How the TP53 Family Proteins TP63 and TP73 Contribute to Tumorigenesis: Regulators and Effectors

In mammals, the p53 family comprises two additional members, p63 and p73 (hereafter referred to as TP53, TP63, and TP73, respectively). The usage of two alternative promoters produces protein variants either with (transactivating [TA] isoforms) or without (N isoforms) the N-terminal transactivation domain (TAD). In general, the TA proteins exert TP53-like tumor-suppressive activities through their ability to activate a common set of target genes. The N proteins can act as dominant-negative inhibitors of the transcriptionally active family members. Additionally, they possess intrinsic-specific biological activities due to the presence of alternative TADs, and as a result of engaging a different set of regulators. This review summarizes the current understanding of upstream regulators and downstream effectors of the TP53 family proteins, with particular emphasis on those that are relevant for their role in tumorigenesis. Furthermore, we highlight the existence of networks and cross-talks among the TP53 family members, their modulators, as well as the transcriptional targets.