PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jnaJournal's HomeManuscript SubmissionAims and ScopeAuthor GuidelinesEditorial BoardHome
 
J Nucleic Acids. 2012; 2012: 687359.
Published online Oct 9, 2011. doi:  10.1155/2012/687359
PMCID: PMC3191818
p53 Family: Role of Protein Isoforms in Human Cancer
Jinxiong Wei, Elena Zaika, and Alexander Zaika *
Department of Surgery and Cancer Biology, Vanderbilt University Medical Center, 1255 Light Hall, 2215 Garland Avenue, Nashville, TN 37232, USA
*Alexander Zaika: alex.zaika/at/vanderbilt.edu
Academic Editor: Didier Auboeuf
Received April 29, 2011; Accepted July 4, 2011.
Abstract
TP53, TP63, and TP73 genes comprise the p53 family. Each gene produces protein isoforms through multiple mechanisms including extensive alternative mRNA splicing. Accumulating evidence shows that these isoforms play a critical role in the regulation of many biological processes in normal cells. Their abnormal expression contributes to tumorigenesis and has a profound effect on tumor response to curative therapy. This paper is an overview of isoform diversity in the p53 family and its role in cancer.
Alternative splicing allows a single gene to express multiple protein variants. It is estimated that 92–95% of human multiexon genes undergo alternative splicing [1, 2]. Abnormal alterations of splicing may interfere with normal cellular homeostasis and lead to cancer development [35].
The p53 protein family is comprised of three transcription factors: p53, p63, and p73. Phylogenetic analysis revealed that this family originated from a p63/73-like ancestral gene early in metazoan evolution [6, 7]. Maintenance of genetic stability of germ cells seems to be its ancestral function [8]. The p53 family regulates many vital biological processes, including cell differentiation, proliferation, and cell death/apoptosis [9, 10]. Dysregulation of the p53 family plays a critical role in tumorigenesis and significantly affects tumor response to therapy. This review summarizes current data on the regulation of p53, p63, and p73 isoforms and their roles in cancer.
p53, p63, and p73 genes are located on chromosomes 17p13.1, 3q27-29, and 1p36.2-3, respectively. These genes encode proteins with similar domain structures and significant amino acid sequence homology in the transactivation, DNA-binding and oligomerization domains (Figure 1). The highest amino acid identity is in the DNA-binding domain (~60%). Evolutionally, this domain is the most conserved, suggesting that regulation of transcription plays a pivotal role in an array of functions attributed to the p53 family. Less similarity is found in the oligomerization and transactivation domains (~30%).
Figure 1
Figure 1
Architectures of human TP53, TP73, and TP63 genes. (A) TP53, TP73, and TP63 genes encode the transactivation (TAD), DNA-binding (DBD), and oligomerization (OD) domains. TP73 and TP63 encode additional SAM (Sterile Alpha Motif) domain. Percentage homology (more ...)
The founding member of the p53 family, the p53 protein, had been discovered more than three decades ago [12, 13]. For a long time, it had been assumed that p53 is expressed as a single polypeptide. However, when it had been found that the p63 and p73 genes encoded a large variety of diverse transcripts, the p53 gene transcription was revisited. Now we know that p53 forms multiple variants.
Transcriptions of p53, p63, and p73 genes are regulated by similar mechanisms. It is controlled by two promoters: P1 and P2, where P2 is an alternative intragenic promoter (Figure 1). One study in silico provided evidence for the existence of a third putative promoter in the first intron of human TP73 gene [14]. Therefore, it would not be surprising if additional gene promoters will be found in the future. An extensive alternative splicing adds further diversity to the promoters' products. The produced transcripts and proteins can be generally categorized into two main groups, termed TA and ΔN [15, 16]. TA variants contain the N-terminal transactivation domain while ΔN isoforms lack the entire (or part of) domain. It was initially thought that ΔN isoforms are only generated by the P2 promoter whereas the P1 promoter regulates TA isoforms. Further analysis of alternative mRNA splicing revealed that some transcriptionally deficient isoforms are products of the P1 promoter. For example, the P1 promoter of the TP73 gene regulates TAp73 isoforms and isoforms, which lack the TA domain: ΔEx2p73, ΔEx2/3p73, and ΔN′p73. The latter isoforms are missing either exon 2 (ΔEx2p73) or both exon 2 and 3 (ΔEx2/3p73) or contain an additional exon 3′ (ΔN′p73) [17, 18]. Other ΔNp73 transcripts are products of the P2 promoter. Similar to p73, the P1 promoter of the p53 gene produces transcriptionally active isoforms [5]. The alternative splicing is responsible for transcriptionally deficient isoforms of Δ40p53, which missing the first 40 amino acids at the N-terminus [5, 19, 20]. Additional p53 transcriptionally deficient isoforms (Δ133p53 and Δ160p53) are regulated by the P2 promoter located in intron 4 of the p53 gene [5, 21].
Additional diversity of p53, p63, and p73 transcripts is generated by alternative splicing at the 3′ end of the transcripts (Figure 1). These splice variants are traditionally named with letters of the Greek alphabet. Initially, three such splice variants have been described for p63 and p53 (α, β, γ), and nine for p73 (α, β, γ, δ, ε, θ, ζ, η, and η1) [2225]. Later, additional p63 splice variants (δ, ε) and p53 (δ, ε, ζ, ΔE6) were reported [2628]. However, it should be noted that a majority of p53, p63, and p73 studies focus on a few isoforms, primarily α, β, and γ. Little is known about the functions of other isoforms. The combination of alternative splicing at the 5′ and 3′ ends, alternative initiation of translation and alternative promoter usage can significantly increase protein diversity. For example, N-terminal variants (p53, Δ40p53, Δ133p53, and Δ160p53) can be produced in α, β, and γ “flavors” [20, 21]. Theoretically, the p53 gene can produce at least 20 isoforms, p63 at least 10, and p73 more than 40, though not all have been experimentally confirmed.
p53, TAp63, and TAp73 share significant functional resemblance. They can induce cell cycle arrest, apoptosis, or cellular senescence. This similarity can be explained, at least in part, by transactivation of the same transcriptional targets. Genome-wide analyses found an overlap of the transcription profiles of p53, TAp73, and TAp63, though unique targets were identified as well. Analyses using chromatin immunoprecipitation, reporter, and gel-shift assays found that TAp73 and TAp63 interact with p53-responsive elements.
The transactivation and apoptotic potential of p53, TAp73, and TAp63 vary greatly depending on the isoform. TAp63γ and TAp73β are similar to that of p53α [29]. Other isoforms are considered less active on the p53 target gene promoters [9, 23, 30]. Some isoforms are characterized by a variation in domain structure. TAp73α and TAp63α have an additional domain at the COOH-terminus that is not found in p53. This domain, termed SAM or Sterile Alpha Motif, is responsible for protein-protein interactions and is found in a diverse range of proteins that are involved in developmental regulation. It is also implicated in transcriptional repression [31]. Beta and gamma isoforms of p53 are missing most of the oligomerization domain that results in decreased transcriptional activity [5, 32, 33].
ΔN isoforms function as dominant-negative inhibitors of TA counterparts (Figure 2). Promoter competition and heterocomplex formation have been suggested to explain this phenomenon [17, 34, 35]. In the promoter competition mechanism, the suggestion is that ΔN competes off TA isoforms from their target gene promoters, thus preventing efficient transcription. In the heterocomplex formation mechanism, ΔN isoforms would inhibit TA by forming hetero-oligomeric complexes.
Figure 2
Figure 2
Interactions of p53 family isoforms. N-terminally truncated isoforms of p53, p73, and p63 play a dominant-negative role inhibiting transcriptional and other biological activities of TA isoforms.
ΔN isoforms of p53 and p73 are regulated by a negative feedback loop mechanism. Analogous mechanism was not described for p63 despite its significant similarity to p73. In a nutshell, TA isoforms are able to induce transcription of ΔN isoforms by activating P2 promoters. The induced ΔN isoforms, in turn, inhibit TA isoforms. A good example of these interactions is an induction of Δ133p53 by p53 [5, 3638]. Similarly, TAp73 and p53 are important regulators of transcriptions of ΔNp73 [39]. It appears that the balance between ΔN and TA isoforms is finely tuned to regulate the activities of TA isoforms. The net effect of these interactions in a given context appears to be dependent on the TA/ΔN expression ratio. Deregulation of this mechanism may lead to tumor development [4042]. However, it has become clear that the role of ΔN isoforms is multifaceted. The dominant negative concept cannot explain the complexity of all the interactions attributed to ΔN isoforms. Several studies reported that ΔN isoforms can retain transcription activity through additional transactivation domains.
Although many aspects of p53 biology have been thoroughly investigated, the role and regulation of p53 isoforms remain not well understood.
Recent studies suggested that Δ133p53 isoform may play an oncogenic role. Mice overexpressing the Δ122p53 isoform (murine homolog of human Δ133p53) show reduced apoptosis, increased cell proliferation and develop a wide-spectrum of aggressive tumors including lymphoma, osteosarcoma, and other malignant and benign tumors [43]. Another phenotypic characteristic of these mice is elevated cytokine levels in the blood and widespread inflammation in many organs. Interestingly, transgenic expression of another p53 isoform, Δ40p53, does not lead to tumor formation in mice, but is associated with a short life span, cognitive decline, and overt diabetes, suggesting a significant difference between these isoforms [4446].
Several studies reported an elevated expression of Δ133p53 in tumors (Table 1). In breast tumors, 24 of 30 cases showed an increased expression of Δ133p53, but low or undetectable levels in normal breast tissue [5]. An increase of Δ133p53α mRNA was also found in renal cell carcinoma [47]. In colon tumors, progression from colon adenoma to carcinoma is accompanied by an increase of Δ133p53 mRNA. This study suggested that Δ133p53 helps to escape from the senescence barrier during colon tumor progression [48]. Interestingly, the Δ133p53 expression level is associated with the mutation status of p53; colon tumors expressing wildtype p53 had higher levels of Δ133p53 than p53 mutant tumors [48]. In addition to Δ133p53, an increased expression of Δ40p53 was also reported in human melanoma cell lines and primary melanoma isolates [33]. However, not all tumors overexpress Δ133p53. Analysis of squamous carcinoma of the head and neck did not reveal any significant changes in the Δ133p53 levels, suggesting that this isoform may only play a tumor-promoting role in a subset of tissues [49].
Table 1
Table 1
Summary of alterations of the p53 family members in human cancers.
Alterations of p53β and p53γ isoforms were also reported in different types of cancers (Table 1). An increased expression of p53β was found in renal cell carcinoma and in most melanoma cell lines. In renal cell carcinoma, p53β expression was associated with tumor progression [47]. p53β was also found to correlate with worse recurrence-free survival in ovarian cancer patients with functionally active p53 [28]. Decreased p53β and p53γ mRNA levels were reported in breast cancer [5]. In breast tumors, p53β is associated with the expression of estrogen receptor but not with disease outcome [50]. Breast cancer patients expressing both mutant p53 and p53γ have lower cancer recurrence and favorable prognosis [51]. Currently, specific functions of p53β and p53γ remain unclear. A significant hurdle to the studies of p53 isoforms in tumors is the lack of isoform-specific antibodies. The generation of new antibodies, animal models, and additional tumor studies may help to better understand the role of p53 isoforms in tumorigenesis.
The role of p73 in tumorigenesis is still a matter of debate. In contrast to p53, p73 is rarely mutated and frequently overexpressed in human tumors [23, 5256]. An initial study of p73-deficient mice found a number of developmental defects and no spontaneous tumors [57]. Follow-up studies have revealed spontaneous tumorigenesis, although the late onset of tumors and smaller tumor sizes compared to p53-deficient animals were reported. The basis for these conflicting results in cancer susceptibility remains obscure but might be related to the animal genetic background and housing conditions. Mice with isoform-specific knockouts of p73 have also been generated; phenotypes of these animals generally reflect previously reported differences between p73 isoforms. TAp73 null mice are tumor prone while ΔNp73 knockouts have increased sensitivity to DNA-damaging agents and elevated p53-dependent apoptosis [58, 59].
Several studies have found that N-terminally truncated isoforms of p73 play an oncogenic role and are linked to cancer development (Table 1). Targeted transgenic overexpression of human ΔEx2/3p73 in the mouse liver resulted in the development of hepatocellular carcinoma [60]. The N-terminally truncated isoforms are upregulated in many human cancers including liver, ovarian, breast, vulvar cancers, and melanoma [23, 6168]. Overexpression of ΔEx2p73 and ΔEx2/3p73 was found to be associated with metastases in melanoma [68].
ΔNp73, which is produced by the P2 promoter, has also been found to behave as an oncogene. ΔNp73 facilitates immortalization of primary mouse embryonic fibroblasts and cooperates with oncogenic Ras in their transformation. These transformed cells produce tumors following a subcutaneous injection into nude mice [121, 122]. ΔNp73 also inhibits differentiation of myoblasts and protects them against apoptosis [123]. Studies by others and us found that ΔNp73 is upregulated in a number of tumors and is associated with metastases, chemotherapeutic failure, and poorer patient prognosis [62, 74, 96, 124130].
An important question is what causes deregulation of p73 isoforms in tumors? One of the mechanisms is tumor-specific alternative mRNA splicing. It has been demonstrated that the alternative splicing causes incorporation of a new exon 3' into TAp73 transcripts resulting in a translational switch from TAp73 to [increment]Np73 isoform [18, 61]. An interesting observation was also made in hepatocellular carcinoma where an aberrant switch from TAp73 to ΔEx2p73 was found to be mediated by the activation EGFR by amphiregulin. This leads to activation of JNK1 kinase, suppression of splicing factor Slu7, and alternative splicing of p73 transcripts [65]. Activated Ras has also been shown to decrease TAp73 levels and increase ΔNp73 expression during cellular transformation [131]. Abnormal regulation of the P2 promoter has also been reported. We found that transcriptional repressor HIC1 (Hypermethylated In Cancer 1) can suppress expression of ΔNp73 by inhibiting the P2 promoter in normal cells. Loss of HIC1 in esophagus and gastric cancer cells leads to up-regulation of ΔNp73 [96]. In a subset of tumors, abnormal epigenetic changes cause deregulation of p73 isoforms [132134]. Hypomethylation of the P2 promoter was found in more than half of non-small lung cancers [76].
An increased expression of TAp73 isoforms was also found in tumors, although its role remains unclear (Table 1). Several studies suggested that in specific circumstances TAp73 might play a tumor-promoting role [30, 135]. Interestingly, some tumors tend to increase a variety of p73 splice isoforms (Figure 3). In the normal colon and breast, p73α and p73β isoforms are predominant whereas other spliced variants (γ, δ, ϕ, and ε) are primarily detected in colon and breast cancers [15, 23]. This phenomenon was also observed in acute myeloid leukemia. Moreover, the p73ε isoform was only expressed in leukemic cells and completely absent in mature myeloid cells [136]. It is currently unclear what role these changes play in tumorigenesis.
Figure 3
Figure 3
An increased diversity of alternatively spliced species of p73 in colon adenocarcinoma. p73 gene transcription was analyzed in 10 colon tumors and normal colonic mucosa by RT-PCR. Normal specimen 2 represents 14 pooled normal samples. For details, see (more ...)
Similar to p73, mutations in the p63 gene are rare in human cancers [90, 137, 138]. Several studies reported that ΔNp63 has oncogenic properties. Ectopic overexpression of ΔNp63 in Rat-1A cells promotes colony formation in soft agar. When xenografted into immunocompromised mice, these cells formed tumors [139]. ΔNp63α inhibits oncogene-induced cellular senescence and cooperates with Ras to promote tumor-initiating stem-like proliferation [140]. Analysis of p63-deficient mice led to conflicting results with regard to the p63 role in tumorigenesis. p63−/− null mice showed striking developmental defects demonstrating a critical role of p63 in epithelial development [141, 142]. p63+/- heterozygous mice were shown to be susceptible to tumor development [143]. However, other mouse models were not consistent with this observation. Conflicting phenotypes of TAp63 and ΔNp63 transgenic mice have also been reported [144, 145].
ΔNp63 is a predominant isoform expressed in most epithelial cells. Overexpression of ΔNp63 is found in cancers of nasopharyngeal, head and neck, urinary tract, lung, and ovarian tumors and correlated with poor outcome [78, 146149]. In metastases, ΔNp63 expression was found to be reduced or lost [91, 101]. Microarray analyses revealed the up-regulation of genes associated with tumor invasion and metastasis in p63-deficient cells [150]. It was also reported that p63 suppresses the TGFβ-dependent cell migration, invasion, and metastasis [151]. This suggests that ΔNp63 plays a dual role by promoting tumor development but suppressing metastases [151, 152]. Expression of ΔNp63 was found to be associated with an increased chemoresistance in a subset of breast and head and neck tumors [153, 154].
TAp63 isoforms induce cellular senescence and inhibit cell proliferation [155157]. TAp63 deficiency increases proliferation and enhances Ras-mediated oncogenesis [155]. Decreased TAp63 expression is associated with metastasis in bladder and breast cancers as well as poor outcome [42, 90, 158]. TAp63 impedes the metastatic potential of epithelial tumors by controlling the expression of a crucial set of metastasis suppressor genes [151, 159].
Clearly, additional studies are needed to understand the complex regulation of p63 isoforms.
Interactions between members of the p53 family and their isoforms have a profound effect on tumorigenesis and anticancer drug response. Perhaps, the most studied are interactions between ΔN and TA isoforms. Inhibition of TAp73 by ΔNp63 has been shown to negatively affect the response to platinum-based chemotherapy in head and neck squamous cell carcinomas and a subset of breast tumors [153, 154]. In carcinomas of ovary and childhood acute lymphoblastic leukemia, increased expression of dominant-negative p73 isoforms correlates with resistance to conventional chemotherapy [129, 130]. Moreover, ΔNp73 is primarily expressed in ovarian tumors, which express wildtype p53 [64]. However, crosstalk between the p53 family members is not limited to dominant-negative interactions. Accumulating evidence suggests that the p53 family interacts on multiple levels comprising protein-protein interactions between multiple p53, p63, and p73 isoforms, shared regulation of target genes as well as TP53 and TP73 gene promoters [160163]. In addition, mutant p53 can affect activities of TAp73 and TAp63. It has been shown that certain tumor-derived p53 mutants (R175H, R248W, Y220C, R249S, R283H, and D281G) can physically associate and inhibit activation of TAp73 and/or TAp63 [164166].
Current analyses suggest that the function of a particular isoform needs to be investigated in the context of expression of other isoforms. For example, ΔNp73β inhibits p53-dependent apoptosis in primary sympathetic neurons [167], but when overexpressed in cancer cells, ΔNp73β induces cell cycle arrest and apoptosis [168].
An interesting observation has been made in mouse embryonic fibroblasts, where the combined loss of p73 and p63 results in the failure of p53 to induce apoptosis in response to DNA damage [169]. More recent studies have reported that the p53 family members can simultaneously co-occupy the promoters of p53 target genes and regulate their transcription [15, 170, 171]. Notably, the integral activity of the entire p53 family, as measured by reporter analysis, is a better predictor of chemotherapeutic drug response than p53 status alone [15].
The p53 family plays a pivotal role in the control of many critical cellular functions. In recent years, it has been revealed that all members of the p53 family are expressed as a diverse variety of isoforms. We only just started to uncover the mechanisms that regulate this diversity. A number of studies also provided the first glimpses of their functional significance. Clearly, isoforms add a new level of functional regulation to many critical biological processes including cell death, proliferation, cell cycle control, and tumorigenesis. Depending on the isoform expressed, the role of a gene can dramatically change from a tumor suppressor to an oncogene. It is also clear that p53, p73, and p63 isoforms tightly interact. A better understanding of this interacting network and its regulation holds the key to future therapeutic benefits.
Acknowledgments
The authors thank Dr. El-Rifai for the valuable discussions. This paper was supported by the National Cancer Institute Grants NIH CA138833 and NIH CA108956.
1. Wang ET, Sandberg R, Luo S, et al. Alternative isoform regulation in human tissue transcriptomes. Nature. 2008;456(7221):470–476. [PMC free article] [PubMed]
2. Pan Q, Shai Q, Lee LJ, Frey BJ, Blencowe BJ. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nature Genetics. 2008;40(12):1413–1415. [PubMed]
3. Klinck R, Bramard A, Inkel L, et al. Multiple alternative splicing markers for ovarian cancer. Cancer Research. 2008;68(3):657–663. [PubMed]
4. Venables JP, Klinck R, Koh C, et al. Cancer-associated regulation of alternative splicing. Nature Structural and Molecular Biology. 2009;16(6):670–676. [PubMed]
5. Bourdon JC, Fernandes K, Murray-Zmijewski F, et al. p53 isoforms can regulate p53 transcriptional activity. Genes and Development. 2005;19(18):2122–2137. [PubMed]
6. Dötsch V, Bernassola F, Coutandin D, Candi E, Melino G. p63 and p73, the ancestors of p53. Cold Spring Harbor perspectives in biology. 2010;2(9):p. a004887. [PMC free article] [PubMed]
7. Rutkowski R, Hofmann K, Gartner A. Phylogeny and function of the invertebrate p53 superfamily. Cold Spring Harbor Perspectives in Biology. 2010;2(7) Article ID a001131. [PMC free article] [PubMed]
8. Petre-Lazar B, Livera G, Moreno SG, et al. The role of p63 in germ cell apoptosis in the developing testis. Journal of Cellular Physiology. 2007;210(1):87–98. [PubMed]
9. Kaghad M, Bonnet H, Yang A, et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell. 1997;90(4):809–819. [PubMed]
10. Yang A, Kaghad M, Wang Y, et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Molecular Cell. 1998;2(3):305–316. [PubMed]
11. Melino G, Lu X, Gasco M, Crook T, Knight RA. Functional regulation of p73 and p63: development and cancer. Trends in Biochemical Sciences. 2003;28(12):663–670. [PubMed]
12. Lane DP, Crawford LV. T antigen is bound to a host protein in SV40 transformed cells. Nature. 1979;278(5701):261–263. [PubMed]
13. Linzer DIH, Levine AJ. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40 transformed cells and uninfected embryonal carcinoma cells. Cell. 1979;17(1):43–52. [PubMed]
14. Sayan AE, Rossi M, Melino G, Knight RA. p73: in silico evidence for a putative third promoter region. Biochemical and Biophysical Research Communications. 2004;313(3):765–770. [PubMed]
15. 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. Molecular Cancer Therapeutics. 2010;9(3):693–705. [PMC free article] [PubMed]
16. Yang A, McKeon F. p63 and p73: p53 mimics, menaces and more. Nature Reviews Molecular Cell Biology. 2000;1(3):199–207. [PubMed]
17. Stiewe T, Theseling CC, Pützer BM. Transactivation-deficient ΔTA-p73 inhibits p53 by direct competition for DNA binding. Implications for tumorigenesis. Journal of Biological Chemistry. 2002;277(16):14177–14185. [PubMed]
18. Ishimoto O, Kawahara C, Enjo K, Obinata M, Nukiwa T, Ikawa S. Possible oncogenic potential of ΔNp73: a newly identified isoform of human p73. Cancer Research. 2002;62(3):636–641. [PubMed]
19. Yin Y, Stephen CW, Luciani MG, Fåhraeus R. p53 stability and activity is regulated by Mdm2-mediated induction of alternative p53 translation products. Nature Cell Biology. 2002;4(6):462–467. [PubMed]
20. Courtois S, Verhaegh G, North S, et al. ΔN-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53. Oncogene. 2002;21(44):6722–6728. [PubMed]
21. Marcel V, Perrier S, Aoubala M, et al. Δ160p53 is a novel N-terminal p53 isoform encoded by Δ133p53 transcript. FEBS Letters. 2010;584(21):4463–4468. [PubMed]
22. Zaika A, Irwin M, Sansome C, Moll UM. Oncogenes induce and activate endogenous p73 protein. Journal of Biological Chemistry. 2001;276(14):11310–11316. [PubMed]
23. Zaika AI, Kovalev S, Marchenko ND, Moll UM. Overexpression of the wild type p73 gene in breast cancer tissues and cell lines. Cancer Research. 1999;59(13):3257–3263. [PubMed]
24. de Laurenzi V, Catani MV, Terrinoni A, et al. Additional complexity in p73: induction by mitogens in lymphoid cells and identification of two new splicing variants ε and ζ Cell Death and Differentiation. 1999;6(5):389–390. [PubMed]
25. Ueda Y, Hijikata M, Takagi S, Chiba T, Shimotohno K. New p73 variants with altered C-terminal structures have varied transcriptional activities. Oncogene. 1999;18(35):4993–4998. [PubMed]
26. Vanbokhoven H, Melino G, Candi E, Declercq W. p63, a story of mice and men. Journal of Investigative Dermatology. 2011;131(6):1196–1207. [PubMed]
27. Mangiulli M, Valletti A, Caratozzolo MF, et al. Identification and functional characterization of two new transcriptional variants of the human p63 gene. Nucleic Acids Research. 2009;37(18):6092–6104. [PMC free article] [PubMed]
28. Hofstetter G, Berger A, Fiegl H, et al. Alternative splicing of p53 and p73: the novel p53 splice variant p53 is an independent prognostic marker in ovarian cancer. Oncogene. 2010;29(13):1997–2004. [PubMed]
29. Dohn M, Zhang S, Chen X. p63α and ΔNp63α can induce cell cycle arrest and apoptosis and differentially regulate p53 target genes. Oncogene. 2001;20(25):3193–3205. [PubMed]
30. Tomkova K, Belkhiri A, El-Rifai W, Zaika AI. p73 isoforms can induce T-cell factor-dependent transcription in gastrointestinal cells. Cancer Research. 2004;64(18):6390–6393. [PubMed]
31. Sauer M, Bretz AC, Beinoraviciute-Kellner R, et al. C-terminal diversity within the p53 family accounts for differences in DNA binding and transcriptional activity. Nucleic Acids Research. 2008;36(6):1900–1912. [PMC free article] [PubMed]
32. Graupner V, Schulze-Osthoff K, Essmann F, Jänicke RU. Functional characterization of p53β and p53γ, two isoforms of the tumor suppressor p53. Cell Cycle. 2009;8(8):1238–1248. [PubMed]
33. Avery-Kiejda KA, Xu DZ, Adams LJ, et al. Small molecular weight variants of p53 are expressed in human melanoma cells and are induced by the DNA-damaging agent cisplatin. Clinical Cancer Research. 2008;14(6):1659–1668. [PubMed]
34. Nakagawa T, Takahashi M, Ozaki T, et al. Autoinhibitory regulation of p73 by ΔNp73 to modulate cell survival and death through a p73-specific target element within the ΔNp73 promoter. Molecular and Cellular Biology. 2002;22(8):2575–2585. [PMC free article] [PubMed]
35. Zaika AI, Slade N, Erster SH, et al. δNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors. Journal of Experimental Medicine. 2002;196(6):765–780. [PMC free article] [PubMed]
36. Moore HC, Jordan LB, Bray SE, et al. The RNA helicase p68 modulates expression and function of the Δ133 isoform(s) of p53, and is inversely associated with Δ133p53 expression in breast cancer. Oncogene. 2010;29(49):6475–6484. [PMC free article] [PubMed]
37. Marcel V, Vijayakumar V, Fernández-Cuesta L, et al. P53 regulates the transcription of its Δ133p53 isoform through specific response elements contained within the TP53 P2 internal promoter. Oncogene. 2010;29(18):2691–2700. [PubMed]
38. Aoubala M, Murray-Zmijewski F, Khoury MP, et al. p53 directly transactivates Δ133p53α, regulating cell fate outcome in response to DNA damage. Cell Death and Differentiation. 2010;18(2):248–258. [PMC free article] [PubMed]
39. Grob TJ, Novak U, Maisse C, et al. Human ΔNp73 regulates a dominant negative feedback loop for TAp73 and p53. Cell Death and Differentiation. 2001;8(12):1213–1223. [PubMed]
40. Arvanitis DA, Lianos E, Soulitzis N, Delakas D, Spandidos DA. Deregulation of p73 isoform equilibrium in benign prostate hyperplasia and prostate cancer. Oncology Reports. 2004;12(5):1131–1137. [PubMed]
41. Malaguarnera R, Vella V, Vigneri R, Frasca F. p53 family proteins in thyroid cancer. Endocrine-Related Cancer. 2007;14(1):43–60. [PubMed]
42. Iacono ML, Monica V, Saviozzi S, et al. p63 and p73 isoform expression in non-small cell lung cancer and corresponding morphological normal lung tissue. Journal of Thoracic Oncology. 2011;6(3):473–481. [PubMed]
43. Slatter TL, Hung N, Campbell H, et al. Hyperproliferation, cancer, and inflammation in mice expressing a Δ133p53-like isoform. Blood. 2011;117(19):5166–5177. [PubMed]
44. Maier B, Gluba W, Bernier B, et al. Modulation of mammalian life span by the short isoform of p53. Genes and Development. 2004;18(3):306–319. [PubMed]
45. Pehar M, O’Riordan KJ, Burns-Cusato M, et al. Altered longevity-assurance activity of p53 : p44 in the mouse causes memory loss, neurodegeneration and premature death. Aging Cell. 2010;9(2):174–190. [PMC free article] [PubMed]
46. Ungewitter E, Scrable H. Δ40p53 controls the switch from pluripotency to differentiation by regulating IGF signaling in ESCs. Genes and Development. 2010;24(21):2408–2419. [PubMed]
47. Song W, Huo SW, Lü JJ, et al. Expression of p53 isoforms in renal cell carcinoma. Chinese Medical Journal. 2009;122(8):921–926. [PubMed]
48. Fujita K, Mondal AM, Horikawa I, et al. p53 isoforms Δ133p53 and p53β are endogenous regulators of replicative cellular senescence. Nature Cell Biology. 2009;11(9):1135–1142. [PMC free article] [PubMed]
49. Boldrup L, Bourdon JC, Coates PJ, Sjöström B, Nylander K. Expression of p53 isoforms in squamous cell carcinoma of the head and neck. European Journal of Cancer. 2007;43(3):617–623. [PMC free article] [PubMed]
50. Bourdon J-C, Khoury MP, Diot A, et al. p53 mutant breast cancer patients expressing p53gamma have as good a prognosis as wild-type p53 breast cancer patients. Breast Cancer Research. 2011;13(1, article R7) [PMC free article] [PubMed]
51. Dugani CB, Paquin A, Fujitani M, Kaplan DR, Miller FD. p63 antagonizes p53 to promote the survival of embryonic neural precursor cells. Journal of Neuroscience. 2009;29(20):6710–6721. [PubMed]
52. Schwartz DI, Lindor NM, Walsh-Vockley C, et al. p73 mutations are not detected in sporadic and hereditary breast cancer. Breast Cancer Research and Treatment. 1999;58(1):25–29. [PubMed]
53. Kovalev S, Marchenko N, Swendeman S, LaQuaglia M, Moll UM. Expression level, allelic origin, and mutation analysis of the p73 gene in neuroblastoma tumors and cell lines. Cell Growth and Differentiation. 1998;9(11):897–903. [PubMed]
54. Mai M, Huang H, Reed C, et al. Genomic organization and mutation analysis of p73 in oligodendrogliomas with chromosome 1 p-arm deletions. Genomics. 1998;51(3):359–363. [PubMed]
55. Yokomizo A, Mai M, Tindall DJ, et al. Overexpression of the wild type p73 gene in human bladder cancer. Oncogene. 1999;18(8):1629–1633. [PubMed]
56. Nimura Y, Mihara M, Ichimiya S, et al. p73, a gene related to p53, is not mutated in esophageal carcinomas. International Journal of Cancer. 1998;78(4):437–440. [PubMed]
57. Yang A, Walker N, Bronson R, et al. p73-Deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature. 2000;404(6773):99–103. [PubMed]
58. Tomasini R, Tsuchihara K, Wilhelm M, et al. TAp73 knockout shows genomic instability with infertility and tumor suppressor functions. Genes and Development. 2008;22(19):2677–2691. [PubMed]
59. Wilhelm MT, Rufini A, Wetzel MK, et al. Isoform-specific p73 knockout mice reveal a novel role for ΔNp73 in the DNA damage response pathway. Genes and Development. 2010;24(6):549–560. [PubMed]
60. Tannapfel A, John K, Miše N, et al. Autonomous growth and hepatocarcinogenesis in transgenic mice expressing the p53 family inhibitor DNp73. Carcinogenesis. 2008;29(1):211–218. [PubMed]
61. Stiewe T, Tuve S, Peter M, Tannapfel A, Elmaagacli AH, Pützer BM. Quantitative TP73 transcript analysis in hepatocellular carcinomas. Clinical Cancer Research. 2004;10(2):626–633. [PubMed]
62. Domínguez G, García JM, Peña C, et al. ΔTAp73 upregulation correlates with poor prognosis in human tumors: putative in vivo network involving p73 isoforms, p53, and E2F-1. Journal of Clinical Oncology. 2006;24(5):805–815. [PubMed]
63. Fillippovich I, Sorokina N, Gatei M, et al. Transactivation-deficient p73α (p73Δexon2) inhibits apoptosis and competes with p53. Oncogene. 2001;20(4):514–522. [PubMed]
64. Concin N, Becker K, Slade N, et al. Transdominant ΔTAp73 isoforms are frequently up-regulated in ovarian cancer. Evidence for their role as epigenetic p53 inhibitors in vivo. Cancer Research. 2004;64(7):2449–2460. [PubMed]
65. Castillo J, Goñi S, Latasa MU, et al. Amphiregulin induces the alternative splicing of p73 into its oncogenic isoform ΔEx2p73 in human hepatocellular tumors. Gastroenterology. 2009;137(5):1805–1815, article e4. [PubMed]
66. Ng SW, Yiu GK, Liu Y, et al. Analysis of p73 in human borderline and invasive ovarian tumor. Oncogene. 2000;19(15):1885–1890. [PubMed]
67. O’Nions J, Brooks LA, Sullivan A, et al. p73 is over-expressed in vulval cancer principally as the δ2 isoform. British Journal of Cancer. 2001;85(10):1551–1556. [PMC free article] [PubMed]
68. Tuve S, Wagner SN, Schitrek B, Pützer BM. Alterations of ΔTA-p73 splice transcripts during melanoma development and progression. International Journal of Cancer. 2004;108(1):162–166. [PubMed]
69. Shishikura T, Ichimiya S, Ozaki T, et al. Mutational analysis of the p73 gene in human breast cancers. International Journal of Cancer. 1999;84(3):321–325. [PubMed]
70. Koker MM, Kleer CG. p63 expression in breast cancer: a highly sensitive and specific marker of metaplastic carcinoma. American Journal of Surgical Pathology. 2004;28(11):1506–1512. [PubMed]
71. Ribeiro-Silva A, Ramalho LNZ, Garcia SB, Zucoloto S. Does the correlation between EBNA-1 and p63 expression in breast carcinomas provide a clue to tumorigenesis in Epstein-Barr virus-related breast malignancies? Brazilian Journal of Medical and Biological Research. 2004;37(1):89–95. [PubMed]
72. Hanker L, Karn T, Ruckhaeberle E, et al. Clinical relevance of the putative stem cell marker p63 in breast cancer. Breast Cancer Research and Treatment. 2010;122(3):765–775. [PubMed]
73. Tokuchi Y, Hashimoto T, Kobayashi Y, et al. The expression of p73 is increased in lung cancer, independent of p53 gene alteration. British Journal of Cancer. 1999;80(10):1623–1629. [PMC free article] [PubMed]
74. Uramoto H, Sugio K, Oyama T, et al. Expression of ΔNp73 predicts poor prognosis in lung cancer. Clinical Cancer Research. 2004;10(20):6905–6911. [PubMed]
75. Di Vinci A, Sessa F, Casciano I, et al. Different intracellular compartmentalization of TA and ΔNp73 in non-small cell lung cancer. International Journal of Oncology. 2009;34(2):449–456. [PubMed]
76. Daskalos A, Logotheti S, Markopoulou S, et al. Global DNA hypomethylation-induced ΔNp73 transcriptional activation in non-small cell lung cancer. Cancer Letters. 2011;300(1):79–86. [PubMed]
77. Pelosi G, Pasini F, Stenholm CO, et al. p63 immunoreactivity in lung cancer: yet another player in the development of squamous cell carcinomas? Journal of Pathology. 2002;198(1):100–109. [PubMed]
78. Massion PP, Taflan PM, Rahman SMJ, et al. Significance of p63 amplification and overexpression in lung cancer development and prognosis. Cancer Research. 2003;63(21):7113–7121. [PubMed]
79. Chen F, Chen H, Tao H, Zhang Y, Ye B, Liu M. Different expressions of p53 gene family members and their clinical significance in human non-small cell lung cancer. Zhongguo Fei Ai Za Zhi. 2004;7(4):339–343. [PubMed]
80. Iwata T, Uramoto H, Sugio K, et al. A lack of prognostic significance regarding ΔNp63 immunoreactivity in lung cancer. Lung Cancer. 2005;50(1):67–73. [PubMed]
81. Narahashi T, Niki T, Wang T, et al. Cytoplasmic localization of p63 is associated with poor patient survival in lung adenocarcinoma. Histopathology. 2006;49(4):349–357. [PubMed]
82. Yokomizo A, Mai M, Bostwick DG, et al. Mutation and expression analysis of the p73 gene in prostate cancer. Prostate. 1999;39(2):94–100. [PubMed]
83. Guan M, Chen Y. Aberrant expression of ΔNp73 in benign and malignant tumours of the prostate: correlation with Gleason score. Journal of Clinical Pathology. 2005;58(11):1175–1179. [PMC free article] [PubMed]
84. Parsons JK, Saria EA, Nakayama M, et al. Comprehensive mutational analysis and mRNA isoform quantification of TP63 in normal and neoplastic human prostate cells. Prostate. 2009;69(5):559–569. [PMC free article] [PubMed]
85. Dhillon PK, Barry M, Stampfer MJ, et al. Aberrant cytoplasmic expression of p63 and prostate cancer mortality. Cancer Epidemiology Biomarkers and Prevention. 2009;18(2):595–600. [PMC free article] [PubMed]
86. Guan M, Peng HX, Yu B, Lu Y. p73 overexpression and angiogenesis in human colorectal carcinoma. Japanese Journal of Clinical Oncology. 2003;33(5):215–220. [PubMed]
87. Carneiro FP, Ramalho LNZ, Britto-Garcia S, Ribeiro-Silva A, Zucoloto S. Immunohistochemical expression of p16, p53, and p63 in colorectal adenomas and adenocarcinomas. Diseases of the Colon and Rectum. 2006;49(5):588–594. [PubMed]
88. Chi SG, Chang SG, Lee SJ, Lee CH, Kim JI, Park JH. Elevated and biallelic expression of p73 is associated with progression of human bladder cancer. Cancer Research. 1999;59(12):2791–2793. [PubMed]
89. Puig P, Capodieci P, Drobnjak M, et al. p73 Expression in human normal and tumor tissues: loss of p73α expression is associated with tumor progression in bladder cancer. Clinical Cancer Research. 2003;9(15):5642–5651. [PubMed]
90. Park BJ, Lee SJ, Kim JI, et al. Frequent alteration of p63 expression in human primary bladder carcinomas. Cancer Research. 2000;60(13):3370–3374. [PubMed]
91. Koga F, Kawakami S, Fujii Y, et al. Impaired p63 expression associates with poor prognosis and uroplakin III expression in invasive urothelial carcinoma of the bladder. Clinical Cancer Research. 2003;9(15):5501–5507. [PubMed]
92. Karni-Schmidt O, Castillo-Martin M, HuaiShen T, et al. Distinct expression profiles of p63 variants during urothelial development and bladder cancer progression. American Journal of Pathology. 2011;178(3):1350–1360. [PubMed]
93. Kroiss MM, Bosserhoff AK, Vogt T, et al. Loss of expression or mutations in the p73 tumour suppressor gene are not involved in the pathogenesis of malignant melanomas. Melanoma Research. 1998;8(6):504–509. [PubMed]
94. Kang MJ, Park BJ, Byun DS, et al. Loss of imprinting and elevated expression of wild-type p73 in human gastric adenocarcinoma. Clinical Cancer Research. 2000;6(5):1767–1771. [PubMed]
95. Tannapfel A, Schmelzer S, Benicke M, et al. Expression of the p53 homologues p63 and p73 in multiple simultaneous gastric cancer. Journal of Pathology. 2001;195(2):163–170. [PubMed]
96. Vilgelm AE, Hong SM, Washington MK, et al. Characterization of Δnp73 expression and regulation in gastric and esophageal tumors. Oncogene. 2010;29(43):5861–5868. [PubMed]
97. Cai YC, Yang GY, Nie V, et al. Molecular alterations of p73 in human esophageal squamous cell carcinomas: loss of heterozygosity occurs frequently; loss of imprinting and elevation of p73 expression may be related to defective p53. Carcinogenesis. 2000;21(4):683–689. [PubMed]
98. Masuda N, Kato H, Nakajima T, et al. Synergistic decline in expressions of p73 and p21 with invasion in esophageal cancers. Cancer Science. 2003;94(7):612–617. [PubMed]
99. Glickman JN, Yang A, Shahsafaei A, McKeon F, Odze RD. Expression of p53-related protein p63 in the gastrointestinal tract and in esophageal metaplastic and neoplastic disorders. Human Pathology. 2001;32(11):1157–1165. [PubMed]
100. Geddert H, Kiel S, Heep HJ, Gabbert HE, Sarbia M. The role of p63 and ΔNp63 (p40) protein expression and gene amplification in esophageal carcinogenesis. Human Pathology. 2003;34(9):850–856. [PubMed]
101. Morita M, Uramoto H, Nakata S, et al. Expression of DeltaNp63 in squamous cell carcinoma of the esophagus. Anticancer Research. 2005;25(5):3533–3539. [PubMed]
102. Takahashi Y, Noguchi T, Takeno S, Kimura Y, Okubo M, Kawahara K. Reduced expression of p63 has prognostic implications for patients with esophageal squamous cell carcinoma. Oncology Reports. 2006;15(2):323–328. [PubMed]
103. Cao LY, Yin Y, Li H, Jiang Y, Zhang HF. Expression and clinical significance of S100A2 and p63 in esophageal carcinoma. World Journal of Gastroenterology. 2009;15(33):4183–4188. [PMC free article] [PubMed]
104. El-Naggar AK, Lai S, Clayman GL, et al. P73 gene alterations and expression in primary oral and laryngeal squamous carcinomas. Carcinogenesis. 2001;22(5):729–735. [PubMed]
105. Faridoni-Laurens L, Bosq J, Janot F, et al. P73 expression in basal layers of head and neck squamous epithelium: a role in differentiation and carcinogenesis in concert with p53 and p63? Oncogene. 2001;20(38):5302–5312. [PubMed]
106. Weber A, Bellmann U, Bootz F, Wittekind C, Tannapfel A. Expression of p53 and its homologues in primary and recurrent squamous cell carcinomas of the head and neck. International Journal of Cancer. 2002;99(1):22–28. [PubMed]
107. Chen YK, Hsue SS, Lin LM. p73 expression for human buccal epithelial dysplasia and squamous cell carcinoma: does it correlate with nodal status of carcinoma and is there a relationship with malignant change of epithelial dysplasia? Head and Neck. 2004;26(11):945–952. [PubMed]
108. Lo Muzio L, Santarelli A, Caltabiano R, et al. p63 overexpression associates with poor prognosis in head and neck squamous cell carcinoma. Human Pathology. 2005;36(2):187–194. [PubMed]
109. Liu SS, Chan KYK, Cheung ANY, Liao XY, Leung TW, Ngan HYS. Expression of ΔNp73 and TAp73α independently associated with radiosensitivities and prognoses in cervical squamous cell carcinoma. Clinical Cancer Research. 2006;12(13):3922–3927. [PubMed]
110. Cheung AN, Tsun K-L, Ng K-M, et al. P634A4 and TAp73 immunocytochemistry in liquid-based cervical cytology—potential biomarkers for diagnosis and progress prediction of cervical neoplasia. Modern Pathology. 2010;23(4):559–566. [PubMed]
111. Wang TY, Chen BF, Yang YC, et al. Histologic and immunophenotypic classification of cervical carcinomas by expression of the p53 homologue p63: a study of 250 cases. Human Pathology. 2001;32(5):479–486. [PubMed]
112. Lin Z, Liu M, Li Z, Kim C, Lee E, Kim I. ΔNp63 protein expression in uterine cervical and endometrial cancers. Journal of Cancer Research and Clinical Oncology. 2006;132(12):811–816. [PubMed]
113. Mai M, Qian C, Yokomizo A, et al. Loss of imprinting and allele switching of p73 in renal cell carcinoma. Oncogene. 1998;17(13):1739–1741. [PubMed]
114. Tuna B, Unlu M, Asian G, Secil M, Yorukoglu K. Diagnostic and prognostic impact of p63 immunoreactivity in renal malignancies. Analytical and Quantitative Cytology and Histology. 2009;31(2):118–122. [PubMed]
115. Ferru A, Denis S, Guilhot J, et al. Expression of TAp73 and ΔNp73 isoform transcripts in thyroid tumours. European Journal of Surgical Oncology. 2006;32(2):228–230. [PubMed]
116. Ito Y, Uramoto H, Funa K, et al. Delta Np73 expression in thyroid neoplasms originating from follicular cells. Pathology. 2006;38(3):205–209. [PubMed]
117. Malaguarnera R, Mandarino A, Mazzon E, et al. The p53-homologue p63 may promote thyroid cancer progression. Endocrine-Related Cancer. 2005;12(4):953–971. [PubMed]
118. Ito Y, Takeda T, Wakasa K, Tsujimoto M, Sakon M, Matsuura N. Expression of p73 and p63 proteins in pancreatic adenocarcinoma: p73 overexpression is inversely correlated with biological aggressiveness. International Journal of Molecular Medicine. 2001;8(1):67–71. [PubMed]
119. House MG, Guo MZ, Iacobuzio-Donahue C, Herman JG. Molecular progression of promoter methylation in intraductal papillary mucinous neoplasms (IPMN) of the pancreas. Carcinogenesis. 2003;24(2):193–198. [PubMed]
120. Basturk O, Khanani F, Sarkar F, Levi E, Cheng JD, Adsay NV. DeltaNp63 expression in pancreas and pancreatic neoplasia. Modern Pathology. 2005;18(9):1193–1198. [PubMed]
121. Petrenko O, Zaika A, Moll UM. ΔNp73 facilitates cell immortalization and cooperates with oncogenic Ras in cellular transformation in vivo. Molecular and Cellular Biology. 2003;23(16):5540–5555. [PMC free article] [PubMed]
122. Stiewe T, Zimmermann S, Frilling A, Esche H, Pützer BM. Transactivation-deficient δTA-p73 acts as an oncogene. Cancer Research. 2002;62(13):3598–3602. [PubMed]
123. Cam H, Griesmann H, Beitzinger M, et al. p53 family members in myogenic differentiation and rhabdomyosarcoma development. Cancer Cell. 2006;10(4):281–293. [PubMed]
124. Casciano I, Banelli B, Croce M, et al. Role of methylation in the control of ΔNp73 expression in neuroblastoma. Cell Death and Differentiation. 2002;9(3):343–345. [PubMed]
125. Vilgelm A, Wei JX, Piazuelo MB, et al. ΔNp73α regulates MDR1 expression by inhibiting p53 function. Oncogene. 2008;27(15):2170–2176. [PubMed]
126. Uramoto H, Sugio K, Oyama T, et al. Expression of the p53 family in lung cancer. Anticancer Research. 2006;26(3):1785–1790. [PubMed]
127. Müller M, Schilling T, Sayan AE, et al. TAp73/ΔNp73 influences apoptotic response, chemosensitivity and prognosis in hepatocellular carcinoma. Cell Death and Differentiation. 2005;12(12):1564–1577. [PubMed]
128. Wager M, Guilhot J, Blanc JL, et al. Prognostic value of increase in transcript levels of Tp73 ΔEx2-3 isoforms in low-grade glioma patients. British Journal of Cancer. 2006;95(8):1062–1069. [PMC free article] [PubMed]
129. Meier M, den Boer ML, Meijerink JPP, et al. Differential expression of p73 isoforms in relation to drug resistance in childhood T-lineage acute lymphoblastic leukaemia. Leukemia. 2006;20(8):1377–1384. [PubMed]
130. Concin N, Hofstetter G, Berger A, et al. Clinical relevance of dominant-negative p73 isoforms for responsiveness to chemotherapy and survival in ovarian cancer: evidence for a crucial p53-p73 cross-talk in vivo. Clinical Cancer Research. 2005;11(23):8372–8383. [PubMed]
131. Beitzinger M, Hofmann L, Oswald C, et al. p73 poses a barrier to malignant transformation by limiting anchorage-independent growth. EMBO Journal. 2008;27(5):792–803. [PubMed]
132. Corn PG, Kuerbitz SJ, van Noesel MM, et al. Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt’s lymphoma is associated with 5’ CpG island methylation. Cancer Research. 1999;59(14):3352–3356. [PubMed]
133. Shen LL, Toyota M, Kondo Y, et al. Aberrant DNA methylation of p57KIP2 identifies a cell-cycle regulatory pathway with prognostic impact in adult acute lymphocytic leukemia. Blood. 2003;101(10):4131–4136. [PubMed]
134. Garcia-Manero G, Daniel J, Smith TL, et al. DNA methylation of multiple promoter-associated CpG islands in adult acute lymphocytic leukemia. Clinical Cancer Research. 2002;8(7):2217–2224. [PubMed]
135. Vikhanskaya F, Toh WH, Dulloo I, et al. p73 supports cellular growth through c-Jun-dependent AP-1 transactivation. Nature Cell Biology. 2007;9(6):698–706. [PubMed]
136. Tschan MP, Grob TJ, Peters UR, et al. Enhanced p73 expression during differentiation and complex p73 isoforms in myeloid leukemia. Biochemical and Biophysical Research Communications. 2000;277(1):62–65. [PubMed]
137. Hagiwara K, McMenamin MG, Miura K, Harris CC. Mutational analysis of the p63/p73L/p51/p40/CUSP/KET gene in human cancer cell lines using intronic primers. Cancer Research. 1999;59(17):4165–4169. [PubMed]
138. Sunahara M, Shishikura T, Takahashi M, et al. Mutational analysis of p51A/TAp63γ, a p53 homolog, in non-small cell lung cancer and breast cancer. Oncogene. 1999;18(25):3761–3765. [PubMed]
139. Hibi K, Trink B, Patturajan M, et al. AIS is an oncogene amplified in squamous cell carcinoma. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(10):5462–5467. [PubMed]
140. Keyes WM, Pecoraro M, Aranda V, et al. Δnp63α is an oncogene that targets chromatin remodeler Lsh to drive skin stem cell proliferation and tumorigenesis. Cell Stem Cell. 2011;8(2):164–176. [PubMed]
141. Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature. 1999;398(6729):708–713. [PubMed]
142. Yang A, Schweitzer R, Sun D, et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature. 1999;398(6729):714–718. [PubMed]
143. Flores ER, Sengupta S, Miller JB, et al. Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell. 2005;7(4):363–373. [PubMed]
144. Koster MI, Kim S, Mills AA, DeMayo FJ, Roop DR. p63 is the molecular switch for initiation of an epithelial stratification program. Genes and Development. 2004;18(2):126–131. [PubMed]
145. Romano RA, Ortt K, Birkaya B, Smalley K, Sinha S. An active role of the ΔN isoform of p63 in regulating basal keratin genes K5 and K14 and directing epidermal cell fate. PLoS ONE. 2009;4(5) Article ID e5623. [PMC free article] [PubMed]
146. Crook T, Nicholls JM, Brooks L, O’Nions J, Allday MJ. High level expression of ΔN-p63: a mechanism for the inactivation of p53 in undifferentiated nasopharyngeal carcinoma (NPC)? Oncogene. 2000;19(30):3439–3444. [PubMed]
147. Yamaguchi K, Wu L, Caballero OL, et al. Frequent gain of the p40/p51/p63 gene locus in primary head and neck squamous cell carcinoma. International Journal of Cancer. 2000;86(5):684–689. [PubMed]
148. Compérat E, Bièche I, Dargère D, et al. p63 gene expression study and early bladder carcinogenesis. Urology. 2007;70(3):459–462. [PubMed]
149. Marchini S, Marabese M, Marrazzo E, et al. ΔNp63 expression is associated with poor survival in ovarian cancer. Annals of Oncology. 2008;19(3):501–507. [PubMed]
150. Barbieri CE, Tang LJ, Brown KA, Pietenpol JA. Loss of p63 leads to increased cell migration and up-regulation of genes involved in invasion and metastasis. Cancer Research. 2006;66(15):7589–7597. [PubMed]
151. Adorno M, Cordenonsi M, Montagner M, et al. A Mutant-p53/Smad complex opposes p63 to empower TGFβ-induced metastasis. Cell. 2009;137(1):87–98. [PubMed]
152. Truong AB, Kretz M, Ridky TW, Kimmel R, Khavari PA. p63 regulates proliferation and differentiation of developmentally mature keratinocytes. Genes and Development. 2006;20(22):3185–3197. [PubMed]
153. Leong CO, Vidnovic N, DeYoung MP, Sgroi D, Ellisen LW. The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers. Journal of Clinical Investigation. 2007;117(5):1370–1380. [PMC free article] [PubMed]
154. Rocco JW, Leong CO, Kuperwasser N, DeYoung MP, Ellisen LW. p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis. Cancer Cell. 2006;9(1):45–56. [PubMed]
155. Guo X, Keyes WM, Papazoglu C, et al. TAp63 induces senescence and suppresses tumorigenesis in vivo. Nature Cell Biology. 2009;11(12):1451–1457. [PMC free article] [PubMed]
156. Djelloul S, Tarunina M, Barnouin K, Mackay A, Jat PS. Differential protein expression, DNA binding and interaction with SV40 large tumour antigen implicate the p63-family of proteins in replicative senescence. Oncogene. 2002;21(7):981–989. [PubMed]
157. Wang D-Y, Cheng C-C, Kao M-H, Hsueh Y-J, Ma DHK, Chen J-K. Regulation of limbal keratinocyte proliferation and differentiation by TAp63 and ΔNp63 transcription factors. Investigative Ophthalmology and Visual Science. 2005;46(9):3102–3108. [PubMed]
158. Guo W, Fan S, Jiang Y, Chen J, Li Z, Niu H. The expression of p63 gene in human non-small cell lung cancer. Zhongguo Fei Ai Za Zhi. 2004;7(1):31–34. [PubMed]
159. Su X, Chakravarti D, Cho MS, et al. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature. 2010;467(7318):986–990. [PMC free article] [PubMed]
160. Wang S, El-Deiry WS. p73 or p53 directly regulates human p53 transcription to maintain cell cycle checkpoints. Cancer Research. 2006;66(14):6982–6989. [PubMed]
161. Chen X, Zheng Y, Zhu J, Jiang J, Wang J. p73 is transcriptionally regulated by DNA damage, p53, and p73. Oncogene. 2001;20(6):769–774. [PubMed]
162. Wang J, Liu YX, Hande MP, Wong AC, Jin YJ, Yin Y. TAp73 is a downstream target of p53 in controlling the cellular defense against stress. Journal of Biological Chemistry. 2007;282(40):29152–29162. [PubMed]
163. Johnson J, Lagowski J, Lawson S, Liu Y, Kulesz-Martin M. p73 expression modulates p63 and Mdm2 protein presence in complex with p53 family-specific DNA target sequence in squamous cell carcinogenesis. Oncogene. 2008;27(19):2780–2787. [PubMed]
164. Strano S, Fontemaggi G, Costanzo A, et al. Physical interaction with human tumor-derived p53 mutants inhibits p63 activities. Journal of Biological Chemistry. 2002;277(21):18817–18826. [PubMed]
165. Di Como CJ, Gaiddon C, Prives C. p73 Function is inhibited by tumor-derived p53 mutants in mammalian cells. Molecular and Cellular Biology. 1999;19(2):1438–1449. [PMC free article] [PubMed]
166. Gaiddon C, Lokshin M, Ahn J, Zhang T, Prives C. A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain. Molecular and Cellular Biology. 2001;21(5):1874–1887. [PMC free article] [PubMed]
167. Pozniak CD, Radinovic S, Yang A, McKeon F, Kaplan DR, Miller FD. An anti-apoptotic role for the p53 family member, p73, during developmental neuron death. Science. 2000;289(5477):304–306. [PubMed]
168. Liu G, Nozell S, Xiao H, Chen X. ΔNp73β is active in transactivation and growth suppression. Molecular and Cellular Biology. 2004;24(2):487–501. [PMC free article] [PubMed]
169. Flores ER, Tsai KY, Crowley D, et al. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature. 2002;416(6880):560–564. [PubMed]
170. Cui R, Nguyen TT, Taube JH, Stratton SA, Feuerman MH, Barton MC. Family members p53 and p73 act together in chromatin modification and direct repression of α-fetoprotein transcription. Journal of Biological Chemistry. 2005;280(47):39152–39160. [PubMed]
171. Yang A, Zhu Z, Kettenbach A, et al. Genome-wide mapping indicates that p73 and p63 Co-occupy target sites and have similar DNA-binding profiles in vivo. PLoS ONE. 2010;5(7) Article ID e11572. [PMC free article] [PubMed]
Articles from Journal of Nucleic Acids are provided here courtesy of
Hindawi Publishing Corporation