From p53 to p63 and p73

Abstract

The cellular response to the local environment has been shown to be mediated through the p53 (TP53 human gene; Trp53, mouse gene) tumour suppresser, which controls both cell-cycle arrest and apoptosis. Consistent with proposed functions for p53, mice that lack p53 undergo normal embryogenesis but show a susceptibility to a wide range of cancers. However, the p53 phenotype appears to be in conflict with that observed for its direct downstream target Cdkn1a (p21WAF); homozygous Cdkn1a mice have defects in cell-cycle control but show no propensity for spontaneous tumours. These and other observations led to the cloning of two p53-related genes, p73 and p63. In contrast to the ubiquitous expression of p53, p63 is expressed in the epidermis and regions of the embryo that undergo epidermal–mesencyhymal interactions. Now two independent studies1xp63 is a p53 homoloque required for limb and epidermial morphogenesis. Mills, A. et al. Nature. 1999; 398: 708–713Crossref | PubMed | Scopus (1445)See all References, 2xp63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Yang, A. et al. Nature. 1999; 398: 714–718Crossref | PubMed | Scopus (1605)See all References have shown that p63 further differs from p53 in being required for normal embryogenesis: mice lacking p63 have numerous defects, including dramatic limb truncations, craniofacial abnormalities, and a complete absence of epidermis. Both groups have characterized the limb and skin defects in greater detail and have reached similar conclusions. In the limb, the most striking feature of p63 –/– mice is a complete absence of the AER, which probably results from defects with in the ectoderm as shown by the absence of Msx1 expression. Interestingly, these defects show a striking resemblance to the limbless phenotype in chickens raising the interesting possibility that limbless might arise due to a defect in p63 or another member of the p63 signalling pathway. In the skin, the p63 –/– mice appear to lack all stratified epidermis and their derivatives. Although the basal or progenitor cells do appear to be present these cells fail to differentiate1xp63 is a p53 homoloque required for limb and epidermial morphogenesis. Mills, A. et al. Nature. 1999; 398: 708–713Crossref | PubMed | Scopus (1445)See all References, 2xp63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Yang, A. et al. Nature. 1999; 398: 714–718Crossref | PubMed | Scopus (1605)See all References and subsequently undergo apoptosis2xp63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Yang, A. et al. Nature. 1999; 398: 714–718Crossref | PubMed | Scopus (1605)See all References. Although these initial studies define an essential role for p63 in epidermal cell types we await answers to the following most interesting questions. Does p63 function directly in cell-cycle control and/or apoptosis in vivo? Does it function as a tumour suppresser gene? And, if so, does it share direct downstream targets, such as CDKN1A, with p53?