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

Abstract

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...

p63 in Mytilus galloprovincialis and p53 family members in the phylum Mollusca

“…2, be divided into three regions: the N-terminal region with at least two alternative forms, the central part which is conserved in all the sequences and the C-terminal region again with at least two alternative forms. As already discussed by other authors (Goodson et al, 2006), this suggests we here deal with alternative sequences originating from the same gene, which is not surprising given that all p53 family genes are able to express alternative products (Murray-Zmijewski et al, 2006).…”

“…The central region of all p53 family sequences codes for the DNA binding domains and is very similar in all members of the family (Murray-Zmijewski et al, 2006). Within the phylum of mollusks, all the sequences originating from the same species have an identical or almost identical central region (differing in up to a few single nucleotide differences in almost 1kb of DNA sequence).…”

“…Both genes code for two 3'UTRs, having the distal 3'UTR situated at the very end. One distinct structural difference regards the position of the other (proximal) 3'UTR which is, in p63 genes situated at the end of exon 10', and in p73 genes at the end of exon 13 (Murray-Zmijewski et al, 2006; see H. sapiens p63 and p73 in Fig. 6).…”

“…Protein isoforms expressed from any of the three genes are numerous (Levrero et al, 2000) and their regulation elaborate (Strano et al, 2001). Their overlapping and distinct functions as well as many regulation mechanisms have been continuously discovered since (Murray-Zmijewski et al, 2006;Halaby & Yang, 2007).…”

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

“…In general, the full-length TA versions of p63/p73 can exert p53-like activities, whereas the DN versions have the opposite effect (reviewed by Yang et al, 2002). More recently it was reported that p53 can also be expressed as multiple isoforms differing in N and C-termini (reviewed by Murray-Zmijewski et al, 2006). The different p53 C-termini, however, are quite distinct from those of p63 and p73.…”