Role of the newer p53 family proteins in malignancy.
The most recently identified members of the p53 family, p63 and p73, share certain structural and functional similarities with p53. Both p63 and p73 can bind to canonical p53-DNA-binding sites, transactivate the promoters of known p53 target genes and induce apoptosis. Despite these similarities there are many important differences. In contrast to p53, p63 and p73 give rise to multiple distinct protein isoforms that have different functional properties. Upstream signaling pathways involved in the activation of p63 and p73 differ from those involved in p53 activation. Only a subset of the DNA damaging agents that induce p53 can induce p73. Cellular and viral oncoproteins can discriminate between p53 and the newer family members. In addition, the levels of p63 and p73 are affected by certain states of cellular differentiation. Finally, it is becoming clear that the newest members of the p53 family are not classical tumor suppressor genes. In contrast to the high prevalence of p53 mutations in human cancers, p63 and p73 mutations are rare. Indeed, levels of p73 increase during malignant progression. In addition, unlike p53-/- mice, mice lacking p63 and p73 do not develop tumors, but instead have significant developmental abnormalities. Mutations in p63 have also been detected in humans with the ectodermal dysplastic syndrome EEC. Further studies are required to determine whether qualitative or quantitative differences in the expression of p63 and p73 isoforms are important in the development of human cancers.
Irwin
M S
MS
Dana Farber Cancer Institute, Dept. of Adult Oncology, and Harvard Medical School, Boston, MA 02115, USA.
Kaelin
W G
WG
D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000209:etiology / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53