Tumor predisposition in mice mutant for p63 and p73: Evidence for broader tumor suppressor functions for the p53 family

Flores, Elsa R.; Sengupta, Shomit; Miller, John B.; Newman, Jamie J.; Bronson, Roderick T.; Crowley, Denise; Yang, Annie; McKeon, Frank; Jacks, Tyler

doi:10.1016/j.ccr.2005.02.019

Cited by 462 publications

(524 citation statements)

References 33 publications

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“…Some p63 þ /À mice are cancer-prone 25 while other genetic background p63 þ /À mice show premature aging but no cancer. 26 In humans, the p63 gene can be frequently amplified in squamous cells in lung 27 and cervical carcinomas.…”

Section: P63 and Cancermentioning

confidence: 99%

“…Together, this illustrates that either p63 or p73 are vital for p53-induced apoptosis and, furthermore, that they themselves are an important component of the p53 tumour suppressor activity. 25 Although the presence of p63 and p73 at p53-responsive promoters is significant, it will also be crucial to identify p63/p73 specific targets. Within the entire family, there are common and preferred gene targets and it will be essential to assess the functions of each of the isoforms, based on their binding to specific promoters or proteins.…”

Section: Interaction On Promoters Of Target Genesmentioning

confidence: 99%

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p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress

2006

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Abstractp63, p73 and p53 compose a family of transcription factors involved in cell response to stress and development. p53 is the most frequently mutated gene in cancer (50%) and loss of p53 activity is considered to be ubiquitous to all cancers. Recent publications may have a profound impact on our understanding of p53 tumour suppressor activity. p63, p73 and p53 genes have a dual gene structure conserved in drosophila, zebrafish and man. They encode for multiple p63, p73 or p53 proteins containing different protein domains (isoforms) due to multiple splicing, alternative promoter and alternative initiation of translation. In this review, we describe the different isoforms of p63, p73, p53 and their roles in development and cancer. The changes in the interactions between p53, p63 and p73 isoforms are likely to be fundamental to our understanding in the transition between normal cell cycling and the onset of tumour formation. Cell Death and Differentiation (2006) Introduction p53 was discovered in 1979 as a protein interacting with the oncogenic T antigen from SV40 virus. 1-5 p53 protein is the product of a pivotal tumor-suppressor gene whose inactivation by mutation or interaction with viral or overexpressed cellular proteins occurs in almost all cancers. 6 The p53 protein integrates multiple cellular stress signals assessing cellular damages to trigger either cell-cycle arrest or programmed cell death (apoptosis). 7 These effects are predominantly due to p53's ability to bind DNA through p53-responsive element (p53RE) 8,9 and regulate the transcription of genes involved in these processes, such as p21 10 (cell cycle arrest), Puma 11 or Scotin 12 (apoptosis). Thereby, p53 prevents proliferation of genetically abnormal cells and thus cancer formation.Two p53-related genes, p63 and p73, were identified in 1997. 13,14 The high level of sequence similarity between p63, p73 and p53 proteins, particularly in the DNA binding domain, allows p63 and p73 to transactivate p53-responsive genes causing cell cycle arrest and apoptosis. Therefore, p63, p73 and p53 genes form a family of transcription factor. However, they are not functionally entirely redundant and the primary role of each p53 family member -as determined by transgenetic knockout mice -illustrates that each protein has its own unique functions.We recently published that the p53 gene family has a dual gene structure conserved from drosophila to man. 15 Like most of the genes in the human genome, 16 p53 gene family members express multiple mRNA variants due to multiple splicing and alternative promoters. Hence, p53 gene family members express different forms of p53 protein containing different domain of the protein (isoforms). In this review, we will summarise the different isoforms of p63, p73 and p53 expressed in human, mouse and drosophila. p63The mouse p63 gene is composed of 15 exons spanning over 208 000 bp (GenBank Accession Number: AF533892) on chromosome 16, while the human p63 gene is composed of 15 exons, spanning over 270 000 bp on chromosome 3q2...

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Section: P63 and Cancermentioning

confidence: 99%

Section: Interaction On Promoters Of Target Genesmentioning

confidence: 99%

p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress

2006

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“…Furthermore, hTERT expression is known to be downregulated both by cellular stress and during the terminal differentiation of progenitor cells when TAp73 expression is induced, suggesting that TAp73 might also play a causal role in hTERT regulation under these conditions (Sharma et al, 1995;Xu et al, 1996). Considering that p73 loss predisposes mice to various types of cancer (Flores et al, 2005), it is intriguing to speculate that p73 haploinsufficiency might result in elevated levels of mTERT, thus selecting for cells that have acquired the proper genetic hits to become cancerous. In contrast to downregulation of hTERT by differentiation or proapoptotic stress signals, hTERT is typically activated in immortal cells and established tumors .…”

Section: Regulation Of Htert By P73 M Beitzinger Et Almentioning

confidence: 99%

Regulation of telomerase activity by the p53 family member p73

Beitzinger

Oswald

Beinoraviciute-Kellner

et al. 2005

Oncogene

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The terminal ends of eukaryotic chromosomes, termed telomeres, progressively shorten during each round of cell division eventually leading cells into senescence. Tumor cells typically overcome this barrier to unlimited proliferation by activation of the human telomerase reverse transcriptase (hTERT) gene. In contrast, in most human somatic cells hTERT expression is tightly repressed by multiple tumor suppressors. Here, we studied the regulation of hTERT by the p53 family member p73. We show that forced expression of p73 or activation of endogenous p73 by E2F1 results in the downregulation of telomerase activity. Vice versa, siRNA-mediated knockdown of p73 induces hTERT expression. Responsiveness to p73 is conferred by Sp1 binding sites within the hTERT core promoter. In tumor cells, p73 isoforms lacking the transactivation domain (DNp73) are frequently overexpressed and believed to function as oncogenes. We show that DNp73 antagonizes the repressive effect of the proapoptotic p53 family members on hTERT expression and, in addition, induces hTERT expression in telomerase-negative cells by interfering with E2F-RB-mediated repression of the hTERT core promoter. These data provide evidence that the p73 gene functions as an important regulator of telomerase activity with implications for embryonic development, cellular differentiation and tumorigenesis.

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“…Third, Flores et al (2002) showed that p63 and p73 are required by p53 to activate a few proapoptotic genes in mouse embryo fibroblasts (MEFs) expressing adenoviral E1A. Finally, in one genetic background mice heterozygous for p63 and p73 can develop tumors (Flores et al, 2005). Nevertheless, in contrast to p63 or p73, the central role of wild-type p53 in protection from cancer is unequivocal.…”

Section: Introductionmentioning

confidence: 99%

Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function?

2007

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Although still controversial, the presence of mutant p53 in cancer cells may result in more aggressive tumors and correspondingly worse outcomes. The means by which mutant p53 exerts such pro-oncogenic activity are currently under extensive investigation and different models have been proposed. We focus here on a proposed mechanism by which a subset of tumor-derived p53 mutants physically interact with p53 family members, p63 and p73, and negatively regulate their proapoptotic function. Both cell-based assays and knock-in mice expressing mutant forms of p53 support this model. As more than half of human tumors harbor mutant forms of p53 protein, approaches aimed at disrupting the pathological interactions among p53 family members might be of clinical value.

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Tumor predisposition in mice mutant for p63 and p73: Evidence for broader tumor suppressor functions for the p53 family

Cited by 462 publications

References 33 publications

p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress

p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress

Regulation of telomerase activity by the p53 family member p73

Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function?

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