Early diversification and complex evolutionary history of the p53 tumor suppressor gene family

The p53 tumor suppressor plays the leading role in malignancy and in maintaining the genome's integrity and stability. p53 belongs to a gene family that in vertebrates includes two additional members, p63 and p73. Although similar in sequence, gene structure, and expression potential, the three p53 members differ in domain organization (in addition to the transactivation, DNA-binding, and tetramerization domains, p63 and p73 encode a sterile alpha motif, SAM, domain) and functional roles (with p63 and p73 assuming additional key roles in development). It is interesting to note that outside vertebrates, p53-like sequences have only been found as single genes, of either the p53 or the p63/p73 type (i.e., without or with a SAM domain, respectively). In this paper, we report that the diversification of this family is not restricted to the vertebrate lineage, as both a p53- and a p63/p73-type sequence are present in the unicellular choanoflagellate, Monosiga brevicollis. Furthermore, multiple independent duplication events involving p53-type sequences took place in several other animal lineages (cnidarians, flat worms, insects). These findings argue that selective factors other than those associated with the evolution of vertebrates are also relevant to the diversification of this family. Understanding the selective pressures associated with the multiple independent duplication events that took place in the p53 family and the roles of p53-like proteins outside vertebrates will provide further insight into the evolution of this very important family. In addition, the presence of both a p53 and a p63/73 copy in the unicellular M. brevicollis argues for its suitability as a model system for elucidating the functions of the p53 members and the mechanisms associated with their functional diversification.     

p63: oncogene or tumor suppressor?

p53, the original member of the family of genes now known to include p63 and p73, was first heralded as an oncogene because of its potent transformation capabilities and its robust expression in human tumors. However, it was later discovered that only mutant p53 was oncogenic, and that wild type p53 functioned as a tumor suppressor. Decades later, p63, the newest member of this gene family, is involved in a similar controversy: is p63 an oncogene or a tumor suppressor? Recent progress on understanding the in vivo role of p63 in cancer has focused primarily on investigating its involvement in the tumor-suppressive mechanism of apoptosis, by analyzing mouse models to assess its tumor-suppressive capabilities, and by assessing its expression in human cancers.     

Interrelations between p73 and p53: a model, neuroblastoma

Homologies in sequence and gene organization of p53 and their relatives, p73 and p63, suggest similar biological functions. However differences exist between the p53 family members. Indeed in human tumors p53 is often mutated while p63 and p73 are very rarely mutated. In addition, in contrast to p53 which is transcribed in a unique mRNA species spanning all gene exons, each homologue expresses two types of isoforms: some with transactivation domain (TAD) showing tumor suppressive properties, the others deprived of TAD, with oncogenic properties. If p53 responds to immediate genotoxic stress, its homologues participate to the cell homeostasis of specific tissues along their development and differentiation, neuronal tissue for p73, epithelial for p63. However a collaboration between the three p53 family members has been shown to occur in response to cell genotoxic damages. Neuroblastic tumors characterized by a large spectrum of neuronal differentiation constitute a good model to study relationship between p73 and p53 as well as the regulation of their respective expression.     

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.     

The p53 family: same response, different signals?

TP53, the gene that encodes p53, is a well-defined tumor suppressor gene that is frequently mutated in human cancers. Recently, two proteins homologous to p53, termed p73 and p63, were identified. Current data indicate that both p73 and p63, like p53, can induce cell-cycle arrest and apoptosis, suggesting that they might also be tumor suppressors. However, the physiological signals that can regulate p53, for example, DNA damage, have no effect on p73, as tested in several cell lines. Furthermore, the signaling pathways by which p73 (and possibly p63) induces cell-cycle arrest and apoptosis appear to be similar to those of p53, but also have important differences. Thus, the p53 family proteins are closely related but might have distinct physiological functions.