic characterization of colorectal adenocarcinomas. Genes Chromosomes Cancer. 1995;12:97–109. [PubMed]
23. Gerdes H, Chen Q, Elahi AH, et al. Recurrent deletions involving chromosomes 1, 5, 17, and 18 in colorectal carcinoma: Possible role in biological and clinical behavior of tumors. Anticancer Res. 1995;15:13–24. [PubMed]
24. Lothe RA, Andersen SN, Hofstad B, et al. Deletion of 1p loci and microsatellite instability in colorectal polyps. Genes Chromosomes Cancer. 1995;14:182–188. [PubMed]
25. Praml C, Finke LH, Herfarth C, Schlag P, Schwab M, Amler L. Deletion mapping defines different regions in 1p34.2-pter that may harbor genetic information related to human colorectal cancer. Oncogene. 1995;11:1357–1362. [PubMed]
26. Di Vinci A, Infusini E, Peveri C, Risio M, Rossini FP, Giaretti W. Deletions at chromosome 1p by fluorescence in situ hybridization are an early event in human colorectal tumorigenesis. Gastroenterol. 1996;111:102–107. [PubMed]
27. Bomme L, Bardi G, Pandis N, Fenger C, Kronborg O, Heim S. Chromosome abnormalities in colorectal adenomas: Two cytogenetic subgroups characterized by deletion of 1p and numerical aberrations. Hum Pathol. 1996;27:1192–1197. [PubMed]
28. Bardi G, Parada LA, Bomme L, et al. Cytogenetic findings in metastases from colorectal cancer. Int J Cancer. 1997;72:604–607. [PubMed]
29. Ogunbiyi OA, Goodfellow PJ, Gagliardi G, et al. Prognostic value of chromosome 1p allelic loss in colon cancer. Gastroenterology. 1997;113:761–766. [PubMed]
30. Di Vinci A, Infusini E, Peveri C, et al. Correlation between 1p deletions and aneusomy in human colorectal adenomas. Int J Cancer. 1998;75:45–50. [PubMed]
31. Di Vinci A, Infusini E, Nigro S, Monaco R, Giaretti W. Intratumor distribution of 1p deletions in human colorectal adenocarcinoma is commonly homogeneous. Indirect evidence of early involvement in colorectal tumorigenesis. Cancer. 1998;83:415–422. [PubMed]
32. Tomlinson I, Ilyas M, Johnson V, et al. A comparison of the genetic pathways involved in the pathogenesis of three types of colorectal cancer. J Pathol. 1998;184:148–152. [PubMed]
33. Bomme L, Heim S, Bardi G, et al. Allelic imbalance and cytogenetic deletion of 1p in colorectal adenomas: A target region identified between D1S199 and D1S234. Genes Chromosomes Cancer. 1998;21:185–194. [PubMed]
34. Di Vinci A, Infusini E, Peveri C, et al. Intratumor heterogeneity of chromosome 1, 7, 17, and 18 aneusomies obtained by FISH and association with flow cytometric DNA index in human colorectal adenocarcinomas. Cytometry. 1999;35:369–375. [PubMed]
35. Parada LA, Maranon A, Hallen M, et al. Cytogenetic analyses of secondary liver tumors reveal significant differences in genomic imbalances between primary and metastatic colon carcinomas. Clin Exp Metastasis. 1999;17:471–479. [PubMed]
36. Ragnarsson G, Eiriksdottir G, Johannsdottir JT, Jonasson JG, Egilsson V, Ingvarsson S. Loss of heterozygosity at chromosome 1p in different solid human tumours: association with survival. Br J Cancer. 1999;79:1468–1474. [PMC free article] [PubMed]
37. Rashid A, Houlihan PS, Booker S, Petersen GM, Giardiello FM, Hamilton SR. Phenotypic and molecular characteristics of hyperplastic polyposis. Gastroenterology. 2000;119:323–332. [PubMed]
38. Thorstensen L, Qvist H, Heim S, et al. Evaluation of 1p losses in primary carcinomas, local recurrences and peripheral metastases from colorectal cancer patients. Neoplasia. 2000;2:514–522. [PMC free article] [PubMed]
39. Couterier-Turpin MH, Bertrand V, Couturier D. Distal deletion of 1p in colorectal tumors: An initial event and/or a step in carcinogenesis? Study by fluorescence in situ hybridization interphase cytogenetics. Cancer Genet Cytogenet. 2001;124:47–55. [PubMed]
40. Thiagalingam S, Laken S, Willson JK, et al. Mechanisms underlying losses of heterozygosity in human colorectal cancers. Proc Natl Acad Sci U S A. 2001;98:2698–2702. [PubMed]
41. Shih IM, Zhou W, Goodman SN, Lengauer C, Kinzler KW, Vogelstein B. Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis. Cancer Res. 2001;61:818–822. [PubMed]
42. Nowak MA, Komarova NL, Sengupta A, et al. The role of chromosomal instability in tumor initiation. Proc Natl Acad Sci U S A. 2002;99:16226–16231. [PubMed]
43. Hoglund M, Gisselssonm D, Hansen GB, Sall T, Mitelman F, Nilbert M. Dissecting karyotypic patterns in colorectal tumors: Two distinct but overlapping pathways in the adenoma-carcinoma transition. Cancer Res. 2002;62:5939–5946. [PubMed]
44. Cianciulli A, Cosimelli M, Marzano R, et al. Genetic and pathologic significance of 1p, 17p, and 18q aneusomy and the ERBB2 gene in colorectal cancer and related normal colonic mucosa. Cancer Genet Cytogenet. 2004;151:52–59. [PubMed]
45. Giaretti W, Molinu S, Ceccarelli J, Prevosto C. Chromosomal instability, aneuploidy, and gene mutations in human sporadic colorectal adenomas. Cell Oncol. 2004;26:301–305. [PubMed]
46. Zhou CZ, Qiu GQ, Zhang F, He L, Peng ZH. Loss of heterozygosity on chromosome 1 in sporadic colorectal carcinoma. World J Gastroenterol. 2004;10:1431–1435. [PubMed]
47. Tsafrir D, Bacolod M, Selvanayagam Z, et al. Relationship of gene expression and chromosomal abnormalities in colorectal cancer. Cancer Res. 2006;66:2129–2137. [PubMed]
48. Fijneman RJ, Carvalho B, Postma C, Mongera S, van Hinsbergh VW, Meijer GA. Loss of 1p36, gain of 8q24, and loss of 9q34 are associated with stroma percentage of colorectal cancer. Cancer Lett. 2007;258:223–229. [PubMed]
49. Brosens RP, Haan JC, Carvalho B, et al. Candidate driver genes in focal chromosomal aberrations of stage II colon cancer. J Pathol. 2010;221:411–424. [PubMed]
50. Sandforth F, Witzel L, Balzer T, Gutschmidt S, Janicke I, Riecken EO. Identification of patients at high risk for colorectal carcinoma from biopsy studies of the apparently normal colorectal mucosa. A multivariate analysis. Eur J Clin Invest. 1991;21:295–302. [PubMed]
51. Chhatwal VJ, Ngoi SS, Chan ST, Chia YW, Moochhala SM. Aberrant expression of nitric oxide synthase in human polyps, neoplastic colonic mucosa and surrounding peritumoral normal mucosa. Carcinogenesis. 1994;15:2081–2085. [PubMed]
52. Bernstein C, Bernstein H, Garewal H, et al. A bile acid-induced apoptosis assay for colon cancer risk, and associated quality control studies. Cancer Res. 1999;59:2353–2357. [PubMed]
53. Bernstein C, Bernstein H, Payne CM, Garewal H. Field defects in progression to adenocarcinoma of the colon and esophagus. Electronic J Biotechnol. 2000;3:1–17. Available on the Web:
54. Bernstein H, Holubec H, Warneke JA, et al. Patchy field defects of apoptosis resistance and dedifferentiation in flat mucosa of colon resections from colon cancer patients. Ann Surg Oncol. 2002;9:505–517. [PubMed]
55. Suter CM, Martin DI, Ward RL. Hypomethylation of L1 retrotransposons in colorectal cancer and adjacent normal tissue. Int J Colorectal Dis. 2004;19:95–101. [PubMed]
56. Roy HK, Liu Y, Wali RK, et al. Four-dimensional elastic light-scattering fingerprints as preneoplastic markers in the rat model of colon carcinogenesis. Gastroenterology. 2004;126:1071–1081. [PubMed]
57. Roy HK, Kim YL, Liu Y, et al. Risk stratification of colon carcinogenesis through enhanced backscattering spectroscopy analysis of the uninvolved colonic mucosa. Clin Cancer Res. 2006;12:961–968. [PubMed]
58. Hao CY, Moore DH, Wong P, Bennington JL, Lee NM, Chen LC. Alteration of gene expression in macroscopically normal colonic mucosa from individuals with a family history of sporadic colon cancer. Clin Cancer Res. 2005;11:1400–1407. [PubMed]
59. Payne CM, Holubec H, Bernstein C, et al. Crypt-restricted loss and decreased protein expression of cytochrome c oxidase subunit I as potential hypothesis-driven biomarkers of colon cancer risk. Cancer Epidemiol Biomarkers Prev. 2005;14:2066–2075. [PubMed]
60. Badvie S, Hanna-Morris A, Anreyev HJ, Cohen P, Saini S, Allen-Mersh TG. A “field change” of inhibited apoptosis occurs in colorectal mucosa adjacent to colorectal adenocarcinoma. J Clin Pathol. 2006;59:942–946. [PMC free article] [PubMed]
61. Bernstein H, Prasad A, Holubec H, et al. Reduced Pms2 in non-neoplastic flat mucosa from patients with colon cancer correlates with reduced apoptosis competence. Appl Immunohistochem Mol Morphol. 2006;14:166–172. [PubMed]
62. Kawakami K, Ruszkiewicz A, Bennett G, et al. DNA hypermethylation in the normal colonic mucosa of patients with colon cancer. Br J Cancer. 2006;94:593–598. [PMC free article] [PubMed]
63. Alberts DS, Einspahr JG, Krouse RS, et al. Karyometry of the colonic mucosa. Cancer Epidemiol Biomarkers Prev. 2007;16:2704–2716. [PubMed]
64. Payne CM, Bernstein C, Bernstein H. Field change of apoptosis resistance in colonic mucosa of patients with colorectal carcinoma. J Clin Path. 2007 [electronic letter published February 5, 2007].
65. Bernstein C, Bernstein H, Payne CM, Dvorak K, Garewal H. Field defects in progression to gastrointestinal tract cancers. Cancer Lett. 2008;260:1–10. [PMC free article] [PubMed]
66. Belshaw NJ, Elliott GO, Foxall RJ, et al. Profiling CpG island field methylation in both morphologically normal and neoplastic human colonic mucosa. Br J Cancer. 2008;99:136–142. [PMC free article] [PubMed]
67. Chao H, Brown RE. Field effect in cancer – an update. Ann Clin Lab Sci. 2009;39:331–337. [PubMed]
68. Daniel CR, Bostick RM, Flanders WD, et al. TGF-α expression as a potential biomarker of risk within the normal-appearing colorectal mucosa of patients with and without incident sporadic adenoma. Cancer Epidemiol Biomarkers Prev. 2009;18:65–73. [PMC free article] [PubMed]
69. Belshaw NJ, Pal N, Tapp HS, et al. Patterns of DNA methylation in individual colonic crypts reveal aging and cancer-related field defects in the morphologically normal mucosa. Carcinogenesis. 2010;31:1158–1163. [PubMed]
70. Nguyen H, Loustaunau C, Facista A, et al. Deficient Pms2, ERCC1, Ku86, CcOI in field defects during progression to colon cancer. J Vis Exp. 2010 1931 Jul 28;41 doi: 10.3791/1931. Pii: [PubMed] [Cross Ref]
71. Paraskeva C, Buckle BG, Sheer D, Wigley CB. The isolation and characterization of colorectal epithelial cell lines at different stages in malignant transformation from familial polyposis coli patients. Int J Cancer. 1984;34:49–56. [PubMed]
72. Paraskeva C, Finerty S, Powell S. Immortalization of a human colorectal adenoma cell line by continuous in vitro passage: Possible involvement of chromosome 1 in tumour progression. Int J Cancer. 1988;41:908–912. [PubMed]
73. Paraskeva C, Finerty S, Mountford RA, Powell SC. Specific cytogenetic abnormalities in two new human colorectal adenoma-derived epithelial cell lines. Cancer Res. 1989;49:1282–1286. [PubMed]
74. Paraskeva C, Harvey A, Finerty S, Powell S. Possible involvement of chromosome 1 in in vitro immortalization: Evidence from progression of a human adenoma-derived cell line in vitro. Int J Cancer. 1989b;43:743–746. [PubMed]
75. Williams AC, Harper SJ, Paraskeva C. Neoplastic transformation of a human colonic epithelial cell line: In vitro evidence for the adenoma to carcinoma sequence. Cancer Res. 1990;50:4724–4730. [PubMed]
76. Tanaka K, Yanoshita R, Konishi M, et al. Suppression of tumourigenicity in human colon carcinoma cells by introduction of normal chromosome 1p36 region. Oncogene. 1993;8:2253–2258. [PubMed]
77. Roschke AV, Glebov OK, Lababidi S, Gehlhaus KS, Weinstein JN, Kirsch IR. Chromosomal instability is associated with higher expression expression of genes implicated in epithelial-mesenchymal transition, cancer invasiveness, and metastasis and with lower expression of genes involved in cell cycle checkpoints, DNA repair, and chromatin maintenance. Neoplasia. 2008;10:1222–1230. [PMC free article] [PubMed]
78. Negrini S, Gorgoulis VG, Halazonetis TD. Genetic instability – an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010;11:220–228. [PubMed]
79. Sawyer JR, Husain M, Lukacs JL, Stangeby C, Binz RL, Al-Mefty O. Telomeric fusion as a mechanism for the loss of 1p in meningioma. Cancer Genetics Cytogenet. 2003;145:38–48. [PubMed]
80. Gregory SG, Barlow KF, McLay KE, et al. The DNA sequence and biological annotation of human chromosome 1. Nature. 2006;44:315–321. [PubMed]
81. Bartek J, Bartkova J, Lukas J. DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene. 2007;26:7773–7779. [PubMed]
82. Harper JW, Elledge The DNA damage response: Ten years after. Mol Cell. 2007;28:739–745. [PubMed]
83. Jackson SP, Bartek The DNA-damage response in human biology and disease. Nature. 2009;461:1071–1078. [PMC free article] [PubMed]
84. Ciccia A, Elledge SJ. The DNA damage response: Making it safe to play with knives. Mol Cell. 2010;40:179–204. [PMC free article] [PubMed]
85. Nigg EA. Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol. 2001;2:21–32. [PubMed]
86. Nyberg KA, Michelson RJ, Putnam CW, Weinert TA. Toward maintaining the genome: DNA damage and replication checkpoints. Annu Rev Genet. 2002;36:617–656. [PubMed]
87. Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem. 2004;73:39–85. [PubMed]
88. Su TT. Cellular responses to DNA damage: One signal, multiple choices. Annu Rev Genet. 2006;40:187–208. [PubMed]
89. Hakem R. DNA-damage repair; the good, the bad, and the ugly. EMBO J. 2008;27:589–605. [PubMed]
90. Wood JL, Chen J. DNA-damage checkpoints: Location, location, location. Trends Cell Biol. 2008;18:451–455. [PubMed]
91. Reinhardt HC, Yaffe MB. Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2. Curr Opin Cell Biol. 2009;21:245–255. [PMC free article] [PubMed]
92. Decordier I, Cundari E, Kirsch-Volders M. Mitotic checkpoints and the maintenance of the chromosome karyotype. Mutat Res. 2008;651:3–13. [PubMed]
93. Gimenez-Abian JF, Diaz-Martinez LA, Wirth KG, Andrews CA, Gimenez-Martin G, Clarke DJ. Regulated separation of sister centromeres depends on the spindle assembly checkpoint but not on the anaphase promoting complex/cyclosome. Cell Cycle. 2005;4:1561–1575. [PubMed]
94. Kops GJPL, Weaver BAA, Cleveland DW. On the road to cancer: Aneuploidy and the mitotic checkpoint. Nat Rev Cancer. 2005;5:773–785. [PubMed]
95. May KM, Hardwick KG. The spindle checkpoint. J Cell Sci. 2006;119:4139–4142. [PubMed]
96. Musacchio A, Salmon ED. The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol. 2007;8:379–393. [PubMed]
97. Suijkerbuijk SJE, Kops GJPL. Preventing aneuploidy: The contribution of mitotic checkpoint proteins. Biochim Biophys Acta. 2008;1786:24–31. [PubMed]
98. Thirthagiri E, Robinson CM, Huntley S, et al. Spindle assembly checkpoint and centrosome abnormalities in oral cancer. Cancer Lett. 2007;258:276–285. [PubMed]
99. Mikhailov A, Cole RW, Rieder CL. DNA damage during mitosis in human cells delays the metaphase/anaphase transition via the spindle-assembly checkpoint. Curr Biol. 2002;12:1797–1806. [PubMed]
100. D’Adda di Fagagna F, Reaper PM, Clay-Farrace, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426:194–198. [PubMed]
101. Longhese MP. DNA damage response at functional and dysfunctional telomeres. Genes Develop. 2008;22:125–140. [PubMed]
102. Maser RS, DePinho RA. Telomeres and the DNA damage response: Why the fox is guarding the henhouse. DNA Repair. 2004;3:979–988. [PubMed]
103. Meier A, Fiegler H, Munoz P, et al. Spreading of mammalian DNA-damage response factors studied by ChIP-chip at damaged telomeres. EMBO J. 2007;26:2707–2718. [PubMed]
104. Pantic M, Zimmermann S, El Daly H, et al. Telomere dysfunction and loss of p53 cooperate in defective mitotic segregation of chromosomes in cancer cells. Oncogene. 2006;25:4413–4420. [PubMed]
105. Takai H, Smogorzewska A, de Lange T. DNA damage foci at dysfunctional telomeres. Curr Biol. 2003;13:1549–1556. [PubMed]
106. Viscardi V, Clerici M, Cartagena-Lirola H, Longhese MP. Telomeres and DNA damage checkpoints. Biochimie. 2005;87:613–624. [PubMed]
107. Gisselsson D, Pettersson L, Hoglund M, et al. Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. Proc Natl Acad Sci U S A. 2000;97:5357–5362. [PubMed]
108. Hoffelder DR, Luo L, Burke NA, Watkins SC, Gollin SM, Saunders WS. Resolution of anaphase bridges in cancer cells. Chromosoma. 2004;112:389–397. [PubMed]
109. Kitada K, Yamasaki T. The complicated copy number alterations in chromosome 7 of a lung cancer cell line is explained by a model based on repeated breakage-fusion-bridge cycles. Cancer Genet Cytogenet. 2008;185:11–19. [PubMed]
110. Lo AWI, Sabatier L, Fouladi B, Pottier G, Ricoul M, Murnane JP. DNA amplification by breakage/fusion/bridge cycles initiated by spontaneous telomere loss in a human cancer cell line. Neoplasia. 2002;4:531–538. [PMC free article] [PubMed]
111. McClintock B. The behavior in successive nuclear divisions of a chromosome broken at meiosis. Proc Natl Acad Sci U S A. 1939;25:405–416. [PubMed]
112. McClintock B. The fusion of broken ends of chromosomes following nuclear fusion. Proc Natl Acad Sci U S A. 1942;28:458–463. [PubMed]
113. Selvarajah S, Yoshimoto M, Park PC, et al. The breakage-fusion-bridge (BFB) cycle as a mechanism for generating genetic heterogeneity in osteosarcoma. Chromosoma. 2006;115:459–467. [PubMed]
114. Shimizu N, Shingaki K, Kaneko-Sasaguri Y, Hashizume T, Kanda T. When, where and how the bridge breaks: Anaphase bridge breakage plays a crucial role in gene amplification and HSR generation. Exp Cell Res. 2005;302:233–243. [PubMed]
115. Bree RT, Neary C, Samali A, Lowndes NF. The switch from survival responses to apoptosis after chromosomal breaks. DNA Repair. 2004;3:989–995. [PubMed]
116. Brodsky MH, Weinert BT, Tsang G, et al. Drosophila melanogaster MNK/Chk2 and p53 regulate multiple DNA repair and apoptotic pathways following DNA damage. Mol Cell Biol. 2004;24:1219–1231. [PMC free article] [PubMed]
117. Kastan MB. DNA damage responses: Mechanisms and roles in human disease. Mol Cancer Res. 2008;6:517–524. [PubMed]
118. Kohn KW, Pommier Y. Molecular interaction map of the p53 and Mdm2 logic elements, which control the Off-On switch of p53 in response to DNA damage. Biochem Biophys Res Comm. 2005;331:816–827. [PubMed]
119. Lee MW, Kim W-J, Beardsley DI, Brown KD. N-Methyl-N’-Nitro-N-Nitrosoguanidine activates multiple cell death mechanisms in human fibroblasts. DNA Cell Biol. 2007;26:683–694. [PubMed]
120. Liontos M, Niforou K, Velimezi G, et al. Modulation of the E2F1-driven cancer cell fate by the DNA damage response machinery and potential novel E2F1 targets in osteosarcomas. Am J Pathol. 2009;175:376–391. [PubMed]
121. Michalak E, Villunger A, Erlacher M, Strasser A. Death squads enlisted by the tumour suppressor p53. Biochem Biophys Res Comm. 2005;331:786–798. [PubMed]
122. Morrison C, Rieder CL. Chromosome damage and progression into and through mitosis in vertebrates. DNA Repair. 2004;3:1133–1139. [PubMed]
123. Kops GJPL, Foltz DR, Cleveland DW. Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint. Proc Natl Acad Sci U S A. 2004;101:68704. [PubMed]
124. Bekier ME, Fischbach R, Lee J, Taylor WR. Length of mitotic arrest induced by microtubule-stabilizing drugs determines cell death after mitotic exit. Mol Cancer Ther. 2009;8:1646–1654. [PubMed]
125. Nitta M, Kobayashi O, Honda S, et al. Spindle checkpoint function is required for mitotic catastrophe induced by DNA-damaging agents. Oncogene. 2004;23:6548–6558. [PubMed]
126. Rieder CL, Maiato H. Stuck in division or passing through: What happens when cells cannot satisfy the spindle assembly checkpoint. Dev Cell. 2004;7:637–651. [PubMed]
127. Weaver BAA, Cleveland DW. Decoding the links between mitosis, cancer, and chemotherapy: The mitotic checkpoint, adaptation, and cell death. Cancer Cell. 2005;8:7–12. [PubMed]
128. Ahmad K, Golic KG. Telomere loss in somatic cells of Drosophila causes cell cycle arrest and apoptosis. Genetics. 1999;151:1041–1051. [PubMed]
129. Aoki H, Iwado E, Eller MS, et al. Telomere 3’ overhang-specific DNA oligonucleotides induce autophagy in malignant glioma cells. FASEB J. 2007;21:2918–2930. [PubMed]
130. Arkus N. A mathematical model of cellular apoptosis and senescence through the dynamics of telomere loss. J Theoret Biol. 2005;235:13–32. [PubMed]
131. Artandi SE, Attardi LD. Pathways connecting telomeres and p53 in senescence, apoptosis, and cancer. Biochem Biophys Res Comm. 2005;331:881–890. [PubMed]
132. Eller MS, Puri N, Hadshiew IM, Venna SS, Gilchrest BA. Induction of apoptosis by telomere 3- overhang-specific DNA. Exp Cell Res. 2002;276:185–193. [PubMed]
133. Espejel S, Franco S, Rodriquez-Perales, Bouffler SD, Cigudosa JC, Blasco MA. Mammalian Ku86 mediates chromosomal fusions and apoptosis caused by critically short telomeres. EMBO J. 2002;21:2207–2219. [PubMed]
134. Hemann MT, Strong MA, Hao L-Y, Greider CW. The shortest telomere, not average telomere length, is critical for cell viability and chromosomal stability. Cell. 2001;107:67–77. [PubMed]
135. Herbert B-S, Pitts AE, Baker SI, et al. Inhibition of human telomerase in immortal human cell cells leads to progressive telomere shortening and cell death. Proc Natl Acad Sci U S A. 1999;96:14276–14281. [PubMed]
136. Kaminker PG, Kim S-H, Taylor RD, et al. TANK2, a new TRF1-associated poly(ADP-ribose) polymerase, causes rapid induction of cell death upon overexpression. J Biol Chem. 2001;276:35891–35899. [PubMed]
137. Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T. p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science. 1999;283:1321–1325. [PubMed]
138. Ramirez R, Carracedo J, Jimenez R, Canela A, Herrera E. Massive telomere loss is an early event of DNA damage-induced apoptosis. J Biol Chem. 2003;278:836–842. [PubMed]
139. Titen SWA, Golic KG. Telomere loss provokes multiple pathways to apoptosis and produces genomic instability in Drosophila melanogaster. Genetics. 2008;180:1821–1832. [PubMed]
140. Zhang X, Mar V, Zhou W, Harrington L, Robinson MO. Telomere shortening and apoptosis in telomerase-inhibited human tumor cells. Genes Dev. 1999;13:2388–2399. [PubMed]
141. Plesca D, Mazumder S, Almasan A. DNA damage response and apoptosis. Methods Enzymol. 2008;446:107–122. [PMC free article] [PubMed]
142. Roos WP, Kaina B. DNA damage-induced cell death by apoptosis. Trends Mol Med. 2006;12:440–450. [PubMed]
143. Yu J, Zhang L. The transcriptional targets of p53 in apoptosis control. Biochem Biophys Res Comm. 2005;331:851–858. [PubMed]
144. Kitagawa K, Niikura Y. Caspase-independent mitotic death (CIMD) Cell Cycle. 2008;7:1001–1005. [PubMed]
145. Castedo M, Perfettini J-L, Roumier T, et al. Mitotic catastrophe constitutes a special case of apoptosis whose suppression entails aneuploidy. Oncogene. 2004;23:4362–4370. [PubMed]
146. Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G. Cell death by mitotic catastrophe: A molecular definition. Oncogene. 23:2825–2837. [PubMed]
147. Mansilla S, Priebe W, Portugal J. Mitotic catastrophe results in cell death by caspase-dependent and caspase-independent mechanisms. Cell Cycle. 2006;5:53–60. [PubMed]
148. Vakifahmetoglu H, Olsson M, Zhivotovsky B. Death through a tragedy: mitotic catastrophe. Cell Death Differ. 2008;15:1153–1162. [PubMed]
149. Borges HL, Linden R, Wang JYJ. DNA damage-induced cell death: Lessons from the central nervous system. Cell Res. 2008;18:17–26. [PMC free article] [PubMed]
150. Wang JY, Cho SK. Coordination of repair, checkpoint and cell death responses to DNA damage. Adv Protein Chem. 2004;69:101–135. [PubMed]
151. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–767. [PubMed]
152. Murray-Zmijewski F, Lane DP, Bourdon JC. p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress. Cell Death Differ. 2006;13:962–972. [PubMed]
153. Bourdon J-C. p53 and its isoforms in cancer. Br J Cancer. 2007;97:277–282. [PMC free article] [PubMed]
154. Marabese M, Vikhanskaya F, Broggini M. p73: a chiaroscuro gene in cancer. Eur J Cancer. 2007;43:1361–1372. [PubMed]
155. Oswald C, Stiewe T. In good times and bad: p73 in cancer. Cell Cycle. 2008;7:1726–1731. [PubMed]
156. Scian MJ, Carchman EH, Mohanraj L, et al. Wild-type p53 and p73 negatively regulate expression of proliferation related genes. Oncogene. 2008;27:2583–2593. [PubMed]
157. Tomkova K, Tomka M, Zajac V. Contributions of p53, p63, and p73 to the developmental diseases and cancer. Neoplasma. 2008;55:177–181. [PubMed]
158. Vilgelm AE, Washington MK, Wei J, Chen H, Prassolov VS, Zaika AI. Interactions of the p53 protein family in cellular stress response in gastrointestinal tumors. Mol Cancer Ther. 2010;9:693–705. [PMC free article] [PubMed]
159. Hsieh SC, Lo PK, Wang FF. Mouse DDA3 gene is a direct transcriptional target of p53 and p73. Oncogene. 2002;21:3050–3057. [PubMed]
160. Jang CY, Wong J, Coppinger JA, Seki A, Yates JR, 3rd, Fang G. DDA3 recruits microtubule depolymerase Kif2a to spindle poles and controls spindle dynamics and mitotic chromosome movement. J Cell Biol. 2008;181:255–267. [PMC free article] [PubMed]
161. Merlo P, Fulco M, Costanzo A, et al. A role of p73 in mitotic exit. J Biol Chem. 289:30354–30360. [PubMed]
162. Tomasini R, Mak TW, Melino G. The impact of p53 and p73 on aneuploidy and cancer. Trends Cell Biol. 2008;18:244–252. [PubMed]
163. Boominathan L. Some facts and thoughts: p73 as a tumor suppressor gene in the network of tumor suppressors. Mol Cancer. 2007;6:27. [PMC free article] [PubMed]
164. Boominathan L. The tumor suppressors p53, p63, and p73 are regulators of microRNA processing complex. PloS One. 2010;5:e10615. [PMC free article] [PubMed]
165. Rosenbluth JM, Pietenpol JA. The jury is in: p73 is a tumor suppressor after all. Genes Dev. 2008;22:2591–2595. [PubMed]
166. Collavin L, Lunardi A, Del Sal G. p53-family proteins and their regulators: Hubs and spokes in tumor suppression. Cell Death Differ. 2010;17:901–911. [PubMed]
167. Zawacka-Pankau J, Kostecka A, Sznarkowska A, Hedstrom E, Kawiak A. p73 tumor suppressor protein. A close relative of p53 not only in structure but also in anti-cancer approach? Cell Cycle. 2010;9:720–728. [PubMed]
168. Simonelli V, Narciso L, Dogliotti E, Fortini P. Base excision repair intermediates are mutagenic in mammalian cells. Nucleic Acids Res. 2005;33:4404–4411. [PMC free article] [PubMed]
169. Neeley WL, Essigmann JM. Mechanisms of formation, genotoxicity, and mutation of guanine oxidation products. Chem Res Toxicol. 2006;19:491–505. [PubMed]
170. David SS, O’Shea VL, Kundu S. Base excision repair of oxidative DNA damage. Nature. 2007;447:941–950. [PMC free article] [PubMed]
171. Lindahl T, Wood RD. Quality control by DNA repair. Science. 1999;286:1897–1905. [PubMed]
172. Kairupan C, Scott RJ. Base excision repair and the role of MUTYH. Hered Cancer Clin Pract. 2007;5:199–209. [PMC free article] [PubMed]
173. Tenesa A, Campbell H, Barnetson R, Porteous M, Dunlop M, Farrington SM. Association of MUTYH and colorectal cancer. Br J Cancer. 2006;95:239–242. [PMC free article] [PubMed]
174. Sieber OM, Howarth KM, Thirlwell C, et al. Myh deficiency enhances intestinal tumorogenesis in multiple intestinal neoplasia (ApcMin/+) mice. Cancer Res. 2004;64:8876–8881. [PubMed]
175. Hirano S, Tominaga Y, Ichinoe A, et al. Mutator phenotype of MUTYH-null mouse embryonic stem cells. J Biol Chem. 2003;278:38121–38124. [PubMed]
176. Slupska MM, Baikalov C, Luther WM, Chiang JH, Wei YF, Miller JH. Cloning and sequencing a human homolog (hMYH) of the Escherichia coli mutY gene whose function is required for the repair of oxidative DNA damage. J Bacteriol. 1996;178:3885–3892. [PMC free article] [PubMed]
177. Shinmura K, Yamaguchi S, Saitoh T, et al. Adenine excisional repair function of MYH protein on the adenine: 8-hydroxyguanine base pair in double-stranded DNA. Nucleic Acids Res. 2000;28:4912–4918. [PMC free article] [PubMed]
178. Bolgogh I, Milligan D, Lee MS, Bassett H, Lloyd S, McCullough AK. hMYH cell cycle-dependent expression, subcellular localization and association with replication foci: evidence suggesting replication-coupled repair of adenine:8-oxoguanine mispairs. Nucleic Acids Res. 2001;29:2802–2809. [PMC free article] [PubMed]
179. Scharer OD, Jiricny J. Recent progress in the biology, chemistry and structural biology of DNA glycosylases. Bioessays. 2001;23:270–281. [PubMed]
180. Jiricny J, Mana G. DNA repair defects in colon cancer. Curr Opin Genet Develop. 2003;13:61–69. [PubMed]
181. De Murcia G, de Murcia JM. Poly(ADP-ribose) polymerase: A molecular nick-sensor. Trends Biol Sci. 1994;19:172–176. [PubMed]
182. Mortusewicz O, Ame J-C, Schreiber V, Leonhardt H. Feedback-regulated poly(ADP-ribosyl)ation by PARP-1 is required for rapid response to DNA damage in living cells. Nucleic Acids Res. 2007;35:7665–7675. [PMC free article] [PubMed]
183. Yoshihara K, Tanaigawa Y, Burzio L, Koide SS. Evidence for adenosine diphosphate ribosylation of Ca2+, Mg2+– dependent endo-nuclease. Proc Natl Acad Sci U S A. 1975;72:289–293. [PubMed]
184. Wielckens K, Schmidt A, George E, Bredehorst R, Hilz H. DNA fragmentation and NAD depletion. Their relationship to the turnover of endogenous mon(ADP-ribosyl) and poly(ADP-ribosyl) proteins. J Biol Chem. 1982;257:12872–12877. [PubMed]
185. Ha HC, Snyder SH. Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci U S A. 1999;96:13978–13982. [PubMed]
186. Zong WX, Ditsworth D, Bauer DE, Wang ZQ, Thompson CB. Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev. 2004;18:1272–1282. [PubMed]
187. Cipriani G, Rapizzi E, Vannacci A, Rizzuto R, Moroni F, Chiarugi A. Nuclear poly(ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction. J Biol Chem. 2005;280:17227–17234. [PubMed]
188. Liu H, Knabb JR, Spike BT, Macleod KF. Elevated poly-(ADP-ribose)-polymerase activity sensitizes retinoblastoma-deficient cells to DNA damage-induced necrosis. Mol Cancer Res. 2009;7:1099–1109. [PMC free article] [PubMed]
189. Bernstein H, Bernstein C, Payne CM, Dvorakova K, Garewal H. Bile acids as carcinogens in human gastrointestinal cancers. Mutat Res. 2005;589:47–65. [PubMed]
190. Payne CM, Bernstein C, Bernstein H. Apoptosis overview emphasizing oxidative stress, DNA damage and signal-transduction pathways. Leuk Lymphoma. 1995;19:43–93. [PubMed]
191. Oka S, Ohno M, Tsuchimoto D, Sakumi K, Furuichi M, Nakabeppu Y. Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs. EMBO J. 2008;27:421–432. [PubMed]
192. Oka S, Ohno M, Nakabeppu Y. Construction and characterization of a cell line deficient in repair of mitochondrial, but not nuclear, oxidative DNA damage. Methods Mol Biol. 2009;554:251–265. [PubMed]
193. Ichikawa J, Tsuchimoto D, Oka S, et al. Oxidation of mitochondrial deoxynucleotide pools by exposure to sodium nitroprusside induces cell death. DNA Repair. 2008;7:418–430. [PubMed]
194. Kagedal K, Johansson AC, Johansson U, et al. Lysosomal membrane permeabilization during apoptosis-involvement of Bax? Int J Exp Pathol. 2005;86:309–321. [PubMed]
195. Wang H, Yu SW, Koh DW, et al. Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death. J Neurosci. 2004;24:10963–10973. [PubMed]
196. Yu SW, Wang H, Poitras MF, et al. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science. 2002;297:259–263. [PubMed]
197. Andrabi SA, Kim NS, Yu S-W, et al. Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci U S A. 2006;103:18308–18313. [PubMed]
198. Wang Y, Dawson VL, Dawson TM. Poly(ADP-ribose) signals to mitochondrial AIF: A key event in parthanatos. Exp Neurol. 2009;218:193–202. [PMC free article] [PubMed]
199. Yu S-W, Andrabi SA, Wang H, et al. Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Proc Natl Acad Sci U S A. 2006;103:18314–18319. [PubMed]
200. Lipton SA, Bossy-Wetzel E. Dueling activities of AIF in cell death versus survival: DNA binding and redox activity. Cell. 2002;111:147–150. [PubMed]
201. Ye H, Cande C, Stephanou NC, et al. DNA binding is required for the apoptogenic action of apoptosis inducing factor. Nat Struct Biol. 2002;9:680–684. [PubMed]
202. Vahsen N, Cande C, Dupaigne P, et al. Physical interaction of apoptosis-inducing factor with DNA and RNA. Oncogene. 2006;25:1763–1774. [PubMed]
203. Susin SA, Lorenzo HK, Zamzami N, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature. 1999;397:441–446. [PubMed]
204. Modjtahedi N, Giordanetto F, Madeo F, Kroemer G. (2006) Apoptosis-inducing factor: Vital and lethal. Trends Cell Biol. 2005;16:264–272. [PubMed]
205. Hong SJ, Dawson TM, Dawson VL. Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharmacol Sci. 2004;25:259–264. [PubMed]
206. Van Wijk SJ, Hageman GJ. Poly(ADP-ribose) polymerase-1 mediated caspase-independent cell death after ischemia/reperfusion. Free Radic Biol Med. 2005;39:81–90. [PubMed]
207. Boujrad H, Gubkina O, Robert N, Krantic S, Susin SA. AIF-mediated programmed necrosis: A highly regulated way to die. Cell Cycle. 2007;6:2611–1618. [PubMed]
208. Krantic S, Mechawar N, Reix S, Quirion R. Apoptosis-inducing factor: A matter of neuron life and death. Prog Neurobiol. 2007;81:179–196. [PubMed]
209. Li GY, Osborne NN. Oxidative-induced apoptosis to an immortalized ganglion cell line is caspase independent but involves the activation of poly(ADP-ribose) polymerase and apoptosis-inducing factor. Brain Res. 2008;1188:35–43. [PubMed]
210. Lorenzo HK, Susin SA. Therapeutic potential of AIF-mediated caspase-independent programmed cell death. Drug Resist Updates. 2007;10:235–255. [PubMed]
211. Moubarak RS, Yuste VJ, Artus C, et al. Sequential activation of poly(ADP-ribose) polymerase 1, calpains, and Bax is essential in apoptosis-inducing factor-mediated programmed necrosis. Mol Cell Biol. 2007;27:4844–4862. [PMC free article] [PubMed]
212. Son Y-O, Jang Y-S, Heo J-S, Chung W-T, Choi K-C, Lee J-C. Apoptosis-inducing factor plays a critical role in caspase-independent, pyknotic cell death in hydrogen peroxide-exposed cells. Apoptosis. 2009;14:796–808. [PubMed]
213. Son YO, Kook SH, Jang YS, Shi X, Lee JC. Critical role of poly(ADP-ribose) polymerase-1 in modulating the mode of cell death caused by continuous oxidative stress. J Cell Biochem. 2009;108:989–997. [PubMed]
214. Norberg E, Orrenius S, Zhivotovsky B. Mitochondrial regulation of cell death: Processing of apoptosis-inducing factor. Biochem Biophys Res Comm. 2010;396:95–100. [PubMed]
215. Otera H, Ohsakaya S, Nagaura Z, Ishihara N, Mihara K. Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space. EMBO J. 2005;24:1375–1386. [PubMed]
216. Uren RT, Dewson G, Bonzon C, Lithgow T, Newmeyer DD, Kluck RM. Mitochondrial release of pro-apoptotic proteins: Electrostatic interactions can hold cytochrome c but not Smac/DIABLO to mitochondrial membranes. J Biol Chem. 2005;280:2266–2274. [PubMed]
217. Polster BM, Basanez G, Etxebarria A, Hardwick JM, Nicholls DG. Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria. J Biol Chem. 2005;280:6447–6454. [PubMed]
218. Yuste VJ, Moubarak RS, Delettre C, et al. Cysteine protease inhibition prevents mitochondrial apoptosis-inducing factor (AIF) release. Cell Death Differ. 2005;12:1445–1448. [PubMed]
219. Norberg E, Gogvadze V, Vakifahmetoglu H, Orrenius S, Zhivotovsky B. Oxidative modification sensitizes mitochondrial apoptosis-inducing factor to calpain-mediated processing. Free Radic Biol Med. 2010;48:791–797. [PubMed]
220. Yacoub A, Park MA, Hanna D, et al. OSU-03012 promotes caspase-independent but PERK-, cathepsin B-, BID-, and AIF-dependent killing of transformed cells. Mol Pharmacol. 2006;70:589–603. [PubMed]
221. Chaitanya GV, Babu PP. Multiple apoptogenic proteins are involved in the nuclear translocation of apoptosis inducing factor during transient focal cerebral ischemia in rat. Brain Res. 2008;1246:178–190. [PubMed]
222. Norberg E, Gogvadze V, Ott M, et al. An increase in intracellular Ca2+ is required for the activation of mitochondrial calpain to release AIF during cell death. Cell Death Differ. 2008;15:1857–1864. [PubMed]
223. Vosler PS, Sun D, Wang S, et al. Calcium dysregulation induces apoptosis-inducing factor release: Cross-talk between PARP-1 and calpain-signaling pathways. Exp Neurol. 2009;218:213–220. [PMC free article] [PubMed]
224. Gagne JP, Hunter JM, Labrecque B, Chabot B, Poirier GG. A proteomic approach to the identification of heterogeneous nuclear ribonucleoproteins as a new family of poly(ADP-ribose)-binding proteins. Biochem J. 2003;371:331–340. [PubMed]
225. Gagne JP, Hendzel MJ, Droit A, Poirier GG. The expanding role of poly(ADP-ribose) metabolism: Current challenges and new perspectives. Curr Opin Cell Biol. 2006;18:145–151. [PubMed]
226. Gagne JP, Isabelle M, Lo KS, et al. Proteome-wide identification of poly(ADP-ribose) binding proteins and poly(ADP-ribose)-associated protein complexes. Nucleic Acids Res. 2008;36:6959–6976. [PMC free article] [PubMed]
227. Chen M, He H, Zhan S, Krajewski S, Reed JC, Gottlieb RA. Bid is cleaved by calpain to an active fragment in vitro and during myocardial ischemia/reperfusion. J Biol Chem. 2001;276:30724–30728. [PubMed]
228. Deng Y, Ren X, Yang L, Lin Y, Wu X. A JNK-dependent pathway is required for TNFalpha-induced apoptosis. Cell. 2003;115:61–70. [PubMed]
229. Culmsee C, Zhu C, Landshamer S, et al. Apoptosis-inducing factor triggered by poly(ADP-ribose) polymerase and bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia. J Neurosci. 2005;25:10262–10272. [PubMed]
230. Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell. 2002;2:183–192. [PubMed]
231. Chen D, Zhou Q. Caspase cleavage of BimEL triggers a psoitive feedback amplification of apoptotic signaling. Proc Natl Acad Sci U S A. 2004;101:1235–1240. [PubMed]
232. Liou AK, Zhou Z, Pei W, Lim TM, Yin XM, Chen J. BimEL up-regulation potentiates AIF translocation and cell death in response to MPTP. FASEB J. 2005;19:1350–1352. [PubMed]
233. Alano CC, Swanson RA. Players in the PARP-1 cell-death pathway: JNK1 joins the cast. Trends Biochem Sci. 2006;31:309–311. [PubMed]
234. Xu Y, Huang S, Liu Z-G, Han J. Poly(ADP-ribose) polymerase-1 signaling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK activation. J Biol Chem. 2006;281:8788–8795. [PubMed]
235. Song ZF, Ji XP, Li XX, Wang SJ, Wang SH, Zhang Y. Inhibition of the activity of poly(ADP-ribose) polymerase reduces heart ischaemia/reperfusion injury via suppressing JNK-mediated AIF translocation. J Cell Mol Med. 2008;12:1220–1228. [PubMed]
236. Lei K, Davis RJ. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci U S A. 2003;100:2432–2437. [PubMed]
237. Heeres JT, Hergenrother PJ. Poly(ADP-ribose) makes a date with death. Curr Opin Chem Biol. 2007;11:644–653. [PubMed]
238. Burton TR, Eisenstat DD, Gibson SP. BNIP3 (Bcl-2 interacting protein) acts as transcriptional repressor of apoptosis-inducing factor expression preventing cell death in human malignant gliomas. J Neurosci. 2009;29:4189–4199. [PMC free article] [PubMed]
239. Pietsch EC, Sykes SM, McMahon SB, Murphy ME. The p53 family and programmed cell death. Oncogene. 2008;27:6507–6521. [PMC free article] [PubMed]
240. Yuan ZM, Shioya H, Ishiko T, et al. p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature. 1999;399:814–817. [PubMed]
241. Stiewe T, Putzer BM. Role of the p53-homologue p73 in E2F1-induced apoptosis. Nat Genet. 2000;26:464–469. [PubMed]
242. Toh WH, Siddique MM, Boominathan L, Lin KW, Sabapathy K. c-Jun regulates the stability and activity of the p53 homologue, p73. J Biol Chem. 2004;279:44713–44722. [PubMed]
243. Melino G, Bernassola F, Ranalli M, et al. p73 induces apoptosis via PUMA transactivation and Bax mitochondrial translocation. J Biol Chem. 2004;279:8076–8083. [PubMed]
244. Rossi M, Sayan AE, Terrinoni A, Melino G, Knight RA. Mechanism of induction of apoptosis by p73 and its relevance to neuroblastoma biology. Ann N Y Acad Sci. 2004;1028:143–149. [PubMed]
245. Ramadan S, Terrinoni A, Catani MV, et al. p73 induces apoptosis by different mechanisms. Biochem Biophys Res Commun. 2005;331:713–717. [PubMed]
246. Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi Z. A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet. 2006;38:1043–1048. [PubMed]
247. Perez de Castro I, de Carcer G, Marcos M. A census of mitotic cancer genes: New insights into tumor cell biology and cancer therapy. Carcinogenesis. 2007;28:899–912. [PubMed]
248. Tarin JJ, Vendrell FJ, Ten J, Blanes R, van Blerom J, Cano A. The oxidizing agent tertiary butyl hydroperoxide induces disturbances in spindle organization, c-meiosis, and aneuploidy in mouse oocytes. Mol Human Reproduct. 1996;2:895–901. [PubMed]
249. Choi WJ, Banerjee J, Falcone T, Bena J, Agarwal A, Sharma RK. Oxidative stress and tumor necrosis factor-α-induced alterations in metaphase II mouse oocyte spindle structure. Fertl Steril. 2007;88(4 Suppl):1220–1231. [PubMed]
250. D’Angiolella V, Santarpia C, Grieco D. Oxidative stress overrides the spindle checkpoint. Cell Cycle. 2007;6:576–579. [PubMed]
251. Chang T-S, Jeong W, Lee D-Y, Cho C-S, Rhee SG. The ring-H2-finger protein APC11 as a target of hydrogen peroxide. Free Rad Biol Med. 2004;37:521–530. [PubMed]
252. Blagosklonny MV. Mitotic arrest and cell fate: Why and how mitotic inhibition of transcription drives mutually exclusive events. Cell Cycle. 2007;6:70–74. [PubMed]
253. Delcuve GP, He S, Davie JR. Mitotic partitioning of transcription factors. J Cell Biochem. 2008;105:1–8. [PubMed]
254. Gascoigne KE, Taylor SS. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell. 2008;14:111–122. [PubMed]
255. Elhajouji A, Cunha M, Kirsch-Volders M. Spindle poisons induce polyploidy by mitotic slippage and micronucleate mononucleates in the cytokinesis-block assay. Mutagenesis. 1998;13:193–198. [PubMed]
256. Dai W, Wang Q, Liu T, et al. Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency. Cancer Res. 2004;64:440–445. [PubMed]
257. Tao W, South VJ, Zhang Y, et al. Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage. Cancer Cell. 2005;8:49–59. [PubMed]
258. Brito DA, Rieder CL. Mitotic checkpoint slippage in humans occurs via cyclin B destruction in the presence of an active checkpoint. Curr Biol. 2006;16:1194–1200. [PMC free article] [PubMed]
259. Stevens FE, Beamish H, Warrener R, Gabrielli B. Histone deacetylase inhibitors induce mitotic slippage. Oncogene. 2008;27:1345–1354. [PubMed]
260. Brito DA, Yang Z, Rieder CL. Microtubules do not promote mitotic slippage when the spindle assembly checkpoint cannot be satisfied. J Cell Biol. 2008;182:623–629. [PMC free article] [PubMed]
261. Riffell JL, Zimmerman C, Khong A, McHardy LM, Roberge M. Effects of chemical manipulation of mitotic arrest and slippage on cancer cell survival and proliferation. Cell Cycle. 2009;8:3029–3042. [PubMed]
262. Lee J, Kim JA, Margolis RL, Fotedar R. Substrate degradation by the anaphase promoting complex occurs during mitotic slippage. Cell Cycle. 2010;9:1792–1801. [PMC free article] [PubMed]
263. Xu FL, Rbaibi Y, Kiselyov K, Lazo JS, Wipf P, Saunders WS. Mitotic slippage in non-cancer cells induced by a microtubule disruptor, disorazole C1. Chem Biol. 2010;10:1. [PMC free article] [PubMed]
264. Dodson H, Bourke E, Jeffers LJ, et al. Centrosome amplification induced by DNA damage occurs during a prolonged G2 phase and involves ATM. EMBO J. 2004;23:3864–3873. [PubMed]
265. Butler LM, Hewett PJ, Fitridge RA, Cowled PA. Deregulation of apoptosis in colorectal carcinoma: Theoretical and therapeutic implications. Aust N Z J Surg. 1999;69:88–94. [PubMed]
266. Payne CM, Bernstein H, Bernstein C, Garewal H. The role of apoptosis in biology and pathology: Resistance to apoptosis in colon carcinogenesis. Ultrastruct Pathol. 1995a;19:221–248. [PubMed]
267. Nelson DA, Tan TT, Rabson AB, Anderson D, Degenhardt K, White E. Hypoxia and defective apoptosis drive genomic instability and tumorigenesis. Genes Develop. 2008;18:2095–2107. [PubMed]
268. Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature. 1998;391:43–50. [PubMed]
269. Halenbeck R, MacDonald H, Roulston A, Chen TT, Conroy L, Williams LT. CPAN, a human nuclease regulated by the caspase-sensitive inhibitor DFF45. Curr Biol. 1998;8:537–540. [PubMed]
270. Liu X, Zou H, Slaughter C, Wang X. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell. 1997;89:175–184. [PubMed]
271. Liu X, Li P, Widlak P, et al. The 40-kDa subunit of DNA fragmentation factor induces DNA fragmentation and chromatin condensation during apoptosis. Proc Natl Acad Sci U S A. 1998;95:8461–8466. [PubMed]
272. Kerr JFR, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26:239–257. [PMC free article] [PubMed]
273. Wyllie AH, Kerr JF, Currie AR. Cell death: The significance of apoptosis. Int Rev Cytol. 1980;68:251–305. [PubMed]
274. Searle J, Kerr JFR, Bishop CJ. Necrosis and apoptosis: Distinct modes of cell death with fundamentally different significance. Pathol Annu. 1982;17:229–259. [PubMed]
275. Wyllie AH, Morris RG, Smith AL, Dunlop D. Chromatin cleavage in apoptosis: Association with condensed chromatin morphology and dependence on macromolecular synthesis. J Pathol. 1984;142:67–77. [PubMed]
276. Payne CM, Bjore CG, Jr, Schultz DA. Change in the frequency of apoptosis after low- and high-dose X-irradiation of human lymphocytes. J Leukocyte Biol. 1992;52:433–440. [PubMed]
277. Oberhammer F, Wilson JW, Dive C, et al. Apoptotic death in epithelial cells: Cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. EMBO J. 1993;12:3679–3684. [PubMed]
278. Widlak P. DFF40/CAD hypersensitive sites are potentially involved in high molecular weight DNA fragmentation during apoptosis. Cell Mol Biol Lett. 2000;5:373–379.
279. Mcllroy D, Sakahira H, Talanian RV, Nagata S. Involvement of caspase 3-activated DNase in internucleosomal DNA cleavage induced by diverse apoptotic stimuli. Oncogene. 1999;18:4401–4408. [PubMed]
280. Widlak P, Gerrard WT. Roles of the major apoptotic nuclease-DNA fragmentation factor in biology and disease. Cell Mol Life Sci. 2009;66:263–274. [PubMed]
281. Yan B, Wang H, Peng Y, et al. A unique role of the DNA fragmentation factor in maintaining genomic stability. Proc Natl Acad Sci U S A. 2006a;103:1504–1509. [PubMed]
282. Zhang J, Liu X, Scherer DC, van Kaer L, Wang X, Xu M. Resistance to DNA fragmentation and chromatin condensation in mice lacking the DNA fragmentation factor 45. Proc Natl Acad Sci U S A. 1998;95:12480–12485. [PubMed]
283. Zhang J, Wang X, Bove KE, Xu M. DNA fragmentation factor 45-deficient cells are more resistant to apoptosis and exhibit different dying morphology than wild-type control cells. J Biol Chem. 1999;274:37450–37454. [PubMed]
284. Yan B, Wang H, Wang H, et al. Apoptotic DNA fragmentation factor maintains chromosome stability in a p53-independent manner. Oncogene. 2006b;25:5370–5376. [PubMed]
285. Zhang J, Guo H, Qian G, et al. MiR-145, a new regulator of the DNA fragmentation factor-45 (DFF45)-mediated apoptotic network. Mol Cancer. 2010;9:211. [PMC free article] [PubMed]
286. Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91:479–489. [PubMed]
287. Hofmann K, Bucher P, Tschopp J. The CARD domain: A new apoptotic signaling motif. Trends Biochem Sci. 1997;22:155–156. [PubMed]
288. Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: Requirement for dATP and cytochrome c. Cell. 1996;86:147–157. [PubMed]
289. Zou H, Li Y, Liu X, Wang X. An APAF-1 cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem. 1999;274:11549–11556. [PubMed]
290. Zuo Y, Xiang B, Yang J, et al. Oxidative modification of caspase-9 facilitates its activation via disulfide-mediated interaction with Apaf-1. Cell Res. 2009;19:449–457. [PubMed]
291. Slee EA, Harte MT, Kluck RM, et al. Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol. 1999;144:281–292. [PMC free article] [PubMed]
292. Zhivotovsky B, Orrenius S. Caspase-2 function in response to DNA damage. Biochem Biophys Res Comm. 2005;331:859–867. [PubMed]
293. Samraj AK, Sohn D, Schulze-Osthoff K, Schmitz I. Loss of caspase-9 reveals its essential role for caspase-2 activation and mitochondrial membrane depolarization. Mol Biol Cell. 2007;18:84–93. [PMC free article] [PubMed]
294. Guerrero AD, Chen M, Wang J. Delineation of the caspase-9 signaling cascade. Apoptosis. 2008;13:177–186. [PubMed]
295. Kuida K, Haydar TF, Kuan CY, et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell. 1998;94:325–337. [PubMed]
296. Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S. Distinct pathways for stimulation of cytochrome c release by etoposide. J Biol Chem. 2000;275:32438–32443. [PubMed]
297. Lassus P, Opitz-Araya X, Lazebnik Y. Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization. Science. 2002;297:1352–1354. [PubMed]
298. Tinel A, Tschopp J. The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science. 2004;304:843–846. [PubMed]
299. Jang TH, Bae JY, Park OK, et al. Identification and analysis of dominant negative mutants of RAIDD and PIDD. Biochim Biophys Acta. 2010;1804:1557–1563. [PubMed]
300. Mace PD, Riedl SJ. Molecular cell death platforms and assemblies. Curr Opin Cell Biol. 2010;22:828–836. [PMC free article] [PubMed]
301. Raina D, Pandey P, Ahmad R, et al. c-Abl tyrosine kinase regulates caspase-9 autocleavage in the apoptotic response to DNA damage. J Biol Chem. 2005;280:11147–11151. [PubMed]
302. Morishima N, Nakanishi K, Takenouchi H, Shibata T, Yasuhiko Y. An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12. J Biol Chem. 2002;277:34287–34294. [PubMed]
303. Jeong W, Lee D-Y, Park S, Rhee SG. ERp16, and endoplasmic reticulum-resident thiol-disulfide oxidoreductase. Biochemical properties and role in apoptosis induced by endoplasmic reticulum stress. J Biol Chem. 2008;283:25557–25566. [PMC free article] [PubMed]
304. Jimbo A, Fujita E, Kouroku Y, et al. ER stress induces caspase-8 activation, stimulating cytochrome c release and caspase-9 activation. Exp Cell Res. 2003;283:156–166. [PubMed]
305. Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschi T. Identification of novel genes coding for small expressed RNAs. Science. 2001;294:853–858. [PubMed]
306. Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–297. [PubMed]
307. Bartel DP, Chen CZ. Micromanagers of gene expression: The potentially widespread influence of metazoan microRNAs. Nat Rev Genet. 2004;5:396–400. [PubMed]
308. He L, Hannon GJ. MicroRNAs: Small RNAs with a big role in gene regulation. Mol Cell. 2004;2007;26:45–752.
309. He L, He X, Lim LP, et al. A microRNA component of the p53 tumour suppressor network. Nature. 2007;447:1130–1134. [PubMed]
310. Kim VN. MicroRNA biogenesis: Coordinated cropping and dicing. Nat Rev Mol Cell Biol. 2005;6:376–385. [PubMed]
311. Farh KK, Grimson A, Jan C, et al. The widespread impact of mammalian microRNAs on mRNA repression and evolution. Science. 2005;310:1817–1821. [PubMed]
312. Carthew RW. Gene regulation by microRNAs. Curr Opin Genet Dev. 2006;16:203–208. [PubMed]
313. Valenci-Sanchez MA, Liu J, Hannon GJ, Parker R. Control of translation and mRNA degradation by miRNAs ans siRNAs. Genes Dev. 2006;20:515–524. [PubMed]
314. Tsang J, Zhu J, van Oudenaarden A. MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals. Mol Cell. 2007;26:753–767. [PMC free article] [PubMed]
315. Kim VN, Han J, Siomi MC. Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol. 2009;10:126–139. [PubMed]
316. Pillai RS. MicroRNA function: Multiple mechanisms for a tiny RNA? RNA. 2005;11:1753–1761. [PubMed]
317. Kloosterman WP, Plasterk RH. The diverse functions of microRNAs in animal development and disease. Dev Cell. 2006;11:441–450. [PubMed]
318. Krek A, Grun D, Poy MN, et al. Combinatorial microRNA target predictions. Nat Genet. 2005;37:495–500. [PubMed]
319. Lewis, et al. Prediction of mammalian microRNA targets. Cell. 2003;115:787–798. [PubMed]
320. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120:15–20. [PubMed]
321. Lim LP, Lau NC, Garrett-Engele P, et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005;433:769–773. [PubMed]
322. Selbach M, Schwanhausser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N. Widespread changes in protein synthesis induced by microRNAs. Nature. 2008;455:58–63. [PubMed]
323. Baek D, Villen J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature. 2008;455:64–71. [PMC free article] [PubMed]
324. Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005;103:3687–3692. [PubMed]
325. Hayashita Y, Osada H, Tatematsu Y, et al. A polycistronic microRNA cluster, mir-17–92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 2005;65:9628–9632. [PubMed]
326. Miska EA. How microRNAs control cell division, differentiation and death. Curr Opin Genet Dev. 2005;15:563–568. [PubMed]
327. Calin GA, Sevignani C, Dumitru CD, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004;101:2999–3004. [PubMed]
328. Chen JF, Mandel EM, Thomson JM, et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet. 2006;38:228–233. [PMC free article] [PubMed]
329. Carleton M, Cleary MA, Linsley PS. MicroRNAs and cell cycle regulation. Cell Cycle. 2007;6:2127–2132. [PubMed]
330. Chang TC, Wentzel EA, Kent OA, et al. Transactivation of mir-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell. 2007;26:745–752. [PMC free article] [PubMed]
331. Yi R, Poy MN, Stoffel M, Fuchs E. A skin microRNA promotes differentiation by repressing “stemness” Nature. 2008;452:225–229. [PubMed]
332. Lal A, Navarro F, Maher CA, et al. miR-24 inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to “seedless” 3’UTR microRNA recognition elements. Mol Cell. 2009;35:610–625. [PMC free article] [PubMed]
333. Bueno MJ, Gomez de Cedron M, Laresgoiti U, Fernandez-Piqueras J, Zubiaga AM, Malumbres M. Multiple E2F-induced microRNAs prevent replicative stress in response to mitogenic signaling. Mol Cell Biol. 2010;30:2983–2995. [PMC free article] [PubMed]
334. Meltzer PS. Cancer genomics: Small RNAs with big impacts. Nature. 2005;435:745–746. [PubMed]
335. Dalmay T, Edwards DR. MicroRNAs and the hallmarks of cancer. Oncogene. 2006;25:6170–6175. [PubMed]
336. Esquela-Kerscher A, Slack FJ. Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–269. [PubMed]
337. Bandres E, Agirre X, Ramirez N, Zarate E, Garcia-Foncillas J. MicroRNAs as cancer players: Potential clinical and biological effects. DNA Cell Biol. 2007;26:273–282. [PubMed]
338. Cho WCS. OncomiRs: The discovery and progress of microRNAs in cancers. Mol Cancer. 2007;6 doi: 10.1186/1476-4598-6-60. 60; [PMC free article] [PubMed] [Cross Ref]
339. Ventura A, Jacks T. MicroRNAs and cancer. Short RNAs go a long way. Cell. 2009;136:586–591. [PubMed]
340. Nicoloso MS, Spizzo R, Shimizu M, Rossi S, Calin GA. MicroRNAs – the micro steering wheel of tumour metastases. Nat Rev Cancer. 2009;9:293–302. [PubMed]
341. Calin GA, Liu CG, Sevignani C, et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc Natl Acad Sci U S A. 2004b;101:11755–11760. [PubMed]
342. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857–866. [PubMed]
343. Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–838. [PubMed]
344. Cummins JM, He Y, Leary RJ, et al. The colorectal microRNAome. Proc Natl Acad Sci U S A. 2006;103:3687–3692. [PubMed]
345. Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A. 2006;103:2257–2261. [PubMed]
346. Lee EJ, Gusev Y, Jiang J, et al. Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer. 2007;120:1046–1054. [PMC free article] [PubMed]
347. Subramanian S, Lui WO, Lee CH, et al. MicroRNA expression signature of human sarcomas. Oncogene. 2008;27:2015–2026. [PubMed]
348. Rosenfeld N, Aharonov R, Meiri E, et al. MicroRNAs accurately identify cancer tissue origin. Nat Biotechnol. 2008;26:462–469. [PubMed]
349. Vandenboom TG, II, Li Y, Philip PA, Sarkar FH. MicroRNA and cancer: tiny molecules with major implications. Curr Genomics. 2008;9:97–109. [PMC free article] [PubMed]
350. Hu X, Schwartz JK, Lewis JS, Jr, et al. A microRNA expression signature for cervical cancer prognosis. Cancer Res. 2010;70:1441–1448. [PMC free article] [PubMed]
351. Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet. 2007;39:673–677. [PubMed]
352. Chang TC, Yu D, Lee YS, et al. Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet. 2008;40:43–50. [PMC free article] [PubMed]
353. Chen CZ. MicroRNAs as oncogenes and tumor suppressors. N Eng J Med. 2005;353:1768–1771. [PubMed]
354. Kent OA, Mendell JT. A small piece in the cancer puzzle: MicroRNAs as tumor suppressors and oncogenes. Oncogene. 2006;25:6188–6196. [PubMed]
355. Zhang B, Pan X, Cobb GP, Anderson TA. MicroRNAs as oncogenes and suppressors. Dev Biol. 2007;302:1–12. [PubMed]
356. Michael MZ, O’Connor SM, van Holst Pellekaan NG, Young GP, James RJ. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res. 2003;1:882–891. [PubMed]
357. Akao Y, Nakagawa Y, Naoe T. let-7 microRNA functions as a potential growth suppressor in human colon cancer cells. Biol Pharm Bull. 2006;29:903–906. [PubMed]
358. Bandres E, Cubedo E, Agirre X, et al. Identification by real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues. Mol Cancer. 2006;5:29. [PMC free article] [PubMed]
359. Xi Y, Shalgi R, Fodstad O, Pilpel Y, Ju J. Differentially regulated micro-RNAs and actively translated messenger RNA transcripts by tumor suppressor p53 in colon cancer. Clin Cancer Res. 2006;12:2014–2024. [PubMed]
360. Shi B, Sepp-Lorenzino L, Prisco M, Linsley P, deAngelis T, Baserga R. Micro RNA 145 targets the insulin receptor substrate-1 and inhibits the growth of colon cancer cells. J Biol Chem. 2007;282:32582–32590. [PubMed]
361. Slaby O, Svoboda M, Fabian P, et al. Altered expression of miR-21. MiR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology. 2007;72:397–402. [PubMed]
362. Tazawa H, Tsuchiya N, Izumiya M, Nakagama H. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci U S A. 2007;104:15472–15477. [PubMed]
363. Schepeler T, Reinert JT, Ostenfeld MS, et al. Diagnostic and prognostic microRNAs in stage II colon cancer. Cancer Res. 2008;68:6416–6424. [PubMed]
364. Schetter AJ, Leung SY, Sohn JJ, et al. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA. 2008;299:425–436. [PMC free article] [PubMed]
365. Motoyama K, Inoue H, Takatsuno Y, et al. Over- and under-expressed microRNAs in human colorectal cancer. Int J Oncol. 2009;34:1069–1075. [PubMed]
366. Ng EK, Tsang WP, Ng SS, et al. MicroRNA-143 targets DNA methyltransferases 3A in colorectal cancer. Br J Cancer. 2009;101:699–706. [PMC free article] [PubMed]
367. Sarver Al, French AJ, Borralho PM, et al. Human colon cancer profiles show differential microRNA expression depending on mismatch repair status and are characteristic of undifferentiated proliferative states. BMC Cancer. 2009;9:401. [PMC free article] [PubMed]
368. Yantiss RK, Goodarzi M, Zhou XK, et al. Clinical, pathologic, and molecular features of early-onset colorectal carcinoma. Am J Surg Pathol. 2009;33:572–582. [PubMed]
369. Wang YX, Zhang XY, Zhang BF, Yang CQ, Chen XM, Gao HJ. Initial study of microRNA expression profiles of colonic cancer without lymph node metastasis. J Dig Dis. 2010;11:50–54. [PubMed]
370. Lanza G, Ferracin M, Gafa R, et al. mRNA/microRNA gene expression profile in microsatellite unstable colorectal cells. Mol Cancer. 2007;6:54. [PMC free article] [PubMed]
371. Atkin NB. Microsatellite instability. Cytogenet Cell Genet. 2001;92:177–181. [PubMed]
372. Bommer GT, Gerin I, Feng Y, et al. p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr Biol. 2007;17:1298–1307. [PubMed]
373. Hermeking H. p53 enters the microRNA world. Cancer Cell. 2007;12:414–418. [PubMed]
374. Raver-Shapira N, Marciano E, Meiri E, et al. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell. 2007;26:731–743. [PubMed]
375. Tarasov V, Jung P, Verdoodt B, et al. Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle. 2007;6:1586–1593. [PubMed]
376. Dijkstra MK, van Lom K, Tielemans D, et al. 17p13/TP53 deletion in B-CLL patients is associated with micoRNA-34a downregulation. Leukemia. 2009;23:625–627. [PubMed]
377. Welch C, Chen Y, Stallings RL. MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma. Oncogene. 2007;26:5017–5022. [PubMed]
378. Rokhlin OW, Scheinker VS, Taghiyev AF, Bumcrot D, Glover RA, Cohen MB. MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer. Cancer Biol Ther. 2008;7:1288–1296. [PubMed]
379. Ruby JG, Jan C, Player C, et al. Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C. elegans. Cell. 2006;127:1193–1207. [PubMed]
380. Cole KA, Attiyeh EF, Mosse YP, et al. A functional screen identifies miR-34a as a candidate neuroblastoma tumor suppressor gene. Mol Cancer Res. 2008;6:735–742. [PubMed]
381. Sun F, Fu H, Liu Q, et al. Downregulation of CCND1 and CDK6y miR-34a induces cell cycle arrest. FEBS Lett. 2008;582:1564–1568. [PubMed]
382. Wei JS, Song YK, Durinck S, et al. The MYCN oncogene is a direct target of miR-34a. Oncogene. 2009;27:5204–5213. [PMC free article] [PubMed]
383. Li Y, Guessous F, Zhang Y, et al. MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res. 2009;69:7569–7576. [PMC free article] [PubMed]
384. Yamakuchi M, Lowenstein CJ. MiR-34, SIRT1 and p53: The feedback loop. Cell Cycle. 2009;8:712–715. [PubMed]
385. Beverly LJ, Felsher DW, Capobianco AJ. Suppression of p53 by Notch in lymphomagenesis: Implications for initiation and regression. Cancer Res. 65:7159–7168. [PubMed]
386. Mungamuri SK, Yang X, Thor AD, Somasundaram K. Survival signaling by Notch1: Mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res. 2006;66:4715–4724. [PubMed]
387. Leong KG, Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood. 2006;107:2223–2233. [PubMed]
388. Miele L, Golde T, Osborne B. Notch signaling in cancer. Curr Mol Med. 2006;6:905–918. [PubMed]
389. Yamakuchi M, Ferlito M, Lowenstein CJ. miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sc U S A. 2008;105:13421–13426. [PubMed]
390. Ginsberg D. E2F3-a novel repressor of the ARF/p53 pathway. Dev Cell. 2004;6:742–743. [PubMed]
391. Su H, Yang JR, Xu T, et al. MicroRNA-101, down-regulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity. Cancer Res. 2009;69:1135–1142. [PubMed]
392. Friedman JM, Liang G, Jones PA. The tumor suppressor microRNA-101 becomes an epigenetic player by targeting the Polycomb group protein EZH2 in cancer. Cell Cycle. 2009;8:2313–2314. [PMC free article] [PubMed]
393. Adams KW, Cooper GM. Rapid turnover of MCL-1 couples translation to cell survival and apoptosis. J Biol Chem. 2007;282:6192–6200. [PMC free article] [PubMed]
394. Cuconati A, Mukherjee C, Perez D, White E. DNA damage response and Mcl-1 destruction initiate apoptosis in adenovirus-infected cells. Genes Dev. 2003;17:2922–2932. [PubMed]
395. Nijhawan D, Fang M, Traer E, et al. Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. Genes Dev. 2003;17:1475–1496. [PubMed]
396. Clohessy JG, Zhuang J, de Boer J, Gil-Gomez G, Brady HJM. Mcl-1 interacts with truncated Bid and inhibits its induction of cytochrome c release and its role in receptor-mediated apoptosis. J Biol Chem. 2006;281:5750–5759. [PubMed]
397. Han J, Goldstein LA, Gastman BR, Rabinowich H. Interrelated roles for Mcl-1 and BIM in regulation of TRAIL-mediated mitochondrial apoptosis. J Biol Chem. 2006;281:10153–10163. [PubMed]
398. Zhong Q, Gao W, Du F, Wang X. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell. 2005;121:1085–1095. [PubMed]
399. Menoret E, Gomez-Bougie P, Surget S, et al. Mcl-1(127–350) fragment induces apoptosis through direct interaction with Bax. FEBS Lett. 2010;584:487–492. [PubMed]
400. Kobayashi S, Lee SH, Meng XW, et al. Serine 64 phosphorylation enhances the antiapoptotic function of Mcl-1. J Biol Chem. 2007;282:18407–18417. [PubMed]
401. Domina AM, Smith JH, Craig RW. Myeloid cell leukemia 1 is phosphorylated through two distinct pathways, one associated with extracellular signal-regulated kinase activation and the other with G2/M accumulation or protein phosphatase 1/2A inhibition. J Biol Chem. 2000;275:21688–21694. [PubMed]
402. Krajewski S, Bodrug S, Krajewska M, et al. Immunohistochemical analysis of Mcl-1 protein in human tissues. Differential regulation of Mcl-1 and Bcl-2 protein production suggests a unique role for Mcl-1 in control of programmed cell death in vivo. Am J Pathol. 1995;146:1309–1319. [PubMed]
403. Backus HH, Van Groeningen CJ, Vos W, et al. Differential expression of cell cycle and apoptosis related proteins in colorectal mucosa, primary colon tumours, and liver metastases. J Clin Pathol. 2002;55:206–211. [PMC free article] [PubMed]
404. Varambally S, Cao Q, Mani RS, et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science. 2008;322:1695–1699. [PMC free article] [PubMed]
405. Li S, Fu H, Wang Y, et al. MicroRNA-101 regulates expression of the v-fos FBJ murine osteosarcoma viral omcogene homolog (FOS) oncogene in human hepatocellular carcinoma. Hepatol. 2009;49:1194–1202. [PubMed]
406. Suzucki HI, Yamagata K, Sugimoto K, Iwamoto T, Kato S, Miyazono K. Modulation of microRNA processing by p53. Nature. 2009;460:529–533. [PubMed]
407. Carmell MA, Xuan Z, Zhang MQ, Hannon GJ. The argoanute family: Tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis. Genes Develop. 2002;16:2733–2742. [PubMed]
408. Pillai RS, Artus CG, Filipowicz W. Tethering of human Ago proteins to mRNA mimics the miRNA-mediated repression of protein synthesis. RNA. 2004;10:1518–1525. [PubMed]
409. Sasaki T, Shiohama A, Minoshima S, Shimizu N. Identification of eight members of the Argonaute family in the human genome small star, filled. Genomics. 2003;82:323–330. [PubMed]
410. Hock J, Weinmann L, Ender C, et al. Proteomic and functional analysis of Argonaute-containing mRNA-protein complexes in human cells. EMBO Rep. 2007;8:1052–1060. [PubMed]
411. Wu L, Fan J, Belasco JG. Importance of translation and nonnucleolytic ago proteins for on-target RNA interference. Curr Biol. 2008;18:1327–1332. [PubMed]
412. Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Develop. 2008;22:894–907. [PubMed]
413. Saydam O, Shen Y, Wurdinger T, et al. Downregulated microRNA-200a in meningiomas promotes tumor growth by reducing E-cadherin and activating the Wnt/β-catenin signaling pathway. Mol Cell Biol. 2009;29:5923–5940. [PMC free article] [PubMed]
414. Schneikert J, Behrens J. The canonical WNT signaling pathway and its APC partner in colon cancer development. Gut. 2007;56:417–425. [PMC free article] [PubMed]
415. Korpal M, Lee ES, Hu G, Kang Y. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem. 2008:14910–14914. [PMC free article] [PubMed]
416. Bendoraite A, Knouf EC, Garg KS, et al. Regulation of miR-200 family microRNAs and ZEB transcription factors in ovarian cancer: Evidence supporting a mesothelial-to-epithelial transition. Gynecol Oncol. 2010:117–125. [PMC free article] [PubMed]
417. Brabletz S, Brabletz T. The ZEB/miR-200 feedback loop – a motor of cellular plasticity in development and cancer. EMBO Rep. 2010:670–677. [PubMed]
418. Huang K, Zhang J-X, Han L, et al. MicroRNA roles in beta-catenin pathway. Mol Cancer. 2010;9:252. [PMC free article] [PubMed]
419. Savagner P. Leaving the neighborhood: Molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays. 2001;23:912–923. [PubMed]
420. Fuchs IB, Lichtenegger W, Buehler H, et al. The prognostic significance of epithelial-mesenchymal transition in breast cancer. Anticancer Res. 2002;22:3415–3419. [PubMed]
421. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127:469–480. [PubMed]
422. Huang H, He Xi. Wnt/-catenin signaling: New (and old) players and new insights. Curr Opin Cell Biol. 2008;20:119–125. [PMC free article] [PubMed]
423. Akiyama T. Wnt/β-catenin signaling. Cytokine Growth Factor Rev. 2000:273–282. [PubMed]
424. Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell. 2000;103:311–320. [PubMed]
425. Peifer M, Polakis P. Wnt signaling in oncogenesis and embryogenesis –a look outside the nucleus. Science. 2000;287:1606–1609. [PubMed]
426. He TC, Sparks AB, Rago C, et al. Identification of c-MYC as a target of the APC pathway. Science. 1998;281:1509–1512. [PubMed]
427. Shtutman M, Zhurinsky J, Simcha I, et al. The cyclin D1 gene is a target of the β-catenin/LEF-1 pathway. Proc Natl acad Sci U S A. 1999;96:5522–5527. [PubMed]
428. Tetsu O, McCormick F. β-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999;398:422–426. [PubMed]
429. Morin PJ, Sparks AB, Korinek V, et al. Activation of β-catenin-Tcf signaling in colon cancer by mutations in β-catenin or APC. Science. 1997;275:1787–1790. [PubMed]
430. Satoh S, Daigo Y, Furukawa Y, et al. AXIN1 mutations in hepatocellular carcinomas and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. 2000;24:245–250. [PubMed]
431. Koyama T, Tago K-I, Nakamura T, et al. Mutation and expression of the β-catenin-interacting protein ICAT in human colorectal tumors. Jpn J Clin Oncol. 2002;32:358–362. [PubMed]
432. Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta. 2003;1653:1–24. [PubMed]
433. Humphries A, Wright NA. Colonic crypt organization and tumorigenesis. Nat Rev Cancer. 2008;8:415–424. [PubMed]
434. Tago K, Nakamura T, Nishita M, et al. Inhibition of Wnt signaling by ICAT, a novel β-catenin-interacting protein. Genes Dev. 2000;14:1741–1749. [PubMed]
435. Daniels DL, Weis WI. ICAT inhibits beta-catenin binding to Tcf/Lef-family transcription factors and the general coactivator p300 using independent structural modules. Mol Cell. 2002;10:573–584. [PubMed]
436. Hossain MZ, Yu Q, Xu M, Sen JM. ICAT expression disrupts β-catenin-TCF interactions and impairs survival of thymocytes and activated mature T cells. Int Immunol. 2008;20:925–935. [PMC free article] [PubMed]
437. Graham TA, Clements WK, Kimelman D, Xu W. The crystal structure of the β-catenin/ICAT complex reveals the inhibitory mechanism of ICAT. Mol Cell. 2002;10:1674–1687. [PubMed]
438. Stow JL. ICAT is a multipotent inhibitor of β-catenin. Focus on “Role for ICAT in β-catenin-dependent nuclear signaling and cadherin functions” Am J Physiol Cell Physiol. 2004;286:C745–C746. [PubMed]
439. Hulsken J, Birchmeier W, Behrens J. E-cadherin and APC compete for the interaction with β-catenin and the cytoskeleton. J Cell Biol. 1994:2061–2069. [PMC free article] [PubMed]
440. Gottardi CJ, Gumbiner BM. Role for ICAT in β-catenin-dependent nuclear signaling and cadherin functions. Am J Physiol Cell Physiol. 2004;286:C747–C756. [PubMed]
441. Sekiya T, Nakamura T, Kazuki Y, et al. Overexpression of Icat induces G2 arrest and cell death in tumor cell mutants for adenomatous polyposis coli, β-catenin, or axin. Cancer Res. 2002;62:3322–3326. [PubMed]
442. Ioannidis V, Beermann F, Clevers H, Held W. The beta-catenin-TCF-1 pathway ensures CD4(+)CD8(+) thymocyte survival. Nat Immunol. 2001;2:691–697. [PubMed]
443. Xie H, Huang Z, Sadim MS, Sun Z. Stabilized beta-catenin extends thymocyte survival by up-regulating Bcl-xL. J Immunol. 2005;175:7981–7988. [PubMed]
444. Walston T, Tuskey C, Edgar L, et al. Multiple Wnt signaling pathways converge to orient the mitotic spindle in early C. elegans embryos. Dev Cell. 2004;7:831–841. [PubMed]
445. McCartney BM, McEwen DG, Grevengoed E, Maddox P, Bejsovec A, Peifer M. Drosophila APC2 and Armadillo participate in tethering mitotic spindles to cortical actin. Nat Cell Biol. 2001;3:933–938. [PubMed]
446. Rogers SL, Rogers GC, Sharp DJ, Vale RD. Drosophila EB1 is important for proper assembly, dynamics, and positioning of the mitotic spindle. J Cell Biol. 2002;158:873–884. [PMC free article] [PubMed]
447. Zumbrunn J, Kinoshita K, Hyman AA, Nathke IS. Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3 beta phosphorylation. Curr Biol. 2001;11:44–49. [PubMed]
448. Kaplan KB, Burds AA, Swedlow JR, Bekir SS, Sorger PK, Nathke IS. A role for the Adenomatous Polyposis Coli protein in chromosome segregation. Nat Cell Biol. 2001;3:429–432. [PubMed]
449. Kaplan DD, Meigs TE, Kelly P, Casey PJ. Identification of a role for β-catenin in the establishment of a bipolar mitotic spindle. J Biol Chem. 2004;279:10829–10832. [PubMed]
450. Wakefield JG, Stephens DJ, Tavare JM. A role for glycogen synthase kinase-3 in mitotic spindle dynamics and chromosome alignment. J Cell Sci. 2003;116:637–646. [PubMed]
451. Bobinnec Y, Morin X, Debec A. Shaggy/GSK-3β kinase localizes to the centrosome and to specialized cytoskeletal structures in Drosophila. Cell Motil Cytoskel. 2006;63:313–320. [PubMed]
452. Kikuchi K, Niikura Y, Kitagawa K, Kikuchi A. Dishevelled, a Wnt signalling component, is involved in mitotic progression in cooperation with Plk1. EMBO J. 2010;29:3470–3483. [PubMed]
453. Hadjihannas MV, Bruckner M, Behrens J. Conductin/axin2 and Wnt signalling regulates centrosome cohesion. EMBO Rep. 2010;11:317–324. [PubMed]
454. Fodde R, Kuiper J, Rosenberg C, et al. Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol. 2001;3:433–438. [PubMed]
455. Green RA, Kaplan KB. Chromosome instability in colorectal tumor cells is associated with defects in microtubule plus-end attachments caused by a dominant mutation in APC attachments caused by a dominant mutation in APC. J Cell Biol. 2003;163:949–961. [PMC free article] [PubMed]
456. Hadjihannas MV, Bruckner M, Jerchow B, Birchmeier W, Dietmaier W, Behrens J. Aberrant Wnt/β-catenin signaling can induce chromosomal instability in colon cancer. Proc Natl Acad Sci U S A. 2006;103:10747–10752. [PubMed]
457. Hadjihannas MV, Behrens J. CIN by WNT. Growth pathways, mitotic control and chromosomal instability in cancer. Cell Cycle. 2006;5:2077–2081. [PubMed]
458. Aoki K, Aoki M, Sugai M, et al. Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells. Oncogene. 2007;26:3511–3520. [PubMed]
459. Harris H, Miller OJ, Klein G, Worst P, Tachibana T. Suppression of malignancy by cell fusion. Nature. 1969;223:363–368. [PubMed]
460. Stanbridge EJ. Suppression of malignancy in human cells. Nature. 1976;260:17–20. [PubMed]
461. Sherr CJ. Principles of tumor suppression. Cell. 2004;116:235–246. 976. [PubMed]
462. Carling T, Imanishi Y, Gaz RD, Arnold A. Analysis of the RAD54 gene on chromosome 1p as a potential tumor-suppressive gene in parathyroid adenomas. Int J Cancer. 1999;83:80–82. [PubMed]
463. Sulman EP, Whit PS, Brodeur GM. Genomic annotation of the meningioma tumor suppressor locus on chromosome p34. Oncogene. 2004;2:1014–1020. [PubMed]
464. Bagchi A, Papazoglu C, Wu, et al. CHD5 is a tumor suppressor at human 1p36. Cell. 2007;128:459–475. [PubMed]
465. Fugita T, Igarashi J, Okawa ER, et al. CDH5, a tumor suppressor gene deleted from 1p36.31 in neuroblastomas. J Natl Cancer Inst. 2008;100:940–949. [PubMed]
466. Okawa ER, Gotoh T, Manne J, et al. Expression and sequence analysis of candidates for the 1p36.31 tumor suppressor gene deleted in neuroblastomas. Oncogene. 2008;27:803–810. [PubMed]
467. Bagchi A, Mills AA. The quest for the 1p36 tumor suppressor. Cancer Res. 2008;68:2551–2556. [PMC free article] [PubMed]
468. Cook WD, McCaw BJ. Accommodating haploinsufficient tumor suppressor genes in Knudson’s model. Oncogene. 2000;19:3434–3438. [PubMed]
469. Santarosa M, Ashworth A. Haploinsufficiency for tumour suppressor genes: When you don’t need to go all the way. Biochim Biophys Acta. 2004;1654:105–122. [PubMed]
470. Forman HJ, Zhang H, Rinna A. Glutathione: Overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med. 2009;30:1–12. [PMC free article] [PubMed]
471. Franklin CC, Backos DS, Mohar I, White CC, Forman HJ, Kavanagh TJ. Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase. Mol Aspects Med. 2009;30:86–98. [PMC free article] [PubMed]
472. Martensson J, Jain A, Meister A. Glutathione is required for intestinal function. Proc Natl Acad Sci U S A. 1990;87:1715–1719. [PubMed]
473. Shiraishi R, Fujise T, Kuroki T, et al. Long-term ingestion of reduced glutathione suppressed an accelerating effect of beef tallow diet on colon carcinogenesis in rats. J Gastroenterol. 2009;44:1026–1035. [PubMed]
474. Yang Y, Dieter MZ, Chen Y, Shertzer HG, Nebert DW, Dalton TP. Initial characterization of the glutamate-cysteine ligase modifier subunit Gclm (−/−) knockout mouse. Novel model system for a severely compromised oxidative stress response. J Biol Chem. 2002;277:49446–49452. [PubMed]
475. Ochi T. Hydrogen peroxide increases the activity of γ-glutamylcysteine synthetase in cultured Chinese hamster V79 cells. Arch Toxicol. 1995;70:96–103. [PubMed]
476. Tian L, Shi MM, Forman HJ. Increased transcription of the regulatory subunit of γ-glutamylcysteine synthetase in rat lung epithelial L2 cells exposed to oxidative stress or glutathione depletion. Arch Biochem Biophys. 1997;342:126–133. [PubMed]
477. Rinna A, Forman HJ. SHP-1 inhibition by 4-hydroxynonenol activates jun N-terminal kinase and glutamate cysteine ligase. Am J Respir Cell Mol Biol. 2008;39:97–104. [PMC free article] [PubMed]
478. Dickinson DA, Iies KE, Watanabe N, et al. 4-hydroxynonenal induces glutamate cysteine ligase through JNK in HBE1 cells. Free Radic Biol Med. 2002;33:974–987. [PubMed]
479. Siitonen T, Alaruikka P, Mantymaa P, et al. Protection of acute myeloblastic leukemia cells against apoptotic cell death by high glutathione and G-glutamylcysteine synthetase levels during etoposide-induced oxidative stress. Ann Oncol. 1999;10:1361–1367. [PubMed]
480. Botta D, Franklin CC, White CC, et al. Glutamate-cysteine ligase attenuates TNF-induced mitochondrial injury and apoptosis. Free Radic Biol Med. 2004;37:632–642. [PubMed]
481. Lu SC. Regulation of glutathione synthesis. Mol Aspects Med. 2009;30:42–59. [PMC free article] [PubMed]
482. Markovic J, Garcia-Gimenez JL, Gimeno A, Vina J, Pallardo FV. Role of glutathione in cell nucleus. Free Radic Res. 2010;44:721–733. [PubMed]
483. Diaz Vivancos P, Wolff T, Markovic J, Pallardo FV, Foyer CH. A nuclear glutathione cycle within the cell cycle. Biochem J. 2010;431:169–178. [PubMed]
484. Giera S, Braeuning A, Kohle C, et al. Wnt/beta-catenin signaling activates and determines hepatic zonal expression of glutathione S-transferases in mouse liver. Toxicol Sci. 2010;115:22–33. [PubMed]
485. Patskovsky YV, Huang MQ, Takayama T, Listowsky I, Pearson WR. Distinctive structure of the human GSTM3 gene – inverted orientation relative to the mu class glutathione transferase gene cluster. Arch Biochem Biophys. 1999;361:85–93. [PubMed]
486. Yu KD, Fan L, Di GH, et al. Genetic variants in GSTM3 gene within GSTM4-GSTM2-GSTM1-GSTM5-GSTM3 cluster influence breast cancer susceptibility depending on GSTM1. Breast Cancer Res Treat. 2010;121:485–496. [PubMed]
487. Pool-Zobel B, Veeriah S, Bohmer F-D. Modulation of xenobiotic metabolising enzymes by anticarcinogens-focus on glutathione S-transferases and their role as targets of dietary chemoprevention in colorectal carcinogenesis. Mutat Res. 2005;591:74–92. [PubMed]
488. Katoh T, Nagata N, Kuroda Y, et al. Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genetic polymorphism and susceptibility to gastric and colorectal adenocarcinoma. Carcinogenesis. 1996;17:1855–1859. [PubMed]
489. Scarpato N, Hirvonen A, Migliore L, Falck G, Norppa H. Influence of GSTM1 and GSTT1 polymorphisms on the frequency of chromosome aberrations in lymphocytes of smokers and pesticide-exposed greenhouse workers. Mutat Res. 1997;389:227–235. [PubMed]
490. Griesmann H, Schlereth K, Krause M, Samans B, Stiewe T. p53 and p73 in suppression of Myc-driven lymphomagenesis. Int J Cancer. 2009;124:502–506. [PubMed]
491. Gao K, Henning SM, Niu Y, et al. The citrus flavonoid naringenin stimulates DNA repair in prostate cancer cells. J Nutr Biochem. 2006;17:89–95. [PubMed]
492. Morel I, Abalea V, Cillard P, Cillard J. Repair of oxidized DNA by the flavonoid myricetin. Methods Enzymol. 2001;335:308–316. [PubMed]
493. Bernstein H, Crowley-Skillicorn C, Bernstein C, Payne CM, Dvorak K, Garewal H. Dietary compounds that enhance DNA repair and their relevance to cancer and aging. In: Lanseer BR, editor. New Research on DNA Repair. Hauppauge, NY: Nova Science Publishers, Inc; 2007. pp. 99–113.
494. Della Ragione F, Cucciolla V, Criniti V, Indaco S, Borriello A, Zappia V. Antioxidants induce different phenotypes by a distinct modulation of signal transduction. FEBS Lett. 2002;532:289–294. [PubMed]
495. Yoshida T, Maeda A, Horinaka M, et al. Quercetin induces gadd45 expression through a p53-independent pathway. Oncol Rep. 2005;14:1299–1303. [PubMed]
496. Catani MV, Costanzo A, Savini I, et al. Ascorbate up-regulates MLH1 (Mut L homologue-1) and p73: Implications for the cellular response to DNA damage. Biochem J. 2002;364:441–447. [PubMed]
497. Davis CD, Ross SA. Evidence for dietary regulation of microRNA expression in cancer cells. Nutr Rev. 2008;66:477–482. [PubMed]
498. Pogribny IP, Tryndyak VP, Ross SA, Beland FA. Differential expression of microRNAs during hepatocarcinogenesis induced by methyl deficiency in rats. Nutr Rev. 2008;66(Suppl 1):S33–S35. [PubMed]
499. Garzon R, Pichiorri F, Palumbo T, et al. MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia. Oncogene. 2007;26:4148–4157. [PubMed]
500. Sun M, Estrov Z, Ji Y, Coombes KR, Harris DH, Kurzrock R. Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells. Mol Cancer Ther. 2008;7:464–473. [PubMed]
501. Boesch-Saadatmandi C, Loboda A, Wagner AE, et al. Effect of quercetin and its metabolites isorhamnetin and quercetin-3-glucuronide on inflammatory gene expression: Role of miR-155. J Nutr Biochem. 2010 Jun 23.; [Epub ahead of print]. [PubMed]
502. Davidson LA, Wang N, Shah MS, et al. n-3 polyunsaturated fatty acids modulate carcinogen-directed non-coding microRNA signatures in rat colon. Carcinogenesis. 2009;30:2077–2084. [PMC free article] [PubMed]
503. Gaedicke S, Zhang X, Schmelzer C, et al. Vitamin E dependent microRNA regulation in rat liver. FEBS Lett. 2008;582:3542–3546. [PubMed]
504. Paul S, DeCastro AJ, Lee HJ, et al. Dietary intake of pterostilbene, a constituent of blueberries, inhibits the β-catenin/p65 downstream signaling 1 pathway and colon carcinogenesis in rats. Carcinogenesis. 2010;31:1272–1278. [PMC free article] [PubMed]
505. Sarkar FH, Li Y, Wang Z, Kong D. Cellular signaling perturbation by natural products. Cell Signal. 2009;21:1541–1547. [PMC free article] [PubMed]
506. Sarkar FH, Li Y, Wang Z, Kong D. The role of neutroceuticals in the regulation of Wnt and Hedgehog signaling in cancer. Cancer Metastasis Rev. 2010;29:383–394. [PMC free article] [PubMed]
507. Ryu MJ, Cho M, Song JY, et al. Natural derivatives of curcumin attenuate the Wnt/beta-catenin pathway through down-regulation of the transcriptional coactivator p300. Biochem Biophys Res Commun. 2008;377:1304–1308. [PubMed]
508. Jaiswal AS, Marlow BP, Gupta N, Narayan S. Beta-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene. 2002:8414–8427. [PubMed]
509. Yan C, Jamaluddin MS, Aggarwal B, Myers J, Boyd DD. Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin. Mol Cancer Ther. 2005;4:233–241. [PubMed]
510. Tarapore RS, Siddiqui IA, Saleem M, Adhami VM, Spiegelman VS, Mukhtar H. Specific targeting of Wnt/β-catenin signaling in human melanoma cells by a dietary triterpene lupeol. Carcinogenesis. 2010;31:1844–1853. [PMC free article] [PubMed]
511. Masella R, Di Benedetto R, Vari R, Filesi C, Giovannini C. Novel mechanisms of natural antioxidant compounds in biological systems: Involvement of glutathione and glutathione-related enzymes. J Nutr Biochem. 2005;16:577–586. [PubMed]
512. Suzucki K, Koike H, Matsui H, et al. Genistein, a soy isoflavone, induces glutathione peroxidase in the human prostate cancer cell lines LNCAP and PC-3. Int J Cancer. 2002;99:846–852. [PubMed]
513. Luceri C, Caderni G, Sanna A, Dolara P. Red wine and black tea polyphenols modulate the expression of cycloxygenase-2, inducible nitric oxide synthase and glutathione-related enzymes in azoxymethane-induced F344 rat colon tumors. J Nutr. 2002;132:1376–1379. [PubMed]
514. Myhrstad MC, Carlsen H, Nordstrom O, Blomhoff R, Moskaug JO. Flavonoids increases the intracellular glutathione level by transactivation of the γ-glutamylcysteine synthetase catalytic subunit promoter. Free Radic Biol Med. 2002;32:386–393. [PubMed]
515. Scharf G, Prustomersky S, Knasmuller S, Schulte-Hermann R, Huber WW. Enhancement of glutathione and γ-glutamylcysteine synthetase, the rate limiting enzyme of glutathione synthesis, by chemopreventive plant-derived food and beverage components in the human hepatoma cell line HepG2. Nutr Cancer. 2003;45:74–83. [PubMed]
516. Moskaug JO, Carlsen H, Myhrstad MC, Blomhoff R. Polyphenols and glutathione synthesis regulation. Am J Clin Nutr. 2005;81(1 Suppl):277S–283S. [PubMed]
517. Na HK, Surh YJ. Modulation of Nrf2-mediated antioxidant and detoxifying enzyme induction by the green tea polyphenol EGCG. Food Chem Toxicol. 2008;46:1271–1278. [PubMed]
518. Dickinson DA, Iies KE, Zhang H, Blank V, Forman HJ. Curcumin alters EpRE and AP-1 binding complexes and elevates glutamate-cysteine ligase gene expression. The FASEB J. 2003;17:473–475. [PubMed]
519. Huber WW, Scharf G, Rossmanith W, et al. The coffee components Kahweol and Cafestol induce γ-glutamylcysteine synthetase, the rate limiting enzyme of chemoprotective glutathione synthesis, in several organs of the rat. Arch Toxicol. 2002b;75:685–694. [PubMed]
520. Fiander H, Schneider H. Dietary orto-phenols that induce glutathione S-transferase and increase the resistance of cells to hydrogen peroxide are potential cancer chemopreventives that act by two mechanisms: The alleviation of oxidative stress and the detoxification of mutagenic xenobiotics. Cancer Lett. 2000;156:117–124. [PubMed]
521. Huber WW, Parzefall W. Modification of N-acetyltransferases and glutathione S-transferases by coffee components: Possible relevance for cancer risk. Methods Enzymol. 2005;401:307–341. [PubMed]
522. Guglielmi F, Luceri C, Giovannelli L, Dolara P, Lodovici M. Effect of 4-coumaric acid and 3,4-dihydroxybenzoic acid on oxidative DNA damage in rat colonic mucosa. Br J Nutr. 2003;89:581–587. [PubMed]
523. Munday R, Munday CM. Low soses of diallyl disulfide, a compound derived from garlic, increase tissue activities of quinone reductase and glutathione transferase in the gastrointestinal tract of the rat. Nutr Cancer. 1999;34:42–48. [PubMed]
524. Ebert MN, Klinder A, Peters WH, et al. Expression of glutathione S-transferases (GST) in human colon cells and inducibility of GSTM2 by butyrate. Carcinogenesis. 2003;24:1637–1644. [PubMed]
525. Huber WW, Teitel CH, Coles BF, et al. Potential chemoprotective effects of the coffee components kahweol and cafestol palmitates via modification of hepatic N-acetyltransferase and glutathione S-transferase activities. Environ Mol Mutagen. 2004;44:265–276. [PubMed]
526. Rice-Evans C. Plant polyphenols: Free radical scavengers or chain-breaking antioxidants? Biochem Soc Symp. 1995;61:103–116. [PubMed]
527. Kasai H, Fukada S, Yamaizumi Z, Sugie S, Mori H. Action of chlorogenic acid in vegetables and fruits as an inhibitor of 8-hydroxydeoxyguanosine formation in vitro and in a rat carcinogenesis model. Food Chem Toxicol. 2000;38:467–471. [PubMed]
528. Schaefer S, Baum M, Eisenbrand G, Dietrich H, Will F, Janzowski C. Polyphenolic apple juice extracts and their major constituents reduce oxidative damage in human colon cell lines. Mol Nutr Food Res. 2006;50:24–33. [PubMed]
529. Fabiani R, Rosignoli P, De Bartolomeo A, et al. Oxidative DNA damage is prevented by extracts of olive oil, hydroxytyrosol, and other olive phenolic compounds in human blood mononuclear cells and HL60 cells. J Nutr. 2008;138:1411–1416. [PubMed]
530. Shi Y, Wang W, Huang C, Jia Z, Yao S, Zheng R. Fast repair of oxidative DNA damage by phenylpropanoid glycosides and their analogues. Mutagenesis. 2008;23:19–26. [PubMed]
531. Lodovici M, Casalini C, De Filippo C, et al. Inhibition of 1,2-dimethylhydrazine-induced oxidative DNA damage in rat colon mucosa by black tea complex polyphenols. Food Chem Toxicol. 2000;38:1085–1088. [PubMed]
532. Bancroft LK, Lupton JR, Davidson LA, et al. Dietary fish oil reduces oxidative DNA damage in rat colonocytes. Free Radic Biol Med. 2003;35:149–159. [PubMed]
533. Machowetz A, Poulsen HE, Gruendel S, et al. Effect of olive oils on biomarkers of oxidative DNA stress in Northern and Southern Europeans. FASEB J. 2007;21:45–52. [PubMed]
534. Quiles JL, Ochoa JJ, Ramirez-Tortosa C, et al. Dietary fat type (virgin olive vs sunflower oils) affects age-related changes in DNA double-strand-breaks, antioxidant capacity and blood lipids in rats. Exp Gerontol. 2004;39:1189–1198. [PubMed]
535. Rosignoli P, Fabiani R, De Bartolomeo A, et al. Protective activity of butyrate on hydrogen peroxide-induced DNA damage in isolated human colonocytes and HT29 tumour cells. Carcinogenesis. 2001;22:1675–1680. [PubMed]
536. Ebert MN, Beyer-Sehlmeyer G, Liegibel UM, Kautenburger T, Becker TW, Pool-Zobel BL. Butyrate induces glutathione S-transferase in human colon cells and protects from genetic damage by 4-hydroxynonenal. Nutr Cancer. 2001;41:156–164. [PubMed]
537. Belloir C, Singh V, Daurat C, Siess MH. Le Bon AM. Protective effects of garlic sulfur compounds against DNA damage induced by direct- and indirect-acting genotoxic agents in HepG2 cells. Food Chem Toxicol. 2006;44:827–834. [PubMed]
538. Fraga CG, Motchnik PA, Shigenaga MK, Helbock HJ, Jacob RA, Amers BN. Ascorbic acid protects against endogenous oxidative DNA damage in human sperm. Proc Natl Acad Sci U S A. 1991;88:11003–11006. [PubMed]
539. Giovannucci E, Goldin B. The role of fat, fatty acids, and total energy intake in the etiology of human colon cancer. Am J Clin Nutr. 1997;66:1564S–1571S. [PubMed]
540. Rieger MA, Parlesak A, Pool-Zobel BL, Rechkemmer G, Bode C. A diet high in fat and meat but low in dietary fibre increases the genotoxic potential of ‘faecal water’ Carcinogenesis. 1999;20:2311–2316. [PubMed]
541. Fujise T, Iwakiri R, Kakimoto T, et al. Long-term feeding of various fat diets modulates azoxymethane-induced colon carcinogenesis through Wnt/beta-catenin signaling in rats. Am J Physiol Gastrointest Liver Physiol. 2007;292:G1150–G1156. [PubMed]
542. Endo H, Hosono K, Fujisawa T, et al. Involvement of JNK pathway in the promotion of the early stage of colorectal carcinogenesis under high-fat dietary conditions. Gut. 2009;58:1637–1643. [PubMed]
543. Pearson JR, Gill CIR, Rowland IR. Diet, fecal water, and colon cancer – development of a biomarker. Nutr Rev. 2009;67:509–526. [PubMed]
544. Xichun Z. Long-term exposure to various types of fat modulates acrylamide-induced preneoplastic lesions of colon mucosa through Wnt/beta-catenin signaling in rats. Toxicol Mech Methods. 2009;19:285–291. [PubMed]
545. Larsson SC, Rafter J, Holmberg L, Bergkvist L, Wolk A. Red meat consumption and risk of cancers of the proximal colon, distal colon, and rectum: the Swedish Mammography Cohort. Int J Cancer. 2005;113:829–834. [PubMed]
546. Glei M, Latunde-Dada GO, Klinder A, et al. Iron-overload induces oxidative DNA damage in the human colon carcinoma cell line HT29 clone 19A. Mutat Res. 2002;519:151–161. [PubMed]
547. Ilsley JNM, Belinsky GS, Guda K, et al. Dietary iron promotes azoxymethane-induced colon tumors in mice. Nutr Cancer. 2004;49:162–169. [PubMed]
548. Bingham SA, Day NE, Luben R, et al. European Prospective Investigation into Cancer and Nutrition Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): An observational study. Lancet. 2003;361:1496–1501. [PubMed]
549. Young GP, Hu Y, Le Leu RK, Nyskohus L. Dietary fibre and colorectal cancer: A model for environment – gene interactions. Mol Nutr Food Res. 2005;49:571–584. [PubMed]
550. Toden S, Bird AR, Topping DL, Conlon MA. High red meat diets induce greater numbers of colonic DNA double-strand breaks than white meat in rats: Attenuation by high-amylose maize starch. Carcinogenesis. 2007;28:2355–2362. [PubMed]
551. Dahm CC, Keogh RH, Spencer EA, et al. Dietary fiber and colorectal cancer risk: A nested case-control study using food diaries. J Natl Cancer Inst. 2010;102:614–626. [PubMed]
552. Hertog MG, Bueno-de-Mesquita HB, Fehily AM, Sweetnam PM, Elwood PC, Kromhout D. Fruit and vegetable consumption and cancer mortality in the Caerphilly study. Cancer Epidemiol Biomarkers Prev. 1996;5:673–677. [PubMed]
553. Millen AE, Subar AF, Graubard BI, et al. Fruit and vegetable intake and prevalance of colorectal adenoma in a cancer screening trial. Am J Clin Nutr. 2007;86:1754–1764. [PubMed]
554. Rimando AM, Suh N. Biological/chemopreventive activity of stilbenes and their effect on colon cancer. Planta Med. 2008;74:1635–1643. [PubMed]
555. Van Duijnhoven FJ, Bueno-De-Mesquita HB, Ferrari P, et al. Fruit, vegetables, and colorectal cancer risk: The European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr. 2009;89:1441–1452. [PubMed]
556. Tseng M, Murray SE, Kupper LL, Sandler RS. Micronutrients and the risk of colorectal adenomas. Am J Epidemiol. 1996;144:1005–1014. [PubMed]
557. Ames BN. Micronutrient deficiencies. A major cause of DNA damage. Ann N Y Acad Sci. 1999;889:87–106. [PubMed]
558. Ames BN. DNA damage from micronutrient deficiencies is likely to be a major cause of cancer. Mutat Res. 2001;475:7–20. [PubMed]
559. Fenech M. Micronutrients and genomic stability: A new paradigm for recommended dietary allowances (RDAs) Food Chem Toxicol. 2002;40:1113–1117. [PubMed]
560. Ames BN. Prevention of mutation, cancer, and other age-associated diseases by optimizing micronutrient intake. J Nucleic Acids. 2010 pii: 725071. [PMC free article] [PubMed]
561. Van Breda SG, van Agen E, Engels LG, et al. Altered vegetable intake affects pivotal carcinogenesis pathways in colon mucosa from adenoma patients and controls. Carcinogenesis. 2004;25:2207–2216. [PubMed]
562. Ricke RM, van Ree JH, van Deursen JM. Whole chromosome instability and cancer: A complex relationship. Trends Genet. 2008;24:457–466. [PMC free article] [PubMed]
563. Munirajan AK, Ando K, Mukai A, et al. KIF1Bbeta functions as a haploinsufficient tumor suppressor gene mapped to chromosome 1p36.2 by inducing apoptotic cell death. J Biol Chem. 2008;283:24426–24434. [PMC free article] [PubMed]
564. Opavsky R, Tsai SY, Guimond M, et al. Specific tumor suppressor function for E2F2 in Myc-induced T cell lymphomagenesis. Proc Natl Acad Sci U S A. 2007;104:15400–15405. [PubMed]
565. Huang N, Lee I, Marcotte EM, Hurles ME. Characterising and predicting haploinsufficiency in the human genome. PLoS Genet. 2010;6:e1001154. [PMC free article] [PubMed]
566. Emerit I, Keck M, Levy A, Feingold J, Michelson AM. Activated oxygen species as the origin of chromosome breakage and sister chromatid exchange. Mutat Res. 1982;103:165–172. [PubMed]
567. Blakeborough MH, Owen RW, Bilton RF. Free radical generating mechanisms in the colon: Their role in the induction and promotion of colorectal cancer? Free Radic Res Commun. 1989;6:359–367. [PubMed]
568. Babbs CF. Free radicals and the etiology of colon cancer. Free Radic Biol Med. 1990;8:191–200. [PubMed]
569. Emerit I. Reactive oxygen species, chromosome mutation and cancer. Possible role of clastogenic factors in carcinogenesis. Free Radic Biol Med. 1994;16:99–109. [PubMed]
570. Poulsen HE, Prieme H, Loft S. Role of oxidative DNA damage in cancer initiation and promotion. Eur J Cancer. 1998;7:9–16. [PubMed]
571. Balkwill F, Mantovani A. Inflammation and cancer: Back to Virchow? Lancet. 2001;357:539–545. [PubMed]
572. Jackson AL, Loeb AA. The contribution of endogenous sources of DNA damage to the multiple mutations in cancer. Mutat Res. 2001;477:7–21. [PubMed]
573. Gackowski D, Banaszkiewicz Z, Rozalski R, Jawien A, Olinski R. Persistent oxidative stress in colorectal carcinoma patients. Int J Cancer. 2002;101:395–397. [PubMed]
574. Klaunig JE, Kamendulis LM. The role of oxidative stress in carcinogenesis. Ann Rev Pharmacol Toxicol. 2004;44:239–267. [PubMed]
575. Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J. Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem. 2004;266:37–56. [PubMed]
576. Storz P. Reactive oxygen species in tumor progression. Front Biosci. 2005;10:1881–1896. [PubMed]
577. Kundu JK, Surh YJ. Inflammation: Gearing the journey to cancer. Mutat Res. 2008;659:15–30. [PubMed]
578. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instability. Carcinogenesis. 2009;30:1073–1081. [PubMed]
579. Sheridan J, Wang LM, Tosetto M, et al. Nuclear oxidative damage correlates with poor survival in colorectal cancer. Br J Cancer. 2009;100:381–388. [PMC free article] [PubMed]
580. Chang CL, Marra G, Chauhan DP, et al. Oxidative stress inactivates the human DNA mismatch repair system. Am J Physiol Cell Physiol. 2002;283:C148–C154. [PubMed]
581. Song JY, Lim JW, Kim H, Morio T, Kim KH. Oxidative stress induces nuclear loss of DNA repair proteins Ku70 and Ku80 and apoptosis in pancreatic acinar AR42J cells. J Biol Chem. 2003;278:36676–36687. [PubMed]
582. Berwick M, Vineis P. Markers of DNA repair and susceptibility to cancer in humans: An epidemiologic review. J Natl Cancer Inst. 2000;92:874–897. [PubMed]
583. Loeb KR, Loeb LA. Genetic instability and the mutator phenotype. Studies in ulcerative colitis. Am J Pathol. 1999;154:1621–1626. [PubMed]
584. Schonfeld P, Wojtczak L. Fatty acids as modulators of the cellular production of reactive species. Free Radic Biol Med. 2008;45:231–241. [PubMed]
585. Lovis P, Roggli E, Laybutt DR, et al. Alterations in microRNA expression contribute to fatty acid-induced pancreatic β-cell dysfunction. Diabetes. 2008;57:2728–2736. [PMC free article] [PubMed]
586. Washo-Stultz D, Crowley-Weber CL, Dvorakova K, et al. Role of mitochondrial complexes I and II, reactive oxygen species and arachidonic acid metabolism in deoxycholate-induced apoptosis. Cancer Lett. 2002;177:129–144. [PubMed]
587. Payne CM, Weber C, Crowley-Skillicorn C, et al. Deoxycholate induces mitochondrial oxidative stress and activates NF-kB through multiple mechanisms in HCT-116 colon epithelial cells. Carcinogenesis. 2007;28:215–222. [PubMed]
588. Washo-Stultz D, Hoglen N, Bernstein H, Bernstein C, Payne CM. Role of nitric oxide and peroxynitrite in bile salt-induced apoptosis. Nutr Cancer. 1999;35:180–188. [PubMed]
589. Dall’Agnol M, Bernstein C, Bernstein H, Garewal H, Payne CM. Identification of S-nitrosylated proteins after chronic exposure of colonic epithelial cells to deoxycholate. Proteomics. 2006;6:1654–1662. [PubMed]
590. Bernstein H, Holubec H, Bernstein C, et al. Unique dietary-related mouse model of colitis. Inflamm Bowel Dis. 2006;12:278–293. [PubMed]
591. Payne CM, Holubec H, Bhattacharyya AK, Bernstein C, Bernstein H. Exposure of mouse colon to dietary bile acid supplement induces sessile adenomas. Inflamm Bowel Dis. 2009;16:729–730. [PubMed]
592. Bernstein C, Holubec H, Bhattacharyya AK, et al. Carcinogenicity of deoxycholate, a secondary bile acid. Arch Toxicol. 2011 doi: 10.1007/s00204-011-0648–7. [PMC free article] [PubMed] [Cross Ref]
593. Holubec H, Payne CM, Bernstein H, et al. Assessment of apoptosis by immunohistochemical markers compared to cellular morphology in ex vivo-stressed colonic mucosa. J Histochem Cytochem. 2005;53:229–235. [PubMed]
594. Payne CM, Crowley C, Washo-Stultz D, et al. The stress-response proteins poly(ADP-ribose) polymerase and NF-κB protect against bile salt-induced apoptosis. Cell Death Differ. 1998;5:623–636. [PubMed]
595. Payne CM, Crowley-Skillicorn C, Bernstein C, Holubec H, Moyer MP, Bernstein H. Hydrophobic bile acid-induced micronuclei formation, mitotic perturbations, and decreases in spindle checkpoint proteins: Relevance to genomic instability in colon carcinogenesis. Nutr Cancer. 2010;62:825–840. [PubMed]
596. Knisely AS, Strautnieks SS, Meier Y, et al. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatol. 2006;44:478–486. [PubMed]
597. Jansen PLM. Endogenous bile acids as carcinogens. Rev Hepatol. 2007;47:434–435. [PubMed]
598. Payne CM, Crowley-Skillicorn C, Holubec H, et al. Deoxycholate, an endogenous cytotoxin/genotoxin, induces the autophagic stress-survival pathway: Implications for colon carcinogenesis. J Toxicol. 2009:1–14. doi: 10.1155/2009/785907. article ID 785907: [PMC free article] [PubMed] [Cross Ref]
599. Crowley-Weber CL, Payne CM, Gleason-Guzman M, et al. Development and molecular characterization of colon cell lines resistant to the tumor promoter and multiple stress-inducer, deoxycholate. Carcinogenesis. 2002;23:2063–2080. [PubMed]
600. Giovannucci E. Meta-analysis of coffee consumption and risk of colorectal cancer. Am J Epidemiol. 1998;147:1043–1052. [PubMed]
601. Tavani A, La Vecchia C. Coffee and cancer: A review of epidemiological studies, 1990–1999. Eur J Cancer Prev. 2000;9:241–256. [PubMed]
602. Tavani A, La Vecchia C. Coffee, decaffeinated coffee, tea and cancer of the colon and rectum: A review of epidemiological studies, 1990–2003. Cancer Causes Control. 2004;15:743–757. [PubMed]
603. Michels KB, Willett WC, Fuchs CS, Giovannucci E. Coffee, tea, and caffeine consumption and incidence of colon and rectal cancer. J Natl Cancer Inst. 2005;97:282–292. [PMC free article] [PubMed]
604. Mattila P, Kumpulainen J. Determination of free and total phenolic acids in plant-derived foods by HPLC with diode-array detection. J Agric Food Chem. 2002;50:3660–3667. [PubMed]
605. Han Y, Haraguchi T, Iwanaga S, et al. Consumption of some polyphenols reduces fecal deoxycholic acid and lithocholic acid, the secondary bile acids of risk factors of colon cancer. J Agric Food Chem. 2009;57:8587–8590. [PubMed]
606. Shibata A, Kamada N, Masumura K, et al. Parp-1 deficiency causes an increase of deletion mutations and inserions/rearrangements in vivo after treatment with an alkylating agent. Oncogene. 2005;24:1328–1337. [PubMed]
607. Crowley C, Payne CM, Bernstein H, Bernstein C, Roe D. The NAD+ precursors, nicotinic acid and nicotinamide protect cells against apoptosis induced by a multiple stress inducer, deoxycholate. Cell Death Differ. 2000;7:314–326. [PubMed]
608. Yan Q, Briehl M, Crowley CL, Payne CM, Bernstein H, Bernstein C. The NAD+ precursors, nicotinic acid and nicotinamide upregulate glyveraldehyde-3-phosphate dehydrogenase and glucose-6-phosphate dehydrogenase mRNA in Jurkat cells. Biochem Biophys Res Comm. 1999;255:133–136. [PubMed]
609. Zaki I, Millard L. Pellagra complicating Crohn’s disease. Postgrad Med J. 1995;71:496–497. [PMC free article] [PubMed]
610. Kiran RP, Khoury W, Church JM, Lavery IC, Fazio VW, Remzi FH. Colorectal cancer complicating inflammatory bowel disease: Similarities and differences between Crohn’s and ulcerative colitis based on three decades of experiemce. Ann Surg. 2010;252:330–335. [PubMed]
611. D’Odorico A, Bortolan S, Cardin R, et al. Reduced plasma antioxidant concentrations and increased oxidative DNA damage in inflammatory bowel disease. Scand J Gastroenterol. 2001;36:1289–1294. [PubMed]
612. Pollack S, Enat R, Haim S, Zinder O, Barzilai D. Pellagra as the presenting manifestation of Crohn’s disease. Gastroenterol. 1982;82(5 Pt 1):948–952. [PubMed]
613. Abu-Qurshin R, Naschitz JE, Zuckermann E, Nash E, Eldar S, Yeshurun D. Crohn’s disease associated with pellagra and increased excretion of 5-hydroxyindolacetic acid. Am J Med Sci. 1997;313:111–113. [PubMed]
614. Martinez-A C, van Wely KH. Are aneuploidy and chromosome breakage caused by a CINgle mechanism? Cell Cycle. 2010;9:2275–2280. [PubMed]
615. Sawyer JR, Swanson CM, Koller MA, North PE, Ross SW. Centromeric instability of chromosome 1 resulting in multi-branched chromosomes, telomeric fusion, and “jumping translocations” of 1q in a human immunodeficiency virus-related non-Hodgkin’s lymphoma. Cancer. 1995;76:1238–1244. [PubMed]
616. Sawyer JR, Husain M, Pravdenkova S, Krisht A, Al-Mefty O. A role for telomeric and centromeric instability in the progression of chromosome aberrations in meningioma patients. Cancer. 2000;88:440–453. [PubMed]
617. Raimondi SC, Ragsdale ST, Behm F, Rivera G, Williams DL. Multiple telomeric associations of a trisomic whole q arm of chromosome 1 in a child with acute lymphoblastic leukemia. Cancer Genet Cytogenet. 1987;47:87–93. [PubMed]
618. Almeida A, Kokalj-Vokac N, Lefrancois D, et al. Hypomethylation of classical satellite DNA and chromosomal instability in lymphoblastoid cell lines. Hum Genet. 1993;91:538–546. [PubMed]
619. Kokalj-Vokac N, Almeida A, Viegas-Pequignot E, Jeanpierre M, Malfoy B, Dutrillaux B. Specific induction of uncoiling and recombination by azacytidine in classical satellite-containing constitutive heterochromatin. Cytogenet Cell Genet. 1993;63:11–15. [PubMed]
620. Sawyer JR, Tricot G, Mattox S, Jagannath S, Barlogie B. Jumping translocations of chromosome 1q in multiple myeloma: Evidence for a mechanism involving decondensation of pericentromeric heterochromatin. Blood. 1998;91:1732–1741. [PubMed]
621. Vukovic B, Beheshti B, Park P, et al. Correlating breakage-fusion-bridge events with the overall chromosomal instability and in vitro karyotype evolution in prostate cancer. Cytogenet Genome Res. 2007;116:1–11. [PubMed]
622. Robbins AR, Jablonski SA, Yen TJ, et al. Inhibitors of histone deacetylases alter kinetochore assembly by disrupting pericentromeric heterochromatin. Cell Cycle. 2005;4:717–726. [PubMed]
623. Demuth I, Digweed M, Concannon P. Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation. Oncogene. 2004;23:8611–8618. [PubMed]
624. Ye J, Lenain C, Bauwens S, et al. TRF2 and Apollo cooperate with topoisomerase 2α to protect human telomeres from replicative damage. Cell. 2010;142:230–242. [PubMed]
625. Nagothu KK, Jaszewski R, Moragoda L, et al. Folic acid mediated attenuation of loss of heterozygosity of DCC tumor suppressor gene in the colonic mucosa of patients with colorectal adenomas. Cancer Detect Prevent. 2003;27:297–304. [PubMed]
626. Wang X, Thomas P, Xue J, Fenech M. Folate deficiency induces aneuploidy in human lymphocytes in vitro-evidence using cytokinesis-blocked cells and probes specific for chromosomes 17 and 21. Mutat Res. 2004;551:167–180. [PubMed]
627. Fenech M, Crott JW. Micronuclei, nucleoplasmic bridges and nuclear buds induced in folic acid deficient human lymphocytes – evidence for breakage-fusion-bridge cycles in the cytokinesis-block micronucleus assay. Mutat Res. 2002;504:131–136. [PubMed]
628. Lindberg HK, Wang X, Jarventaus H, Falck GC, Norppa H, Fenech M. Origin of nuclear buds and micronuclei in normal and folate-deprived human lymphocytes. Mutat Res. 2007;617:33–45. [PubMed]
629. Choi S-W, Mason JB. Folate status: Effects on pathways of colorectal carcinogenesis. J Nutr. 2002;132:2413S–2418S. [PubMed]
630. Kim YI. Folate and colorectal cancer: An evidence-based critical review. Mol Nutr Food Res. 2007;51:267–292. [PubMed]
631. Majumdar AP, Kodali U, Jaszewski R. Chemopreventive role of folic acid in colorectal cancer. Front Biosci. 2004;9:2725–2732. [PubMed]
632. Kim J, Kim DH, Lee BH, et al. Folate intake and the risk of colorectal cancer in a Korean population. Eur J Clin Nutr. 2009;63:1057–1064. [PubMed]
633. Duthie SJ. Folate and cancer: How DNA damage, repair and methylation impact on colon carcinogenesis. J Inherit Metab Dis. 2011;34:101–109. [PubMed]
634. Blount BC, Mack MM, Wehr CM, et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage. Proc Natl Acad Sci U S A. 1997;94:3290–3295. [PubMed]
635. Choi SW, Kim YI, Weitzel JN, Mason JB. Folate depletion impairs DNA excision repair in the colon of the rat. Gut. 1998;43:93–99. [PMC free article] [PubMed]
636. Marsit CJ, Eddy K, Kelsey KT. MicroRNA responses to cellular stresses. Cancer Res. 2006;66:10843–10848. [PubMed]
637. Levine AJ, Siegmund KD, Ervin CM, et al. The methylenetetrahydrofolate reductase 677C→T polymorphism and distal colorectal adenoma risk. Cancer Epidemiol Biomark Prev. 2000;9:657–663. [PubMed]
638. Kawakami K, Omura K, Kanehira E, Watanabe G. Methylenetet-rahydrofolate reductase polymorphism is associated with folate pool in gastrointestinal cancer tissue. Anticancer Res. 2001;21:285–289. [PubMed]
639. Little J, Sharp L, Duthie S, Narayanan S. Colon cancer and genetic variation in folate metabolism: the clinical bottom line. J Nutr. 2003;133:3758S–3766S. [PubMed]
640. Chang SC, Lin PC, Lin JK, Yang SH, Wang HS, Li AF. Role of MTHFR polymorphisms and folate levels in different phenotypes of sporadic colorectal cancers. Int J Colorectal Dis. 2007;22:483–489. [PubMed]

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