TAp63 induces cellular senescence and blocks Ras-driven tumor formation through p53-depdendent and -indepdendent mechanisms

LB-58

p63 encodes at least six different proteins due to multiple promoter usages and alternative splicing. Isoforms with an N-terminal transactivation domain homologous to that of p53 are referred to as the TA isoforms, whereas isoforms lacking this domain are referred to as the ΔN isoforms. p63 not only has critical function during embryonic development, it is also implicated in cancer. However, the specific role of each isoform during tumor development has not been fully characterized. Here we show that TAp63 is induced in response to oncogenic Ras, and p63 is required for Ras-induced cellular senescence in mouse embryonic fibroblasts (mefs). Further, we found that in the absence of p63, Ras- and DNA damage-induced stability of p53 is impaired, indicating that p63 is required for p53 's ability to mediate oncogene-induced senescence (OIS). In order to determine whether TAp63 is sufficient to induce cellular senescence, we ectopically expressed TAp63 in wild type mefs. Indeed, TAp63 caused a senescent morphology, increased SA-β-gal activity and induced cell cycle arrest. Further, we found that TAp63-induced senescence is independent of p19/p53 and p16, but is dependent on activation of p21 and Rb. Lastly, we extended our study to tumorigenic cells. Whereas oncogenic Ras causes transformation and tumor formation in p53-deficient cells, TAp63 was able to block this Ras-driven transformation through induction of cellular senescence. Strikingly, p53-/- cells expressing both Ras and TAp63 no longer formed tumors in vivo. Our observations demonstrate that TAp63 regulates cellular senescence through both p53-dependent and p53-independent pathways, suggesting that TAp63 is a potential target of cancer therapy that may be particularly effective in tumors with compromised p53.