p63 and p73 are required for p53-dependent apoptosis in response to DNA damage

Flores, Elsa R.; Tsai, Kenneth Y.; Crowley, Denise; Sengupta, Shomit; Yang, Annie; McKeon, Frank; Jacks, Tyler

doi:10.1038/416560a

Cited by 768 publications

(728 citation statements)

References 27 publications

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“…[22][23][24] Flores et al then observed that the p632/2; p732/2 double null mouse embryo fibroblasts (MEF) were as resistant to apoptosis as p532/2 MEF cells, pointing out that p63 and p73 are required for p53-induced apoptosis and delineating functional interplay between p53 family members. 25 More recent studies have shown that p73 could be implicated in the cellular response to drugs in cancer cells such as squamous cell carcinomas or osteosarcoma cell lines. [26][27] Today, there are no data regarding a hypothetical role of p73 and p63 in cellular response to ADR in p53-deficient breast cancers.…”

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confidence: 99%

P73 functionally replaces p53 in Adriamycin‐treated, p53‐deficient breast cancer cells

Vayssade

Haddada

Faridoni-Laurens

et al. 2005

Intl Journal of Cancer

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p53-related genes, p73 and p63, encode 2 classes of proteins, TAp73/p63 and DN-p73/p63. TA-p73/p63 demonstrate p53-like properties including gene transactivation and cell death promotion, whereas DN-p73/p63 lack these p53-like functions. Although p53-deficient cancer cells are often less responsive to chemotherapy, they are not completely drug resistant, suggesting that other apoptotic pathways are at work. Here, we compared for the first time to our knowledge p73 and p63 activation in various breast cancer (BC) cell lines after Adriamycin (ADR) treatment, an agent considered as mandatory in breast cancer chemotherapy. Our study was carried out using 1 p53-proficient BC cell line (MCF7 cells) and 3 BC cell lines deficient in p53 response (MCF7/ADR IGR , MDA-MB157 and T47D) after ADR-induced genotoxic stress. We report that in cells with no p53 response after ADR treatment, TAp73, but not TAp63 or DN-p73/p63, may replace p53 in triggering not only apoptosis but also cell cycle arrest or DNA repair effectors such as p21, GADD45, 14-3-3r and p53R2. We also demonstrate that TAp73 siRNA inhibits the accumulation of TAp73 in response to ADR treatment in MDA-MB157 cells and confers protection against ADR. ADR-induced downregulation of the DNp73 isoform in the T47D cell line with nonfunctional mutant p53 further supports anti-apoptotic function of the isoform antagonistic to both p53 and TA-p73/p63. Exogenous TAp73 and DNp73 overexpression in p53-response-deficient cell lines further confirms these results. cDNA microarray techniques demonstrated that the cellular response induced by p73 during ADR treatment could involve specific genes. ' 2005 Wiley-Liss, Inc.

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mentioning

confidence: 99%

P73 functionally replaces p53 in Adriamycin‐treated, p53‐deficient breast cancer cells

Vayssade

Haddada

Faridoni-Laurens

et al. 2005

Intl Journal of Cancer

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“…The significance of p63 and p73 binding to p53-responsive promoters, and the importance of each family member, is demonstrated by the fact that p53 cannot induce apoptosis in response to DNA damage, without the presence of p63 and p73. 74 In p63/p73 À/À double null mouse embryo fibroblasts (MEFs), the apoptotic genes Bax, Noxa and PERP were not induced in response to DNA damage, while p21 induction was normal. p53 was absent at the Bax, Noxa and PERP promoters when p63 and p73 were not there.…”

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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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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“…In some contexts, p63 and p73 are required for recruitment of p53 on pro-apoptotic target promoters. 72 It has also been demonstrated that the prolyl isomerase activity of Pin1 modifies p73 conformation, promoting its acetylation by p300/CBP in a cAbl-dependent fashion, and indeed under genotoxic stress, Pin1 is essential for p73's apoptotic activity. 68 This finding has important implications for cancer therapy, given p73's ability to determine chemosensitivity in some tumor cells lacking functional p53, 73 and also implicates Pin1 in coregulating p53 family members' activities.…”

Section: The Prolyl Isomerase Pin1mentioning

confidence: 99%

Some p53-binding proteins that can function as arbiters of life and death

2006

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Four sets of p53-binding proteins are discussed in this review. These are the E2F family, the ASPP family, Y-boxbinding protein YB1, and the prolyl isomerase Pin1. Each appears to play a role in the decision by p53 to induce an arrest of cell proliferation or apoptosis and they may also be independent markers of cancer. Their activities appear to be linked with the cell cycle and they may also interact with each other. In this review, the properties of each protein class are discussed as well as how they affect p53 functions. A model is proposed as to how their activities might be coordinated.

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p63 and p73 are required for p53-dependent apoptosis in response to DNA damage

Cited by 768 publications

References 27 publications

P73 functionally replaces p53 in Adriamycin‐treated, p53‐deficient breast cancer cells

P73 functionally replaces p53 in Adriamycin‐treated, p53‐deficient breast cancer cells

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

Some p53-binding proteins that can function as arbiters of life and death

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