p53 family update: p73 and p63 develop their own identities.

Introduction p53 continues to be one of the most intensively studied genes in cancer biology. p53 was initially identified .20 years ago as a binding partner for the SV40 T oncoprotein. Further studies revealed that p53 is a tumor suppressor gene that is mutated or inactivated in .50% of human cancers. Furthermore, germ-line p53 mutations cause hereditary cancer in both mice and humans. Molecular and biochemical assays revealed that the p53 protein is a sequence-specific DNA-binding transcription factor. p53 plays a central role in cellular responses to aberrant growth signals and certain cytotoxic stresses, such as DNA damage, by enhancing the transcription of genes that regulate a variety of cellular processes including cell cycle progression, apoptosis, genetic stability, and angiogenesis (1). Interpreting the enormous quantity of p53 data, corresponding to almost 20,000 publications on the National Library of Medicine website, has become more complicated by the recent identification of two p53 paralogues, p63 and p73. Until recently, p53 was thought to be a unique gene with no genetic paralogues. Daniel Caput identified the first p53related gene, p73, ;4 years ago (2). Several groups then independently identified the third member of the family, p63 (also known as p51, KET, p40, p73L, p53CP, and NBP; Refs. 3–9). Additional “p53-like” genes are unlikely to be identified because searches of the recently published human genome sequence revealed no additional p53 family members (10, 11). The structures of the p63 and p73 genes are more similar to one another than to p53. However, p63 and p73 can perform certain “p53-like activities.” Similar to p53, both p63 and p73 can form homo-oligomers, bind DNA, activate transcription from p53-responsive genes, and induce apoptosis (3, 5, 12). However, in contrast to p53, p63 and p73 give rise to multiple functionally distinct protein isoforms, some of which lack the NH2-terminal transactivation domain and can function as “dominant negative” proteins, which block the function of the corresponding full-length proteins. In addition, p63 and p73 are only rarely mutated in the large number of tumors examined to date and are thus unlikely to be classical tumor suppressor genes. However, altered expression of the various isoforms and heterotypic interactions among the different family members may still play a role in tumorigenesis. Also in contrast to p53, severe developmental abnormalities are observed in mice lacking either p63 or p73 and in humans with germ-line p63 mutations. This suggests possible tissue-specific functions for p63 and p73 during development. This article will review the growing compilation of reports addressing similarities and differences between p53, p63, and p73.