p63 and p73: p53 mimics, menaces and more

Less than five years ago, the tumour suppressor p53 was thought to be one of a kind, but the discovery of two related gene products, p63 and p73, raised the possibility that the genome has more than one guardian. All three genes encode transcription factors with an amino-terminal transactivation domain, a central DNA-binding domain and an oligomerization domain. The gene structures encoding p63 and p73 are more complex than that of p53, with two promoters each giving rise to isotypes of opposing functions. In addition, several splicing events contribute to the diversity of p63 and p73 isotypes. These fall into two broad categories: transactivating (TA) isoforms that resemble p53, and ΔN isoforms that are dominant-negative inhibitors of transcription. The ΔN isoforms explain why p63 and p73 can have oncogenic, as well as tumour-suppressor characteristics. Both the TA and ΔN forms have three possible carboxyl termini, and these isoforms are termed α, β and γ. The α isoforms have two domains not present in p53: a steric α-motif (SAM, thought to be involved in protein?protein interactions) and a post-SAM domain whose function is a mystery. Knockout mice have revealed functions for p63 and p73 that go beyond protecting the genome: p63 seems to control the balance of proliferation versus differentiation of epithelial stem cells, whereas p73 seems to be involved in fluid dynamics, neurogenesis and social behaviour. An important question, which could shed light on the our understanding of their function, is which of these three genes evolved first? Equally important is understanding how p63 and p73 control the processes of epithelial stem cell identity, neurogenesis, and secretion regulation, and the respective roles of the apparently contradictory isotypes in these events. Finally, what are the genetic and physical interactions among p53 family members and do they collaborate or clash in mechanisms of tumour suppression?