Targeting the p53-Family in Cancer and Chemosensitivity: Triple Threat

The p53-family of transcription factors consists of three genes - p53, p63, and p73 - that share significant structural and functional similarities. Although these genes encode multiple variants that have opposing functions in cancer biology, the full-length, transactivating (TA) p53-family members are potent inducers of apoptosis and tumor suppression. Many anti-cancer agents, from traditional chemo- and radiation therapies to more recently developed small molecules, exert their effects by enhancing the anti-proliferative effects of p53 and TAp63/p73. In this review, we provide an overview of the regulatory pathways controlling the p53-family proteins as a framework for understanding p53-family targeted drug mechanisms. We will also summarize recent work on promising attempts to re-activate p53 in tumors. In addition, we will discuss how p63 and p73 - the two more recently discovered p53-family members - have affected drug discovery and how these two genes may also hold promise as drug targets for recent and future novel therapies. This review will emphasize how targeting multiple members of the family of p53 proteins is likely to provide an increased threat to the growth of cancer cells.