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Mol Cell Biol. 1999 January; 19(1): 1–11.

c-Myc Target Genes Involved in Cell Growth, Apoptosis, and Metabolism

The c-myc gene was discovered as the cellular homolog of the retroviral v-myc oncogene 20 years ago (23, 25, 167). The c-myc proto-oncogene was subsequently found to be activated in various animal and human tumors (37, 39, 42). It belongs to the family of myc genes that includes B-myc, L-myc, N-myc, and s-myc; however, only c-myc, L-myc, and N-myc have neoplastic potential (54, 82, 102, 118, 178). Targeted homozygous deletion of the murine c-myc gene results in embryonic lethality, suggesting that it is critical for development (43). Homozygous inactivation of c-myc in rat fibroblasts caused a marked prolongation of cell doubling time, further suggesting a central role for c-myc in regulating cell proliferation (121).

The frequency of genetic alterations of c-myc in human cancers (42) has allowed an estimation that approximately 70,000 U.S. cancer deaths per year are associated with changes in the c-myc gene or its expression. Given that c-myc may contribute to one-seventh of U.S. cancer deaths, recent efforts have been directed toward understanding the function of the c-Myc protein in cancer biology with the hope that therapeutic insights will emerge. Past efforts, which have contributed significantly to our current understanding of c-myc, are discussed in a number of excellent reviews (23, 29, 37, 40, 44, 52, 66, 82, 94, 102, 118, 125, 132, 145, 178, 182, 186).


In human cancers, the c-myc gene is activated through several mechanisms. Unlike the normal c-myc gene, whose expression is under exquisitely fine control, translocations that juxtapose the c-myc proto-oncogene at chromosome 8q24 to one of three immunoglobulin genes on chromosome 2, 14, or 22 in B cells activate the c-myc gene and thereby promote the genesis of lymphoid malignancies (37, 118). Similarly, the murine c-myc proto-oncogene is activated through chromosomal translocations in pristane-induced murine plasmacytomas (140). Indeed, transgenic animals that overexpress c-myc in lymphoid cells or other tissues succumb to lymphomas or other tumors (1, 159, 174). The c-myc gene is amplified in various human cancers, including lung carcinoma (107), breast carcinoma (120, 128), and rare cases of colon carcinoma (9). In addition, elevated expression of the c-myc gene is found in almost one-third of breast and colon carcinomas (49, 50). Recent evidence suggests that activation of c-myc gene expression is central to signal transduction through the adenomatous polyposis coli (APC) tumor suppressor protein which negatively regulates β-catenin (Fig. (Fig.1)1) (80). β-Catenin is a coactivator for the transcription factor Tcf, which is able to directly activate c-myc expression, so that when APC is inactivated, activation of β-catenin results. The activities of human transforming proteins BCR-ABL (2, 158) and TEL-PDGFR (31) and proto-oncogenes c-src (13) and Wnt (33) have been shown to depend on the c-myc gene (Fig. (Fig.1).1). In retrospect, the emergence of c-myc as a central oncogenic switch in human cancers might have been predicted by the ability of the oncogenic retroviral v-myc gene to cause the rapid development of a variety of tumors in infected chickens (23, 25).

FIG. 1
The c-myc gene is a central oncogenic switch for oncogenes and the tumor suppressor APC. The APC tumor suppressor protein mediates the degradation of β-catenin. The Wnt oncoprotein is shown activating its receptor, which results in the stabilization ...

In addition to activation of the c-myc gene through deregulated expression, point mutations in the coding sequence have been found in translocated alleles of c-myc in Burkitt’s lymphomas (21, 22, 36, 203). These point mutations, which perhaps arose from somatic hypermutation in B cells, cluster in the transactivation domain of c-Myc around two major phosphorylation sites, one of which is also subject to O-linked glycosylation (Fig. (Fig.2)2) (34, 35, 71, 85, 110112). The consequence of these mutations is hypothesized to be abrogation of a negative regulation of c-Myc activity by phosphorylation of these sites, although hard evidence is still lacking (176). Alternatively, these mutations may prolong the half-lives of the mutant proteins, since the affected c-Myc regions have been implicated in the proteasome-mediated degradation of c-Myc (61).

FIG. 2
Association of factors to functional domains of the c-Myc protein. O-GlcNAc marks a glycosylation site. GSK3 and CDK mark phosphorylation sites. Max is depicted in association with c-Myc through the HLH-LZ motif; b is the basic region. NTS is the nuclear ...


The c-myc gene, located on human chromosome 8, is comprised of three exons (15). Translation of the major 64-kDa polypeptide is initiated at the canonical AUG start codon (exon 2), and a longer polypeptide of 67 kDa results from translation initiated 15 codons upstream of the AUG at a CUG codon (exon 1) (76). An internal translationally initiated c-Myc 45-kDa polypeptide was recently recognized (179).

The primary sequence of the c-Myc protein suggests that it contains a potential transactivation domain within its N-terminal 140 amino acids and a dimerization interface consisting of a helix-loop-helix leucine zipper (HLH/LZ) domain at its C-terminal end (Fig. (Fig.2).2). Evidence from fusion proteins consisting of GAL4 and c-Myc suggested that the c-Myc transactivation domain is localized to its first 143 amino acids (93). Immediately N terminal to the dimerization domain is a domain rich in basic amino acids which directly contacts specific DNA sequences within the DNA major groove (41, 45, 56, 57, 60, 143, 144, 185). c-Myc DNA binding sites (both canonical [5′-CACGTG-3′] and noncanonical) have been identified by using a variety of in vitro protein-DNA binding assays (26, 27, 144). The search for a Myc binding partner protein resulted in the breakthrough discovery of an HLH/LZ human Max protein by Blackwood and Eisenman (28, 29) and the murine Max homolog, Myn, by Prendergast et al. (142). Max, in contrast to Myc, does not contain a transactivation domain (95). Initial models proposed that Myc/Max heterodimers bind to target sites to transactivate genes via the Myc transactivation domain (Fig. (Fig.3).3). Max homodimers were thought to counter the function of the Myc/Max heterodimers through competitive binding to target DNA sites (29, 95); however, functional Max homodimers are not readily detectable in vivo (20, 97, 177).

FIG. 3
Models of c-Myc/Max and Mad/Max in transcriptional regulation. The c-Myc/Max heterodimer is shown at the top tethered to the E box 5′-CACGTG-3′. c-Myc contacts TBP, although the molecular mechanisms involved in c-Myc transactivation are ...

This simple model became more complex with the discovery of the Mad family of proteins, which were identified by their ability to bind Max (11, 8789, 205). The Mad (Fig. (Fig.3)3) proteins contain the Sin3-interacting domain motif (12, 160), which recruits Sin3, the transcriptional corepressor N-Cor, and proteins that have histone deacetylase activity (4, 81, 129). Histone deacetylation is currently thought to be the major mode of transcriptional silencing by the Mad proteins. The Sin3-intacting domain motif, when tethered to an HLH/LZ transcriptional factor, TFEB, that binds Myc DNA sites, is able to inhibit c-Myc-mediated cellular transformation (78). This observation suggests that HLH/LZ proteins have overlapping binding sites within target genes, contributing to another level of gene regulation.

Increased expression of Mad proteins is associated with cellular differentiation and growth arrest, suggesting that certain Mad family members behave as tumor suppressors. The chromosomal localization of the Mxi-1 (Mad 2) protein to 10q24 initially suggested that it is the key tumor suppressor gene in human glioblastomas, which display frequent loss of heterozygosity (LOH) at this region (47, 166, 196198). Although LOH of Mxi-1 at 10q24 is frequent, somatic mutations of Mxi-1 have not been found (3, 14, 46, 68, 96, 171). These findings are unable to confirm the observation that frequent mutations of the Mxi-1 gene occur in human prostate cancers (46). In contrast, the candidate 10q24 tumor suppressor PTEN gene was recently found to have LOH and somatic mutations in some cases of glioblastomas (105). To date, none of the Mad family members has been fully documented as a human tumor suppressor gene, although homozygous deletion of murine Mxi-1 potentiates skin tumor and lymphoma formation (161). Homozygous inactivation of Mad1 resulted in granulocyte differentiation abnormalities, supporting the role of Mad genes in cellular differentiation (62).


The c-Myc protein binds to and transactivates through consensus 5′-CACGTG-3′ sequences or E boxes in transient transfection experiments; however, the potency of transactivation by c-Myc pales when compared to those of other transcription factors, such as the HLH/LZ transcriptional factor USF, which also binds 5′-CACGTG-3′ (6, 7, 72, 98, 101). The variability of c-Myc transactivation has been questioned, and a study has provided evidence that endogenous levels of c-Myc may affect the outcome of transient-transfection experiments (101). Others suggest that the transactivation properties of c-Myc depend on whether the 64- or 67-kDa form is produced (75). The ability of c-Myc to interact with the TATA binding protein (TBP) and the transcriptional machinery (79, 85, 113, 123) may be modulated by its interaction with other factors, such as BIN1 (157), MIZ1 (138), PAM (73), p107 (17, 71, 74, 85), TFII-I (154), TRRAP (124), and YY1 (10, 172, 173) (Fig. (Fig.2).2). Understanding of how each of these proteins modulates the transcriptional activity of c-Myc requires further studies. Another as yet unresolved quagmire in the study of c-Myc is the inability to easily detect c-Myc gel shift activities in nuclear extracts of mammalian cells, although some progress has been achieved recently (108, 130, 177). Notwithstanding these unresolved concerns, evidence accumulated to date supports the model in which c-Myc is able to bind E boxes and transactivate genes.

In addition to its ability to activate transcription, c-Myc is able to repress transcription in in vitro transcription and transient-transfection assays (101, 106, 154). The in vitro data are compatible with the ability of c-Myc to inhibit transcription through the initiator or Inr element, which is a consensus transcriptional initiation motif found in certain gene promoters (175). Likewise, transfection studies using model promoter reporter constructs suggest that c-Myc is able to repress Inr-mediated transcription (100, 106, 138). c-Myc also represses genes that do not contain Inr sequences (202) and may modulate transcription through interactions with other transcription factors, such as C/EBP (127) or AP-2 (65). Since many genes bearing Inr sequences are differentiation marker genes, it is surmised that in addition to its ability to activate growth related genes through E boxes, c-Myc is also able to repress differentiation-related genes. The transcriptional repression function of c-Myc and its transactivation ability are both required for its transforming activity.


The mechanisms by which c-Myc induces neoplastic transformation and apoptosis are beginning to emerge with the identification of authentic target genes, both direct and indirect (Table (Table11 and Fig. Fig.4).4). A direct target gene is one whose expression is altered by direct interaction of the c-Myc protein with the gene regulatory elements or with trans-acting factors that bind these cis elements. The time course of induction of a direct target gene should closely follow the expression of Myc. The Myc-estrogen receptor (Myc-ER) fusion protein system has become a standard for establishing the direct regulation of a candidate target gene by c-Myc (48). In this system, the Myc-ER fusion protein is retained in the cytoplasm via chaperone proteins. Upon exposure of cells expressing the Myc-ER protein to estrogenic ligands, the ligand-bound fusion protein is translocated into the nucleus. The Myc-ER protein then activates Myc target genes without requiring new intervening protein synthesis. Thus, exposure of cells simultaneously to estrogenic compounds and cycloheximide will result in the activation or repression of direct target genes. An indirect target gene of c-Myc is one whose expression is altered as a consequence of expression of the direct Myc target genes and whose expression is connected to c-Myc-dependent phenotypes such as cellular proliferation, transformation, or apoptosis. The search for target genes usually implies identification of the direct targets; however, it stands to reason that indirect targets may provide the missing links between deregulated c-Myc expression and neoplastic transformation or apoptosis.

Putative c-Myc target genesa
FIG. 4
Links between c-Myc, selected putative target genes, cellular functions, and cell growth. This diagram illustrates the complexity of the connections between c-Myc and its putative target genes, which are shown clustered according to their functions. The ...

The study of target genes is confounded, however, by the fact that target genes are likely to be necessary, but not sufficient, for Myc-mediated phenotypes. The use of antisense technology or dominant negative alleles of target genes is a logical approach to the establishment of the necessity of a target gene for a Myc-associated phenotype. This experimental approach is limited, however, to the study of target genes whose disruption leads to drastic fundamental cellular changes such as markedly slowed growth, which poses a problem for the interpretation of other cellular phenotypes that depend on growth rates. If a Myc target gene is sufficient for a specific c-Myc-induced phenotype, it would be expected that expression of this target gene will induce this specific Myc-mediated phenotype. It is more likely, however, that subsets of target genes collaborate to mediate specific Myc-related phenotypes.

There are three major approaches to the identification of target genes. The first, the candidate target gene approach, is based on the biology of c-Myc. The second identifies genes that are differentially expressed as a result of enforced Myc expression. The third implicates genes whose regulatory elements contain c-Myc/Max binding sites.

Candidate direct and indirect c-Myc target genes are listed in Table Table1.1. The gene for ornithine decarboxylase (ODC) is an example of the power of the candidate gene approach. It contains potential Myc/Max binding sites and has been independently verified to be c-Myc responsive by different investigators (18, 131, 134, 136, 190, 200). It is instructive to note that the gene for ODC is inducible by both cycloheximide and c-Myc (133). This characteristic accounts for the biphasic response of ODC expression to growth factor stimulation and demonstrates a weakness in the use of the Myc-ER chimeric system as a criterion for direct target genes. In this case, the high basal cycloheximide induction of ODC can mask the effect of the Myc-ER activator.

Many genes have been implicated as c-Myc targets, although their roles in c-Myc-mediated phenotypes have not been determined. An approach to the cloning of a subset of mid-G1 serum response genes that are regulated by c-Myc was undertaken via differential screening (180). Included in the putative Myc targets from this study were known genes encoding ODC, lactate dehydrogenase A (LDH-A), α-prothymosin, and one novel gene with limited homology to methylenetetrahydrofolate synthetase. Another approach, using representational difference analysis as a differential cloning strategy, was undertaken to identify c-Myc-responsive genes (104) that are expressed differentially between normal and Myc-transformed Rat1a fibroblasts grown in suspension. Under these conditions, genes whose expression is anchorage dependent are expected to be diminished in nontransformed fibroblasts but may be induced by c-Myc in Myc-transformed cells. Twenty genes were identified, i.e., 17 that are upregulated and 3 that are downregulated by c-Myc. Studies using the Myc-ER fusion protein system are consistent with the idea that one novel gene, rcl, is a direct target of c-Myc. In fact, rcl overexpression in Rat1a cells induces the cell transformation phenotype of anchorage-independent growth, albeit to a lesser extent than c-Myc overexpression.

Studies of gene promoters have led to the recognition of the 5′-CACGTG-3′ E box in a variety of genes. It should be noted that this E box could be bound by HLH/LZ protein USF, TFE-3, or TFE-B in addition to c-Myc. Thus, the existence of Myc-type E boxes in promoter regions should include the possibility that USF, TFE-3, or TFE-B can act as the transactivator (16, 59, 69). Several promoters have been proposed to be c-Myc targets based on this criterion; dihydrofolate reductase (DHFR) and carbamoyl-phosphate synthase (CAD) both contain E2F as well as the Myc E-box sequences (116, 126). However, there is no other established regulatory link between DHFR and Myc. The promoter of the p53 gene was noted to contain an E box resembling a Myc binding site (148, 155). Although many genes have been proposed to be targets of c-Myc (Table (Table1),1), the biology of these putative targets (CAD or p53) in c-Myc-mediated neoplastic transformation or apoptosis is only beginning to emerge and needs further study.

A physical approach to the identification of potential c-Myc target genes was recently undertaken (67). In this approach, immunoprecipitation of isolated chromatin with anti-Myc and anti-Max antibodies allowed the identification of potential target sites of Myc/Max complexes. One of the targets identified is a pseudogene whose authentic counterpart, the MrDb RNA helicase, appears to be regulated by c-Myc. Furthermore, pitchoune, the Drosophila homolog of MrDb, appears to be genetically linked to dMyc, the Drosophila homolog of myc (204). Indeed, the use of Drosophila genetics to study links to the diminutive phenotype caused by mutant dMyc may provide an additional approach to the identification of c-Myc target genes that may ultimately be relevant to mammalian biology.


The role of c-Myc in the cell cycle has been a confusing area due to the collection of data from different experimental models, although it is well established that c-myc is an early serum response gene. It should be noted that models of serum or growth factor stimulation of starved cells primarily address the G0/G1 and G1/S transitions. Therefore, early studies implicated c-Myc in the G0/G1 transition (63). In cycling cells, however, the participation of c-Myc in the cell cycle may be different (5). Furthermore, in anchorage-dependent cell growth, c-Myc may affect other components of the cell cycle.

The emergence of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors as cell cycle regulators has provided some insights into c-Myc function (5). Regarding the regulation of G1, the connection between c-Myc and cyclin D1 is complex and may depend on specific stimuli and cell systems (152). Both c-myc and cyclin D1 are required for activation through the CSF1 receptor, and their relationship is nonlinear (153). With serum stimulation of fibroblasts, it is expected that c-Myc may activate the subsequent expression of cyclin D1; however, the role of c-Myc in regulating cyclin D1 expression is complex, since there are conflicting data in the literature (38, 139, 150).

Deregulated c-Myc expression is linked to increased cyclin A and increased cyclin E expression (38, 77, 84, 91). Recent evidence has been provided that c-Myc is able to transactivate the expression of cyclin E directly, although the mechanism is unclear (103, 137). c-Myc increases CDK function through several mechanisms. In one study, c-Myc appeared to cooperate with RAS to induce the CDC2 (CDK1) promoter, which does not contain a consensus Myc E box (30). There are no other data, however, that support the elevation of CDC2 in response to Myc. More recently, evidence has been provided that the cdc25A gene is a direct target of c-Myc (64). The connection between c-Myc and cdc25A has not been confirmed in other studies (5), indicating that differences in experimental models might account for the discrepancy. This gene produces a protein phosphatase that activates both CDK2 and CDK4. Thus, a direct link between c-Myc and the cell cycle machinery may exist through its ability to activate the cdc25A and cyclin E genes directly. c-Myc expression also decreases the levels and interferes with the function of the p27 CDK inhibitor (103, 137, 156, 188). The mechanism by which c-Myc interferes with p27 activity is not known. These activities of c-Myc are all compatible with the ability of c-Myc to promote cell entry into S phase.

The ability of c-Myc to promote cell proliferation suggests that its deregulation contributes to deregulated DNA synthesis and genomic instability (114, 115). Several studies suggest that deregulated c-Myc expression triggers genomic instability as measured by gene amplification or the rate of development of aneuploidy. These studies are intriguing but preliminary, and therefore, additional, confirmatory studies are required for greater appreciation of the role and mechanism of action of c-Myc in genomic instability.

The role of c-Myc in the cell cycle is further highlighted by the marked prolongation of the doubling time of cells in which both alleles of c-myc were eliminated by homologous recombination (121). Cell cycle distribution analysis showed that myc-null cells, which express neither L-myc nor N-myc, have prolonged G1 and G2 phases, whereas the S phase is normal. Cell sizes were normal at each phase of the cell cycle, suggesting that c-Myc has a generalized effect on cell growth. Independent studies using elutriated cells overexpressing Myc-ER suggest that there is inappropriate expression of cyclin E in the G1 phase, but this ectopic cyclin E expression is insufficient to bypass the requirement for proper cell size before entry into S phase (146). These observations suggest that a subset of c-Myc target genes is involved in biosynthetic and metabolic pathways that regulate cell size.


Cells studied as monolayers under experimental conditions do not reflect the three-dimensional growth of an avascular tumor, which is mimicked in soft-agar anchorage-independent growth assays. When a tumor grows to a detectable size, the local environment of the tumor cells often becomes heterogeneous. Microregions of larger tumors, as well as small (<1 mm) tumor nodules, have microecological niches in which there are major gradients of critical metabolites, such as oxygen, glucose, and other nutrients or growth factors. Chronic hypoxia occurs in tumor tissue that is more than 150 μm away from a functional blood supply, and thus, survival of tumors depends on their ability to adapt to hypoxic conditions and to recruit new blood microvessels through angiogenic factors. Tumor cells must adapt to hypoxic conditions as a crucial step in tumor progression. The ability of cancer cells to consume glucose as an energy source without oxygen and overproduce lactic acid aerobically, termed the Warburg effect, was recognized over 7 decades ago, although its molecular basis has been elusive (194, 195).

The basis for the Warburg effect is likely to include activated oncogenes, inactivated tumor suppressors, and the hypoxia-inducible transcription factor 1 HIF-1. Increases in glucose transport and hexokinase activities in cancer cells appear to account for the increased flux of glucose through the cancer cells (122, 135, 149). The gene for LDH-A, which participates in normal anaerobic glycolysis and is frequently increased in human cancers, was recently identified as a c-Myc-responsive target (170). LDH-A has been used as a marker of neoplastic transformation and was previously shown to be induced by hypoxia through the activity of HIF-1 (58, 163, 164, 192). It is noteworthy that c-Myc and HIF-1 binding sites resemble the carbohydrate response element, 5′-CACGTG-3′ (109, 168). In fact, transgenic animals constructed to overexpress c-Myc in the liver have increased glycolytic liver enzymes and also overproduce lactic acid (184). Stably transfected rodent fibroblasts that overexpress LDH-A alone or those transformed by c-Myc overproduce lactate, suggesting that LDH-A is sufficient to induce the Warburg effect (170). LDH-A overexpression is required for c-Myc-mediated transformation, since lowering its expression reduces the soft-agar clonogenicity of c-Myc-transformed fibroblasts, as well as c-Myc-transformed human lymphoblastoid cells and Burkitt’s lymphoma cells.

In addition to the potential role of glycolysis in the transformed phenotype, glycolysis is elevated 20-fold after an initial increase in c-Myc expression during normal T-lymphocyte mitogenesis (70). The increased glycolytic rate results from elevated expression of numerous glycolytic enzymes (including LDH-A) and is thought to reduce oxygen radical damage from oxidative phosphorylation as cells enter S phase (32).

Other putative target genes of c-Myc, such as those that encode CAD (126), ODC (18), DHFR (116), and thymidine kinase (TK) (147), are involved in DNA metabolism and, hence, affect the G1/S transition. CAD performs the first three rate-limiting steps of pyrimidine biosynthesis, whereas ODC participates in the synthesis of polyamines which are required for the activities of enzymes involved in nucleotide biosynthesis. It is noteworthy that a study of selected Myc target genes in myc-null fibroblasts revealed that only the expression of the gene for CAD was significantly decreased compared to its expression in wild-type fibroblasts (162a). While this observation confirms the contention that CAD is a downstream effector of Myc, it also raises a cautionary note on the use of these myc-null cells. Given that Myc is central to cell growth, its elimination by homologous recombination might only be tolerated by a minority of cells that have an inherent compensatory increase in critical c-Myc target genes. As such, expression of genes that are not essential for cell growth might not be increased in cells that tolerate homozygous elimination of myc. DHFR catalyzes the reduction of folate, a step that is necessary for the subsequent methylation of uridylate to produce thymidylate. TK catalyzes the conversion of thymidine to thymidylate.

The involvement of c-Myc in metabolism is further suggested by the roles of the target genes encoding translational regulatory factors eIF-2α (151) and eIF-4E (92, 151) and ECA39 (19), which has been implicated in amino acid transport (162). These connections between c-Myc and cellular metabolism suggest that it is the central integrator of cell proliferation and metabolism. From this vantage point, it is not surprising, in retrospect, that the role of c-Myc in cell growth has been elusive.


c-Myc-induced apoptosis was recognized initially in studies of the 32D.3 myeloid progenitor cell line (8). These cells are dependent on interleukin-3 for c-myc expression and growth, and enforced c-myc expression has no effect on 32D.3 under normal growth conditions. In the absence of IL-3, however, enforced c-myc expression continues to drive cells into S phase and accelerates the rate of cell death. Serum-deprived Rat1 fibroblasts overexpressing c-Myc or expressing activated MycER also undergo dramatic apoptosis (53). This apoptotic pathway appears to be dependent on the activity of wild-type p53 (83, 189) and might be related to an activated Fas/APO-1 (86) pathway. Glucose deprivation of c-Myc-overexpressing cells was recently found to induce extensive apoptosis that is p53 independent and may be linked to increased LDH-A expression (169). The Bcl-2 oncogene is able to protect Myc-overexpressing cells from either serum or glucose deprivation-induced apoptosis (24, 55, 169, 191).

Since the regions of c-Myc required for transcriptional regulation and cellular transformation are also those required for serum deprivation-induced apoptosis (53), it is surmised that c-Myc affects the transcription of genes which participate in apoptosis. ODC, the gene for which is probably the best characterized of the Myc targets, also induces apoptosis, albeit less effectively than Myc itself (134). The expression of cdc25A, however, appears to be necessary for c-Myc-induced apoptosis, since antisense cdc25A oligonucleotides block the serum deprivation-induced death of c-Myc-overexpressing cells (64). In contrast, overexpression of the rcl gene confers anchorage independence but does not predispose Rat1a cells to serum deprivation-induced apoptosis (104). These observations suggest that cellular transformation and apoptosis induced by c-Myc may occur through overlapping and nonoverlapping pathways.

Historically, c-Myc was touted to be an immortalizing gene, ectopic expression of which facilitates the immortalization of primary rodent fibroblasts. This simple view overlooked the initial events following ectopic c-Myc expression and the crisis period that cells must survive to achieve immortality. Since telomerase contributes to the immortality of tumor cells, the ability of increased expression of viral or cellular oncogenes to induce telomerase in normal human mammary epithelial cells and human fibroblasts (IMR-90) was studied (193). Among six candidates, c-Myc emerged as a key switch for induction of telomerase activity, as well as expression of the catalytic subunit of telomerase, termed TERT. Intriguingly, whereas TERT increases the life-span of human mammary epithelial cells, overexpression of TERT was unable to prolong the life-span of IMR-90 cells. It should be noted, however, that the construct used in that study produces a TERT with a C-terminal epitope tag that may have compromised its activity. In contrast to epitope-tagged TERT, c-Myc is able to immortalize IMR-90 cells, even though these cells do not show stabilization of telomeres. These observations suggest an alternative mechanism for c-Myc-mediated immortalization, in addition to the induction of telomerase.

In collaboration with activated RAS, c-Myc was able to transform primary fibroblasts in the classic experiments of Weinberg and coworkers (99). In this role, c-Myc appears to inactivate cellular responses that are normally required for RAS-mediated growth inhibition, thereby switching the gene for RAS into a growth-promoting gene (165). Reciprocally, RAS is able to inhibit Myc-mediated apoptosis (51). Given that p19 ARF-null murine embryonic fibroblasts (MEFs) are immortal and can be transformed by oncogenic RAS independently of c-Myc, it was hypothesized that c-Myc might regulate ARF (206). Indeed, it has been demonstrated that ARF and p53 are induced by ectopic c-Myc expression in wild-type MEFs, triggering a replicative crisis and apoptosis. MEFs that survive myc overexpression and the crisis period sustain ARF loss or p53 mutations. MEFs that lack ARF or p53 showed a decreased apoptotic response to c-Myc overexpression. These observations indicate that ARF participates in a p53-dependent checkpoint that safeguards cells against oncogenic signals, such as overexpression of c-Myc. These new observations indicate that immortalization of primary cells by oncogenes is a complex phenomenon in which normal safeguard apoptotic mechanisms are inactivated, thereby allowing immortalized cells to emerge from a crisis period of massive cell death.


In conclusion, the c-Myc molecule has continued to emerge as a centerpiece and key to the many secrets of cancer biology. Recent studies suggest that c-Myc is able to activate the cell cycle machinery and its safeguards. Intriguingly, its ability to activate glycolysis suggests that in addition to triggering the cell cycle, c-Myc also sustains the fuel necessary to run the cell cycle machinery. Indeed, its ability to enhance the activities of specific enzymes involved in DNA metabolism and other metabolic pathways further suggests that it is a key molecular integrator of cell cycle machinery and cellular metabolism. The future of the study of c-Myc target genes lies in the use of arrayed gene expression analysis to determine the common and divergent patterns of c-Myc target gene expression in a variety of physiological and neoplastic conditions. The benefits from such advances in technology, however, will require the expertise of biologists who are able to tease out the roles of the target genes in producing the multitude of c-Myc-mediated phenotypes. The greatest challenge, however, is the development of a discipline that is capable of dynamically and comprehensively linking transcription factor activities to their target genes and, in turn, to cellular phenotypes.


I have relied on review articles and apologize for the omission of original references. Comments by L. Lee and D. Wechsler are greatly appreciated.

My original work was supported by NIH grants.


1. Adams J M, Cory S. Transgenic models of tumor development. Science. 1991;254:1161–1167. [PubMed]
2. Afar D E, Goga A, McLaughlin J, Witte O N, Sawyers C L. Differential complementation of Bcr-Abl point mutants with c-Myc. Science. 1994;264:424–426. [PubMed]
3. Albarosa R, DiDonato S, Finocchiaro G. Redefinition of the coding sequence of the MXI1 gene and identification of a polymorphic repeat in the 3′ non-coding region that allows the detection of loss of heterozygosity of chromosome 10q25 in glioblastomas. Hum Genet. 1995;95:709–711. [PubMed]
4. Alland L, Muhle R, Hou H, Jr, Potes J, Chin L, Schreiber-Agus N, DePinho R A. Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression. Nature. 1997;387:49–55. [PubMed]
5. Amati B, Alevizopoulos K, Vlach J. Myc and the cell cycle. Front Biosci. 1998;3:D250–D268. [PubMed]
6. Amati B, Dalton S, Brooks M W, Littlewood T D, Evan G I, Land H. Transcriptional activation by the human c-Myc oncoprotein in yeast requires interaction with Max. Nature. 1992;359:423–426. [PubMed]
7. Amin C, Wagner A J, Hay N. Sequence-specific transcriptional activation by Myc and repression by Max. Mol Cell Biol. 1993;13:383–390. [PMC free article] [PubMed]
8. Askew D S, Ashmun R A, Simmons B C, Cleveland J L. Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene. 1991;6:1915–1922. [PubMed]
9. Augenlicht L H, Wadler S, Corner G, Richards C, Ryan L, Multani A S, Pathak S, Benson A, Haller D, Heerdt B G. Low-level c-myc amplification in human colonic carcinoma cell lines and tumors: a frequent, p53-independent mutation associated with improved outcome in a randomized multi-institutional trial. Cancer Res. 1997;57:1769–1775. [PubMed]
10. Austen M, Cerni C, Luscher-Firzlaff J M, Luscher B. YY1 can inhibit c-Myc function through a mechanism requiring DNA binding of YY1 but neither its transactivation domain nor direct interaction with c-Myc. Oncogene. 1998;17:511–520. [PubMed]
11. Ayer D E, Kretzner L, Eisenman R N. Mad: a heterodimeric partner for Max that antagonizes Myc transcriptional activity. Cell. 1993;72:211–222. [PubMed]
12. Ayer D E, Lawrence Q A, Eisenman R N. Mad-Max transcriptional repression is mediated by ternary complex formation with mammalian homologs of yeast repressor Sin3. Cell. 1995;80:767–776. [PubMed]
13. Barone M V, Courtneidge S A. Myc but not Fos rescue of PDGF signalling block caused by kinase-inactive Src. Nature. 1995;378:509–512. [PubMed]
14. Bartsch D, Peiffer S L, Kaleem Z, Wells S, Jr, Goodfellow P J. Mxi1 tumor suppressor gene is not mutated in primary pancreatic adenocarcinoma. Cancer Lett. 1996;102:73–76. [PubMed]
15. Battey J, Moulding C, Taub R, Murphy W, Stewart T, Potter H, Lenoir G, Leder P. The human c-myc oncogene: structural consequences of translocation into the IgH locus in Burkitt lymphoma. Cell. 1983;34:779–787. [PubMed]
16. Beckmann H, Su L K, Kadesch T. TFE3: a helix-loop-helix protein that activates transcription through the immunoglobulin enhancer muE3 motif. Genes Dev. 1990;4:167–179. [PubMed]
17. Beijersbergen R L, Hijmans E M, Zhu L, Bernards R. Interaction of c-Myc with the pRb-related protein p107 results in inhibition of c-Myc-mediated transactivation. EMBO J. 1994;13:4080–4086. [PubMed]
18. Bello-Fernandez C, Packham G, Cleveland J L. The ornithine decarboxylase gene is a transcriptional target of c-Myc. Proc Natl Acad Sci USA. 1993;90:7804–7808. [PubMed]
19. Benvenisty N, Leder A, Kuo A, Leder P. An embryonically expressed gene is a target for c-Myc regulation via the c-Myc-binding sequence. Genes Dev. 1992;6:2513–2523. [PubMed]
20. Berberich S J, Cole M D. Casein kinase II inhibits the DNA-binding activity of Max homodimers but not Myc/Max heterodimers. Genes Dev. 1992;6:166–176. [PubMed]
21. Bhatia K, Huppi K, Spangler G, Siwarski D, Iyer R, Magrath I. Point mutations in the c-Myc transactivation domain are common in Burkitt’s lymphoma and mouse plasmacytoma. Nat Genet. 1993;5:56–61. [PubMed]
22. Bhatia K, Spangler G, Gaidano G, Hamdy N, Dalla-Favera R, Magrath I. Mutations in the coding region of c-myc occur frequently in acquired immunodeficiency syndrome-associated lymphomas. Blood. 1994;84:883–888. [PubMed]
23. Bishop J M. Retroviruses and cancer genes. Adv Cancer Res. 1982;37:1–32. [PubMed]
24. Bissonette R, Echeverri F, Mahboubi A, Green D. Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature. 1992;359:552–554. [PubMed]
25. Bister K, Jansen H W. Oncogenes in retroviruses and cells: biochemistry and molecular genetics. Adv Cancer Res. 1986;47:99–188. [PubMed]
26. Blackwell T K, Huang J, Ma A, Kretzner L, Alt F W, Eisenman R N, Weintraub H. Binding of Myc proteins to canonical and noncanonical DNA sequences. Mol Cell Biol. 1993;13:5216–5224. [PMC free article] [PubMed]
27. Blackwell T K, Kretzner L, Blackwood E M, Eisenman R N, Weintraub H. Sequence-specific DNA binding by the c-Myc protein. Science. 1990;250:1149–1151. [PubMed]
28. Blackwood E M, Eisenman R N. Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science. 1991;251:1211–217. [PubMed]
29. Blackwood E M, Kretzner L, Eisenman R N. Myc and Max function as a nucleoprotein complex. Curr Opin Genet Dev. 1992;2:227–235. [PubMed]
30. Born T L, Frost J A, Schönthal A, Prendergast G C, Feramisco J R. C-Myc cooperates with activated Ras to induce the cdc2 promoter. Mol Cell Biol. 1994;14:5710–5718. [PMC free article] [PubMed]
31. Bourgeade M F, Defachelles A S, Cayre Y E. Myc is essential for transformation by TEL/platelet-derived growth factor receptor beta (PDGFRbeta) Blood. 1998;91:3333–3339. [PubMed]
32. Brand K A, Hermfisse U. Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species. FASEB J. 1997;11:388–395. [PubMed]
33. Cadigan K M, Nusse R. Wnt signaling: a common theme in animal development. Genes Dev. 1997;11:3286–3305. [PubMed]
34. Chou T Y, Dang C V, Hart G W. Glycosylation of the c-Myc transactivation domain. Proc Natl Acad Sci USA. 1995;92:4417–4421. [PubMed]
35. Chou T Y, Hart G W, Dang C V. c-Myc is glycosylated at threonine-58, a known phosphorylation site and a mutational hot spot in lymphomas. J Biol Chem. 1995;270:18961–18965. [PubMed]
36. Clark H M, Yano T, Otsuki T, Jaffe E S, Shibata D, Raffeld M. Mutations in the coding region of c-myc in AIDS-associated and other aggressive lymphomas. Cancer Res. 1994;54:3383–3386. [PubMed]
37. Cole M D. The myc oncogene: its role in transformation and differentiation. Annu Rev Genet. 1986;20:361–384. [PubMed]
38. Daksis J I, Lu R Y, Facchini L M, Marhin W W, Penn L J. Myc induces cyclin D1 expression in the absence of de novo protein synthesis and links mitogen-stimulated signal transduction to the cell cycle. Oncogene. 1994;9:3635–3645. [PubMed]
39. Dalla-Favera R, Gelmann E P, Martinotti S, Franchini G, Papas T S, Gallo R C, Wong-Staal F. Cloning and characterization of different human sequences related to the onc gene (v-myc) of avian myelocytomatosis virus (MC29) Proc Natl Acad Sci USA. 1982;79:6497–6501. [PubMed]
40. Dang C V. c-myc oncoprotein function. Biochim Biophys Acta. 1991;1072:103–113. [PubMed]
41. Dang C V, Dolde C, Gillison M L, Kato G J. Discrimination between related DNA sites by a single amino acid residue of Myc-related basic-helix-loop-helix proteins. Proc Natl Acad Sci USA. 1992;89:599–602. [PubMed]
42. Dang C V, Lee L A. c-Myc function in neoplasia. Austin, Tex: R. G. Landes and Springer-Verlag; 1995.
43. Davis A C, Wims M, Spotts G D, Hann S R, Bradley A. A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice. Genes Dev. 1993;7:671–682. [PubMed]
44. DePinho R A, Schreiber-Agus N, Alt F W. myc family oncogenes in the development of normal and neoplastic cells. Adv Cancer Res. 1991;57:1–46. [PubMed]
45. Dong Q P, Blatter E E, Ebright Y W, Bister K, Ebright R H. Identification of amino acid base contacts in the myc DNA complex by site-specific bromouracil mediated photocrosslinking. EMBO J. 1994;13:200–204. [PubMed]
46. Eagle L R, Yin X, Brothman A R, Williams B J, Atkin N B, Prochownik E V. Mutation of the MXI1 gene in prostate cancer. Nat Genet. 1995;9:249–255. [PubMed]
47. Edelhoff S, Ayer D E, Zervos A S, Steingrimsson E, Jenkins N A, Copeland N G, Eisenman R N, Brent R, Disteche C M. Mapping of two genes encoding members of a distinct subfamily of MAX interacting proteins: MAD to human chromosome 2 and mouse chromosome 6, and MXI1 to human chromosome 10 and mouse chromosome 19. Oncogene. 1994;9:665–668. [PubMed]
48. Eilers M, Schirm S, Bishop J M. The MYC protein activates transcription of the alpha-prothymosin gene. EMBO J. 1991;10:133–141. [PubMed]
49. Erisman M D, Rothberg P G, Diehl R E, Morse C C, Spandorfer J M, Astrin S M. Deregulation of c-myc gene expression in human colon carcinoma is not accompanied by amplification or rearrangement of the gene. Mol Cell Biol. 1985;5:1969–1976. [PMC free article] [PubMed]
50. Escot C, Theillet C, Lidereau R, Spyratos F, Champeme M H, Gest J, Callahan R. Genetic alteration of the c-myc protooncogene (MYC) in human primary breast carcinomas. Proc Natl Acad Sci USA. 1986;83:4834–4838. [PubMed]
51. Evan G, Littlewood T. A matter of life and cell death. Science. 1998;281:1317–1322. [PubMed]
52. Evan G I, Littlewood T D. The role of c-myc in cell growth. Curr Opin Genet Dev. 1993;3:44–49. [PubMed]
53. Evan G I, Wyllie A H, Gilbert C S, Littlewood T D, Land H, Brooks M, Waters C M, Penn L Z, Hancock D C. Induction of apoptosis in fibroblasts by c-myc protein. Cell. 1992;69:119–128. [PubMed]
54. Facchini L M, Penn L Z. The molecular role of Myc in growth and transformation: recent discoveries lead to new insights. FASEB J. 1998;12:633–651. [PubMed]
55. Fanidi A, Harrington E A, Evan G I. Cooperative interaction between c-myc and bcl-2 proto-oncogenes. Nature. 1992;359:554–556. [PubMed]
56. Ferre-D’Amare A R, Pognonec P, Roeder R G, Burley S K. Structure and function of the b/HLH/Z domain of USF. EMBO J. 1994;13:180–189. [PubMed]
57. Ferre-D’Amare A R, Prendergast G C, Ziff E B, Burley S K. Recognition by Max of its cognate DNA through a dimeric b/HLH/Z domain. Nature. 1993;363:38–45. [PubMed]
58. Firth J D, Ebert B L, Ratcliffe P J. Hypoxic regulation of lactate dehydrogenase A. Interaction between hypoxia-inducible factor 1 and cAMP response elements. J Biol Chem. 1995;270:21021–21027. [PubMed]
59. Fisher D E, Carr C S, Parent L A, Sharp P A. TFEB has DNA-binding and oligomerization properties of a unique helix-loop-helix/leucine-zipper family. Genes Dev. 1991;5:2342–2352. [PubMed]
60. Fisher F, Jayaraman P S, Goding C R. C-myc and the yeast transcription factor PHO4 share a common CACGTG-binding motif. Oncogene. 1991;6:1099–1104. [PubMed]
61. Flinn E M, Busch C M C, Wright A P H. myc boxes, which are conserved in myc family proteins, are signals for protein degradation via the proteasome. Mol Cell Biol. 1998;18:5961–5969. [PMC free article] [PubMed]
62. Foley K P, McArthur G A, Queva C, Hurlin P J, Soriano P, Eisenman R N. Targeted disruption of the MYC antagonist MAD1 inhibits cell cycle exit during granulocyte differentiation. EMBO J. 1998;17:774–785. [PubMed]
63. Freytag S O. Enforced expression of the c-myc oncogene inhibits cell differentiation by precluding entry into a distinct predifferentiation state in G0/G1. Mol Cell Biol. 1988;8:1614–1624. [PMC free article] [PubMed]
64. Galaktionov K, Chen X, Beach D. Cdc25 cell-cycle phosphatase as a target of c-myc. Nature. 1996;382:511–517. [PubMed]
65. Gaubatz S, Imho F A, Dosch R, Werne R O, Mitchell P, Buettne R R, Eilers M. Transcriptional activation by Myc is under negative control by the transcription factor AP-2. EMBO J. 1995;14:1508–1519. [PubMed]
66. Grandori C, Eisenman R N. Myc target genes. Trends Biochem Sci. 1997;22:177–181. [PubMed]
67. Grandori C, Mac J, Siebelt F, Ayer D E, Eisenman R N. Myc-Max heterodimers activate a DEAD box gene and interact with multiple E box-related sites in vivo. EMBO J. 1996;15:4344–4357. [PubMed]
68. Gray I C, Phillips S M, Lee S J, Neoptolemos J P, Weissenbach J, Spurr N K. Loss of the chromosomal region 10q23-25 in prostate cancer. Cancer Res. 1995;55:4800–4803. [PubMed]
69. Gregor P D, Sawadogo M, Roeder R G. The adenovirus major late transcription factor USF is a member of the helix-loop-helix group of regulatory proteins and binds to DNA as a dimer. Genes Dev. 1990;4:1730–1740. [PubMed]
70. Greiner E F, Guppy M, Brand K. Glucose is essential for proliferation and the glycolytic enzyme induction that provokes a transition to glycolytic energy production. J Biol Chem. 1994;269:31484–31490. [PubMed]
71. Gu W, Bhatia K, Magrath I T, Dang C V, Dalla-Favera R. Binding and suppression of the Myc transcriptional activation domain by p107. Science. 1994;264:251–254. [PubMed]
72. Gu W, Cechova K, Tassi V, Dalla-Favera R. Opposite regulation of gene transcription and cell proliferation by c-Myc and Max. Proc Natl Acad Sci USA. 1993;90:2935–2939. [PubMed]
73. Guo Q, Xie J, Dang C V, Liu E T, Bishop J M. Identification of a large Myc-binding protein that contains RCC1-like repeats. Proc Natl Acad Sci USA. 1998;95:9172–9177. [PubMed]
74. Haas K, Staller P, Geisen C, Bartek J, Eilers M, Moroy T. Mutual requirement of CDK4 and Myc in malignant transformation: evidence for cyclin D1/CDK4 and p16INK4A as upstream regulators of Myc. Oncogene. 1997;15:179–192. [PubMed]
75. Hann S R, Dixit M, Sears R C, Sealy L. The alternatively initiated c-Myc proteins differentially regulate transcription through a noncanonical DNA-binding site. Genes Dev. 1994;8:2441–2452. [PubMed]
76. Hann S R, Sloan-Brown K, Spotts G D. Translational activation of the non-AUG-initiated c-myc 1 protein at high cell densities due to methionine deprivation. Genes Dev. 1992;6:1229–1240. [PubMed]
77. Hanson K D, Shichiri M, Follansbee M R, Sedivy J M. Effects of c-myc expression on cell cycle progression. Mol Cell Biol. 1994;14:5748–5755. [PMC free article] [PubMed]
78. Harper S E, Qiu Y, Sharp P A. Sin3 corepressor function in Myc-induced transcription and transformation. Proc Natl Acad Sci USA. 1996;93:8536–8540. [PubMed]
79. Hateboer G, Timmers H T, Rustgi A K, Billaud M, van’t Veer L J, Bernards R. TATA-binding protein and the retinoblastoma gene product bind to overlapping epitopes on c-Myc and adenovirus E1A protein. Proc Natl Acad Sci USA. 1993;90:8489–8493. [PubMed]
80. He T C, Sparks A B, Rago C, Hermeking H, Zawel L, da Costa L T, Morin P J, Vogelstein B, Kinzler K W. Identification of c-MYC as a target of the APC pathway. Science. 1998;281:1509–1512. [PubMed]
81. Heinzel T, Lavinsky R M, Mullen T M, Soderstrom M, Laherty C D, Torchia J, Yang W M, Brard G, Ngo S D, Davie J R, Seto E, Eisenman R N, Rose D W, Glass C K, Rosenfeld M G. A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature. 1997;387:43–48. [PubMed]
82. Henriksson M, Luscher B. Proteins of the Myc network: essential regulators of cell growth and differentiation. Adv Cancer Res. 1996;68:109–182. [PubMed]
83. Hermeking H, Eick D. Mediation of c-myc-induced apoptosis by p53. Science. 1994;265:2091–2093. [PubMed]
84. Hoang A T, Cohen K J, Barrett J F, Bergstrom D A, Dang C V. Participation of cyclin A in Myc-induced apoptosis. Proc Natl Acad Sci USA. 1994;91:6875–6879. [PubMed]
85. Hoang A T, Lutterbach B, Lewis B C, Yano T, Chou T-Y, Barrett J F, Raffeld M, Hann S R, Dang C V. A link between increased transforming activity of lymphoma-derived MYC mutant alleles, their defective regulation by p107, and altered phosphorylation of the c-Myc transactivation domain. Mol Cell Biol. 1995;15:4031–4042. [PMC free article] [PubMed]
86. Hueber A, Zornig M, Lyon D, Suda T, Nagata S, Evan G I. Requirement for the CD95 receptor-ligand pathway in c-Myc-induced apoptosis. Science. 1997;278:1305–1309. [PubMed]
87. Hurlin P J, Foley K P, Ayer D E, Eisenman R N, Hanahan D, Arbeit J M. Regulation of Myc and Mad during epidermal differentiation and HPV-associated tumorigenesis. Oncogene. 1995;11:2487–2501. [PubMed]
88. Hurlin P J, Queva C, Eisenman R N. Mnt, a novel Max-interacting protein, is coexpressed with Myc in proliferating cells and mediates repression at Myc binding sites. Genes Dev. 1997;11:44–58. [PubMed]
89. Hurlin P J, Queva C, Koskinen P J, Steingrimsson E, Ayer D E, Copeland N G, Jenkins N A, Eisenman R N. Mad3 and Mad4: novel Max-interacting transcriptional repressors that suppress c-myc dependent transformation and are expressed during neural and epidermal differentiation. EMBO J. 1995;14:5646–5659. [PubMed]
90. Inghirami G, Grignani F, Sternas L, Lombardi L, Knowles D M, Dalla-Favera R. Down-regulation of LFA-1 adhesion receptors by c-myc oncogene in human B lymphoblastoid cells. Science. 1990;250:682–686. [PubMed]
91. Jansen-Durr P, Meichle A, Steiner P, Pagano M, Finke D, Botz J, Wessbecher J, Draetta G, Eilers M. Differential modulation of cyclin gene expression by MYC. Proc Natl Acad Sci USA. 1993;90:3685–3689. [PubMed]
92. Jones R M, Branda J, Johnston K A, Polymenis M, Gadd M, Rustgi A, Callanan L, Schmidt E V. An essential E box in the promoter of the gene encoding the mRNA cap-binding protein (eukaryotic initiation factor 4E) is a target for activation by c-myc. Mol Cell Biol. 1996;16:4754–4764. [PMC free article] [PubMed]
93. Kato G J, Barrett J, Villa-Garcia M, Dang C V. An amino-terminal c-Myc domain required for neoplastic transformation activates transcription. Mol Cell Biol. 1990;10:5914–5920. [PMC free article] [PubMed]
94. Kato G J, Dang C V. Function of the c-Myc oncoprotein. FASEB J. 1992;6:3065–3072. [PubMed]
95. Kato G J, Lee W M, Chen L L, Dang C V. Max: functional domains and interaction with c-Myc. Genes Dev. 1992;6:81–92. [PubMed]
96. Kawamata N, Park D, Wilczynski S, Yokota J, Koeffler H P. Point mutations of the Mxi1 gene are rare in prostate cancers. Prostate. 1996;29:191–193. [PubMed]
97. Koskinen P J, Vastrik I, Makela T P, Eisenman R N, Alitalo K. Max activity is affected by phosphorylation at two nh2-terminal sites. Cell Growth Differ. 1994;5:313–320. [PubMed]
98. Kretzner L, Blackwood E M, Eisenman R N. Myc and Max proteins possess distinct transcriptional activities. Nature. 1992;359:426–429. [PubMed]
99. Land H, Parada L F, Weinberg R A. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature. 1983;304:596–602. [PubMed]
100. Lee L A, Dolde C, Barrett J, Wu C S, Dang C V. A link between c-Myc-mediated transcriptional repression and neoplastic transformation. J Clin Investig. 1996;97:1687–1695. [PMC free article] [PubMed]
101. Lee L A, Resar L M, Dang C V. Cell density and paradoxical transcriptional properties of c-Myc and Max in cultured mouse fibroblasts. J Clin Investig. 1995;95:900–904. [PMC free article] [PubMed]
102. Lemaitre J M, Buckle R S, Mechali M. c-Myc in the control of cell proliferation and embryonic development. Adv Cancer Res. 1996;70:95–144. [PubMed]
103. Leone G, DeGregori J, Sears R, Jakoi L, Nevins J R. Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F. Nature. 1997;387:422–426. [PubMed]
104. Lewis B C, Shim H, Li Q, Wu C S, Lee L A, Maity A, Dang C V. Identification of putative c-Myc-responsive genes: characterization of rcl, a novel growth-related gene. Mol Cell Biol. 1997;17:4967–4978. [PMC free article] [PubMed]
105. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang S I, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner S H, Giovanella B C, Ittmann M, Tycko B, Hibshoosh H, Wigler M H, Parsons R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275:1943–1947. [PubMed]
106. Li L H, Nerlov C, Prendergast G, MacGregor D, Ziff E B. c-Myc represses transcription in vivo by a novel mechanism dependent on the initiator element and Myc box II. EMBO J. 1994;13:4070–4079. [PubMed]
107. Little C D, Nau M M, Carney D N, Gazdar A F, Minna J D. Amplification and expression of the c-myc oncogene in human lung cancer cell lines. Nature. 1983;306:194–196. [PubMed]
108. Littlewood T D, Amati B, Land H, Evan G I. Max and c-Myc/Max DNA-binding activities in cell extracts. Oncogene. 1992;7:1783–1792. [PubMed]
109. Liu Z, Thompson K S, Towle H C. Carbohydrate regulation of the rat L-type pyruvate kinase gene requires two nuclear factors: LF-A1 and a member of the c-myc family. J Biol Chem. 1993;268:12787–12795. [PubMed]
110. Luscher B, Eisenman R N. Mitosis-specific phosphorylation of the nuclear oncoproteins Myc and Myb. J Cell Biol. 1992;118:775–784. [PMC free article] [PubMed]
111. Luscher B, Kuenzel E A, Krebs E G, Eisenman R N. Myc oncoproteins are phosphorylated by casein kinase II. EMBO J. 1989;8:1111–1119. [PubMed]
112. Lutterbach B, Hann S R. Hierarchical phosphorylation at N-terminal transformation-sensitive sites in c-Myc protein is regulated by mitogens and in mitosis. Mol Cell Biol. 1994;14:5510–5522. [PMC free article] [PubMed]
113. Maheswaran S, Lee H, Sonenshein G E. Intracellular association of the protein product of the c-myc oncogene with the TATA-binding protein. Mol Cell Biol. 1994;14:1147–1152. [PMC free article] [PubMed]
114. Mai S, Fluri M, Siwarski D, Huppi K. Genomic instability in MycER-activated Rat1A-MycER cells. Chromosome Res. 1996;4:365–371. [PubMed]
115. Mai S, Hanley-Hyde J, Fluri M. c-Myc overexpression associated DHFR gene amplification in hamster, rat, mouse and human cell lines. Oncogene. 1996;12:277–288. [PubMed]
116. Mai S, Jalava A. C-myc binds to 5′ flanking sequence motifs of the dihydrofolate reductase gene in cellular extracts—role in proliferation. Nucleic Acids Res. 1994;22:2264–2273. [PMC free article] [PubMed]
117. Mai S, Martensson I L. The c-myc protein represses the lambda 5 and TdT initiators. Nucleic Acids Res. 1995;23:1–9. [PMC free article] [PubMed]
118. Marcu K, Bossone S, Patel A. Myc function and regulation. Annu Rev Biochem. 1992;61:809–860. [PubMed]
119. Marhin W W, Chen S, Facchini L M, Fornace A J, Jr, Penn L Z. Myc represses the growth arrest gene gadd45. Oncogene. 1997;14:2825–2834. [PubMed]
120. Mariani-Costantini R, Escot C, Theillet C, Gentile A, Merlo G, Lidereau R, Callahan R. In situ c-myc expression and genomic status of the c-myc locus in infiltrating ductal carcinomas of the breast. Cancer Res. 1988;48:199–205. [PubMed]
121. Mateyak M K, Obaya A J, Adachi S, Sedivy J M. Phenotypes of c-Myc-deficient rat fibroblasts isolated by targeted homologous recombination. Cell Growth Differ. 1997;8:1039–1048. [PubMed]
122. Mathupala S P, Rempel A, Pedersen P L. Glucose catabolism in cancer cells. Isolation, sequence, and activity of the promoter for type II hexokinase. J Biol Chem. 1995;270:16918–16925. [PubMed]
123. McEwan I J, Dahlman-Wright K, Ford J, Wright A P H. Functional interactions of the c-Myc transactivation domain with the TATA binding protein: evidence for an induced fit model of transactivation domain folding. Biochemistry. 1996;35:9584–9593. [PubMed]
124. McMahon S B, Van Buskirk H A, Dugan K A, Copeland T D, Cole M D. The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins. Cell. 1998;94:363–374. [PubMed]
125. Meichle A, Philipp A, Eilers M. The functions of Myc proteins. Biochim Biophys Acta. 1992;1114:129–146. [PubMed]
126. Miltenberger R J, Sukow K A, Farnham P J. An E-box-mediated increase in cad transcription at the G1/S-phase boundary is suppressed by inhibitory c-Myc mutants. Mol Cell Biol. 1995;15:2527–2535. [PMC free article] [PubMed]
127. Mink S, Mutschler B, Weiskirchen R, Bister K, Klempnauer K H. A novel function for Myc: inhibition of C/EBP-dependent gene activation. Proc Natl Acad Sci USA. 1996;93:6635–6640. [PubMed]
128. Munzel P, Marx D, Kochel H, Schauer A, Bock K W. Genomic alterations of the c-myc protooncogene in relation to the overexpression of c-erbB2 and Ki-67 in human breast and cervix carcinomas. J Cancer Res Clin Oncol. 1991;117:603–607. [PubMed]
129. Nagy L, Kao H Y, Chakravarti D, Lin R J, Hassig C A, Ayer D E, Schreiber S L, Evans R M. Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell. 1997;89:373–380. [PubMed]
130. Nozaki N, Naoe T, Okazaki T. Immunoaffinity purification and characterization of CACGTG sequence-binding proteins from cultured mammalian cells using an anti-c-Myc monoclonal antibody recognizing the DNA-binding domain. J Biochem. 1997;121:550–559. [PubMed]
131. Packham G, Bellofernandez C, Cleveland J L. Position and orientation independent transactivation by c-Myc. Cell Mol Biol Res. 1994;40:699–706. [PubMed]
132. Packham G, Cleveland J L. c-Myc and apoptosis. Biochim Biophys Acta. 1995;1242:11–28. [PubMed]
133. Packham G, Cleveland J L. Induction of ornithine decarboxylase by IL-3 is mediated by sequential c-Myc-independent and c-Myc-dependent pathways. Oncogene. 1997;15:1219–1232. [PubMed]
134. Packham G, Cleveland J L. Ornithine decarboxylase is a mediator of c-Myc-induced apoptosis. Mol Cell Biol. 1994;14:5741–5747. [PMC free article] [PubMed]
135. Pedersen P L. Tumor mitochondria and the bioenergetics of cancer cells. Prog Exp Tumor Res. 1978;22:190–274. [PubMed]
136. Pena A, Reddy C D, Wu S, Hickok N J, Reddy E P, Yumet G, Soprano D R, Soprano K J. Regulation of human ornithine decarboxylase expression by the c-Myc.Max protein complex. J Biol Chem. 1993;268:27277–27285. [PubMed]
137. Perez-Roger I, Solomon D L C, Sewing A, Land H. Myc activation of cyclin E/Cdk2 kinase involves induction of cyclin E gene transcription and inhibition of p27Kip1 binding to newly formed complexes. Oncogene. 1997;14:2373–2381. [PubMed]
138. Peukert K, Staller P, Schneider A, Carmichael G, Hanel F, Eilers M. An alternative pathway for gene regulation by Myc. EMBO J. 1997;16:5672–5686. [PubMed]
139. Philipp A, Schneider A, Väsrik I, Finke K, Xiong Y, Beach D, Alitalo K, Eilers M. Repression of cyclin D1: a novel function of MYC. Mol Cell Biol. 1994;14:4032–4043. [PMC free article] [PubMed]
140. Potter M, Wiener F. Plasmacytomagenesis in mice: model of neoplastic development dependent upon chromosomal translocations. Carcinogenesis. 1992;13:1681–1697. [PubMed]
141. Prendergast G C, Diamond L E, Dahl D, Cole M D. The c-myc-regulated gene mr1 encodes plasminogen activator inhibitor 1. Mol Cell Biol. 1990;10:1265–1269. [PMC free article] [PubMed]
142. Prendergast G C, Lawe D, Ziff E B. Association of Myn, the murine homolog of max, with c-Myc stimulates methylation-sensitive DNA binding and ras cotransformation. Cell. 1991;65:395–407. [PubMed]
143. Prendergast G C, Ziff E B. DNA-binding motif. Nature. 1989;341:392. [PubMed]
144. Prendergast G C, Ziff E B. Methylation-sensitive sequence-specific DNA binding by the c-Myc basic region. Science. 1991;251:186–189. [PubMed]
145. Prendergast G C, Ziff E B. A new bind for Myc. Trends Genet. 1992;8:91–96. [PubMed]
146. Pusch O, Bernaschek G, Eilers M, Hengstschlager M. Activation of c-Myc uncouples DNA replication from activation of G1-cyclin-dependent kinases. Oncogene. 1997;15:649–656. [PubMed]
147. Pusch O, Soucek T, Hengstschlager-Ottnad E, Bernaschek G, Hengstschlager M. Cellular targets for activation by c-Myc include the DNA metabolism enzyme thymidine kinase. DNA Cell Biol. 1997;16:737–747. [PubMed]
148. Reisman D, Elkind N, Roy B, Beamon J, Rotter V. c-Myc transactivates the p53 promoter through a required downstream CACGTG motif. Cell Growth Differ. 1993;4:57–65. [PubMed]
149. Rempel A, Mathupala S P, Griffin C A, Hawkins A L, Pedersen P L. Glucose catabolism in cancer cells: amplification of the gene encoding type II hexokinase. Cancer Res. 1996;56:2468–2471. [PubMed]
150. Rosenwald I B, Lazariskaratzas A, Sonenberg N, Schmidt E V. Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E. Mol Cell Biol. 1993;13:7358–7363. [PMC free article] [PubMed]
151. Rosenwald I B, Rhoads D B, Callanan L D, Isselbacher K J, Schmidt E V. Increased expression of eukaryotic translation initiation factors eIF-4E and eIF-2 alpha in response to growth induction by c-myc. Proc Natl Acad Sci USA. 1993;90:6175–6178. [PubMed]
152. Roussel M F. Key effectors of signal transduction and G1 progression. Adv Cancer Res. 1998;74:1–24. [PubMed]
153. Roussel M F, Theodoras A M, Pagano M, Sherr C J. Rescue of defective mitogenic signaling by D-type cyclins. Proc Natl Acad Sci USA. 1995;92:6837–6841. [PubMed]
154. Roy A L, Carruthers C, Gutjahr T, Roeder R G. Direct role for Myc in transcription initiation mediated by interactions with TFII-I. Nature. 1993;365:359–361. [PubMed]
155. Roy B, Beamon J, Balint E, Reisman D. Transactivation of the human p53 tumor suppressor gene by c-Myc/Max contributes to elevated mutant p53 expression in some tumors. Mol Cell Biol. 1994;14:7805–7815. [PMC free article] [PubMed]
156. Rudolph B, Saffrich R, Zwicker J, Henglein B, Muller R, Ansorge W, Eilers M. Activation of cyclin-dependent kinases by Myc mediates induction of cyclin A, but not apoptosis. EMBO J. 1996;15:3065–3076. [PubMed]
157. Sakamuro D, Elliott K J, Wechsler-Reya R, Prendergast G C. BIN1 is a novel MYC-interacting protein with features of a tumour suppressor. Nat Genet. 1996;14:69–77. [PubMed]
158. Sawyers C L, Callahan W, Witte O N. Dominant negative MYC blocks transformation by ABL oncogenes. Cell. 1992;70:901–910. [PubMed]
159. Schoenenberger C A, Andres A C, Groner B, van der Valk M, LeMeur M, Gerlinger P. Targeted c-myc gene expression in mammary glands of transgenic mice induces mammary tumours with constitutive milk protein gene transcription. EMBO J. 1988;7:169–175. [PubMed]
160. Schreiber-Agus N, Chin L, Chen K, Torres R, Rao G, Guida P, Skoultchi A I, DePinho R A. An amino-terminal domain of Mxi1 mediates anti-Myc oncogenic activity and interacts with a homolog of the yeast transcriptional repressor SIN3. Cell. 1995;80:777–786. [PubMed]
161. Schreiber-Agus N, Meng Y, Hoang T, Hou H J, Chen K, Greenberg R, Cordon-Cardo C, Lee H, DePinho R. Role of Mxi1 in ageing organ systems and the regulation of normal and neoplastic growth. Nature. 1998;393:483–487. [PubMed]
162. Schuldiner O, Eden A, Ben-Yosef T, Yanuka O, Simchen G, Benvenisty N. ECA39, a conserved gene regulated by c-Myc in mice, is involved in G1/S cell cycle regulation in yeast. Proc Natl Acad Sci USA. 1996;93:7143–7148. [PubMed]
162a. Sedivy, J. M. Personal communication.
163. Semenza G L, Jiang B H, Leung S W, Passantino R, Concordet J P, Maire P, Giallongo A. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem. 1996;271:32529–32537. [PubMed]
164. Semenza G L, Roth P H, Fang H M, Wang G L. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem. 1994;269:23757–23763. [PubMed]
165. Serrano M, Lin A W, McCurrach M E, Beach D, Lowe S W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88:593–602. [PubMed]
166. Shapiro D N, Valentine V, Eagle L, Yin X, Morris S W, Prochownik E V. Assignment of the human MAD and MXI1 genes to chromosomes 2p12-p13 and 10q24-q25. Genomics. 1994;23:282–285. [PubMed]
167. Sheiness D, Fanshier L, Bishop J M. Identification of nucleotide sequences which may encode the oncogenic capacity of avian retrovirus MC29. J Virol. 1978;28:600–610. [PMC free article] [PubMed]
168. Shih H M, Liu Z, Towle H C. Two CACGTG motifs with proper spacing dictate the carbohydrate regulation of hepatic gene transcription. J Biol Chem. 1995;270:21991–21997. [PubMed]
169. Shim H, Chun Y S, Lewis B C, Dang C V. A unique glucose-dependent apoptotic pathway induced by c-Myc. Proc Natl Acad Sci USA. 1998;95:1511–1516. [PubMed]
170. Shim H, Dolde C, Lewis B C, Wu C S, Dang G, Jungmann R A, Dalla-Favera R, Dang C V. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci USA. 1997;94:6658–6663. [PubMed]
171. Shimizu E, Shirasawa H, Kodama K, Sato T, Simizu B. Expression, regulation and polymorphism of the mxi1 genes. Gene. 1996;176:45–48. [PubMed]
172. Shrivastava A, Saleque S, Kalpana G V, Artandi S, Goff S P, Calame K. Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc. Science. 1993;262:1889–1892. [PubMed]
173. Shrivastava A, Yu J, Artandi S, Calame K. YY1 and c-Myc associate in vivo in a manner that depends on c-Myc levels. Proc Natl Acad Sci USA. 1996;93:10638–10641. [PubMed]
174. Skoda R C, Tsai S F, Orkin S H, Leder P. Expression of c-MYC under the control of GATA-1 regulatory sequences causes erythroleukemia in transgenic mice. J Exp Med. 1995;181:1603–1613. [PMC free article] [PubMed]
175. Smale S T, Baltimore D. The “initiator” as a transcription control element. Cell. 1989;57:103–113. [PubMed]
176. Smith-Sorensen B, Hijmans E M, Beijersbergen R L, Bernards R. Functional analysis of Burkitt’s lymphoma mutant c-Myc proteins. J Biol Chem. 1996;271:5513–5518. [PubMed]
177. Sommer A, Bousset K, Kremmer E, Austen M, Luscher B. Identification and characterization of specific DNA-binding complexes containing members of the Myc/Max/Mad network of transcriptional regulators. J Biol Chem. 1998;273:6632–6642. [PubMed]
178. Spencer C A, Groudine M. Control of c-myc regulation in normal and neoplastic cells. Adv Cancer Res. 1991;56:1–48. [PubMed]
179. Spotts G D, Patel S V, Xiao Q, Hann S R. Identification of downstream-initiated c-Myc proteins which are dominant-negative inhibitors of transactivation by full-length c-Myc proteins. Mol Cell Biol. 1997;17:1459–1468. [PMC free article] [PubMed]
180. Tavtigian S V, Zabludoff S D, Wold B J. Cloning of mid-G1 serum response genes and identification of a subset regulated by conditional myc expression. Mol Biol Cell. 1994;5:375–388. [PMC free article] [PubMed]
181. Tikhonenko A T, Black D J, Linial M L. Viral Myc oncoproteins in infected fibroblasts down-modulate thrombospondin-1, a possible tumor suppressor gene. J Biol Chem. 1996;271:30741–30747. [PubMed]
182. Torres R, Schreiber-Agus N, Morgenbesser S D, DePinho R A. Myc and Max: a putative transcriptional complex in search of a cellular target. Curr Opin Cell Biol. 1992;4:468–474. [PubMed]
183. Tsuneoka M, Nakano F, Ohgusu H, Mekada E. c-myc activates RCC1 gene expression through E-box elements. Oncogene. 1997;14:2301–2311. [PubMed]
184. Valera A, Pujol A, Gregori X, Riu E, Visa J, Bosch F. Evidence from transgenic mice that myc regulates hepatic glycolysis. FASEB J. 1995;9:1067–1078. [PubMed]
185. Van Antwerp M E, Chen D G, Chang C, Prochownik E V. A point mutation in the MyoD basic domain imparts c-Myc-like properties. Proc Natl Acad Sci USA. 1992;89:9010–9014. [PubMed]
186. Vastrik I, Makela T P, Koskinen P J, Klefstrom J, Alitalo K. Myc protein: partners and antagonists. Crit Rev Oncog. 1994;5:59–68. [PubMed]
187. Versteeg R, Noordermeer I, Kruse-Wolters M, Ruiter D, Schrier P. c-myc down-regulates class I HLA expression in human melanomas. EMBO J. 1988;7:1023–1029. [PubMed]
188. Vlach J, Hennecke S, Alevizopoulos K, Conti D, Amati B. Growth arrest by the cyclin-dependent kinase inhibitor p27Kip1 is abrogated by c-Myc. EMBO J. 1996;15:6595–6604. [PubMed]
189. Wagner A J, Kokontis J M, Hay N. Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1. Genes Dev. 1994;8:2817–2830. [PubMed]
190. Wagner A J, Meyers C, Laimins L A, Hay N. c-Myc induces the expression and activity of ornithine decarboxylase. Cell Growth Differ. 1993;4:879–883. [PubMed]
191. Wagner A J, Small M B, Hay N. Myc-mediated apoptosis is blocked by ectopic expression of Bcl-2. Mol Cell Biol. 1993;13:2432–2440. [PMC free article] [PubMed]
192. Wang G L, Jiang B H, Rue E A, Semenza G L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA. 1995;92:5510–5514. [PubMed]
193. Wang J, Xie L Y, Allan S, Beach D, Hannon G J. Myc activates telomerase. Genes Dev. 1998;12:1769–1774. [PubMed]
194. Warburg O. The Metabolism of tumours. London, England: Constable; 1930.
195. Warburg O. On the origin of cancer cells. Science. 1956;123:309–314. [PubMed]
196. Wechsler D S, Hawkins A L, Li X, Jabs E W, Griffin C A, Dang C V. Localization of the human Mxi1 transcription factor gene (MXI1) to chromosome 10q24-q25. Genomics. 1994;21:669–672. [PubMed]
197. Wechsler D S, Shelly C A, Dang C V. Genomic organization of human MXI1, a putative tumor suppressor gene. Genomics. 1996;32:466–470. [PubMed]
198. Wechsler D S, Shelly C A, Petroff C A, Dang C V. MXI1, a putative tumor suppressor gene, suppresses growth of human glioblastoma cells. Cancer Res. 1997;57:4905–4912. [PubMed]
199. Weihua X, Lindner D J, Kalvakolanu D V. The interferon-inducible murine p48 (ISGF3gamma) gene is regulated by protooncogene c-myc. Proc Natl Acad Sci USA. 1997;94:7227–7232. [PubMed]
200. Wu S, Pena A, Korcz A, Soprano D R, Soprano K J. Overexpression of Mxi1 inhibits the induction of the human ornithine decarboxylase gene by the Myc/Max protein complex. Oncogene. 1996;12:621–629. [PubMed]
201. Yang B-S, Geddes T J, Pogulis R J, de Crombrugghe B, Freytag S O. Transcriptional suppression of cellular gene expression by c-Myc. Mol Cell Biol. 1991;11:2291–2295. [PMC free article] [PubMed]
202. Yang B-S, Gilbert J D, Freytag S O. Overexpression of Myc suppresses CCAAT transcription factor/nuclear factor 1-dependent promoters in vivo. Mol Cell Biol. 1993;13:3093–3102. [PMC free article] [PubMed]
203. Yano T, Sander C, Clark H, Dolezal M, Jaffe E, Raffeld M. Clustered mutations in the second exon of the MYC gene in sporadic Burkitt’s lymphoma. Oncogene. 1993;8:2741–2748. [PubMed]
204. Zaffran S, Chartier A, Gallant P, Astier M, Arquier N, Doherty D, Gratecos D, Semeriva M. A Drosophila RNA helicase gene, pitchoune, is required for cell growth and proliferation and is a potential target of d-Myc. Development. 1998;125:3571–3584. [PubMed]
205. Zervos A S, Gyuris J, Brent R. Mxi1, a protein that specifically interacts with Max to bind Myc-Max recognition sites. Cell. 1993;72:223–232. [PubMed]
206. Zindy F, Eischen C M, Randle D H, Kamijo T, Cleveland J L, Sherr C J, Roussel M F. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev. 1998;12:2424–2433. [PubMed]

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