TP63 and TP73 in cancer, an unresolved “family” puzzle of complexity, redundancy and hierarchy

Abstract

a b s t r a c t TP53 belongs to a small gene family that includes, in mammals, two additional paralogs, TP63 and TP73. The p63 and p73 proteins are structurally and functionally similar to p53 and their activity as transcription factors is regulated by a wide repertoire of shared and unique post-translational modifications and interactions with regulatory cofactors. p63 and p73 have important functions in embryonic development and differentiation but are also involved in tumor suppression. The biology of p63 and p73 is complex since both TP63 and TP73 genes are transcribed into a variety of different isoforms that give rise to proteins with antagonistic properties, the TA-isoforms that act as tumorsuppressors and DN-isoforms that behave as proto-oncogenes. The p53 family as a whole behaves as a signaling ''network'' that integrates developmental, metabolic and stress signals to control cell metabolism, differentiation, longevity, proliferation and death. Despite the progress of our knowledge, the unresolved puzzle of complexity, redundancy and hierarchy in the p53 family continues to represent a formidable challenge.

Hepatic p63 regulates steatosis via IKKβ/ER stress

“…The relevant role of p53 and p63 in cancer is well established404142. p53 null mice are viable but this protein is implicated in a large number of biological functions, including longevity, stress and ageing4344.…”

“…In contrast to p53, mice with genetic deletion of p63 have profound developmental alterations leading to early death45. In adult cells, the two major functions of p63 are considered to be tumour suppression and cell maintenance and renewal42. This latter function of p63 is quite attractive in tissues such as the liver with a high regenerative capacity following injury.…”

P63 in health and cancer

“…The p53 family regulates reproduction, DNA repair, metabolic processes, stem cells renewal and changes in epigenetic marks (Costanzo et al, 2014). P53 members undergo extensive posttranslational modifications, which regulate their stability and function.…”

Emerging from the shade of p53 mutants: N-terminally truncated variants of the p53 family in EMT signaling and cancer progression

“…All three genes encode for a plethora of protein isoforms. These isoforms are generated through usage of extrinsic (P1) and intrinsic (P2) promoters, alternative 5′ and 3′ splicing, and alternative initiation of translation (1).…”