Structure, function and regulation of p63 and p73

Abstract

The p53 tumor suppressor gene is one of the most frequently mutated genes in human cancers. 1 p53 is a sequence-specific transcription factor and plays a critical role in activating the expression of genes involved in cell cycle arrest or apoptosis under conditions of genotoxic stress. 2,3 For over two decades, p53 was thought to be the only gene of its kind in the vertebrate genomes. This strong conviction, which was widely accepted in the p53 field, has now been proven to be incorrect. Two genes, referred to as p63 and p73, have been found to encode proteins that share a significant amino-acid identity in the transactivation domain, the DNA binding domain, and the oligomerization domain with p53. In the short period since their cloning, a number of investigators have reported on the structure, the function and the regulation of p63 and p73. This review summarizes the current information on the p63 and the p73 genes, with a focus on the differences between the three members in this newly defined p53-gene family.Keywords: p73; p53; c-Abl; apoptosis Abbreviations: HPV-16, human papilloma virus-16; IGFBP, Insulin-like growth factor binding proteins; IR, ionizing irradiation; MEFs, mouse embryo ®broblasts; MMS, methylmethane sulfonate; OD, oligomerization domain; SAM, sterile alpha motif; TA, transactivation domain; DN p63, N-terminal deleted p63 variants Alternative splicing of p63 and p73The p53 gene generates a single mRNA with a single open reading frame. In contrast, both the p63 and the p73 genes generate several differentially spliced variants. With the p73 gene, alternative splicings not only add or delete coding sequences, but also alter the reading frame. Hence, the p63 and the p73 genes can each encode several different proteins. Most notably, both the p63 and the p73 genes encode alternatively spliced C-terminal regions that are not found in the p53 protein (Figure 1).The p63 gene encodes at least six open reading frames: from the usage of two different promoters/ATG in combination with three alternatively spliced C-terminal ends (Figure 1). The three isoforms (TA-a, TA-b and TAg) are produced by a 5'-promoter and alternative splicing at the 3' end of the gene. These three isoforms contain the coding sequence for the N-terminal transactivation (TA) domain. Each of these three splice variants can also be expressed from an internal promoter upstream of exon 3', that provides a different ATG to initiate translation downstream of the TA domain. These N-terminal deleted p63 isoforms are referred to as DN-alpha, DN-beta and DNgamma. These DN p63 isoforms do not activate transcription but instead can inhibit the transactivation functions of the full length p63 proteins and of p53. 4 The p73 gene generates at least six open reading frames with alternatively spliced 3-region. Initially, two isoforms of p73 were identified: 5 the full length alphaisoform and a C-terminal shortened beta-isoform resulting from the alternative splicing of exon 13. Four other spliced forms of p73 have since been identified in...

PCAF is a coactivator for p73-mediated transactivation

“…Exogenous expression of p73 can lead to cell-cycle arrest or apoptosis (Jost et al, 1997;Kaghad et al, 1997;Levrero et al, 2000;Zhu et al, 2001). To assess whether PCAF modulates these two biological efforts of p73, we examined the percentage of apoptotic cells in transiently transfected Saos-2 cells using various combinations of plasmids.…”

p63α and ΔNp63α can induce cell cycle arrest and apoptosis and differentially regulate p53 target genes

“…The observation that p53-null mice maintain normal embryonic development (Donehower et al, 1992), however, has raised the possibility that there exists a family of closely related proteins with overlapping functions. Recently, two new genes, TP73 and TRP63, have been found to encode several p73 and p63 proteins, respectively, with structures and functions related to p53 (for reviews, see Chen, 1999;Levrero et al, 2000;Lohrum and Vousden, 2000). The ®rst p53 homolog described was p73 (Kaghad et al, 1997).…”

p73 can suppress the proliferation of cells that express mutant p53

“…These two family members are also capable of performing many of the same functions as p53, including induction of cell cycle arrest and apoptosis and, when overexpressed, regulation of many common target genes (Dohn et al, 2001a, b;Jost et al, 1997;Kaghad et al, 1997;Osada et al, 1998;Zhu et al, 1998Zhu et al, , 1999. In contrast to p53, however, p63 and p73 have multiple isoforms that differ in the length of their C-termini (Kaelin, 1999;Levrero et al, 2000;. For example, p73a is the fulllength isoform of p73 with 14 exons, while p73b has a truncation at exon 13.…”