Functional interplay between p53 and Δ133p53 in adaptive stress response

Apart from its well-known prodeath activity, p53 is also implicated in promoting cell survival. How p53 can mediate such seemingly opposing effects is largely unclear. We report here a novel mechanism in which p53-mediated proapoptosis is switched to antiapoptosis via its interaction with a p53 isoform, Δ133p53. We show that the expression of Δ133p53 is induced by mild or a moderate level of stress via an HIF1-dependent mechanism. Increased Δ133p53 levels contribute to the adaptive response by shifting the p53 binding at the Bcl2 promoter from suppressive responsive elements (RE) to activating REs, resulting in induction of Bcl2. In accordance with this mode of action, pretreatment of mice with mild stress induces Δ133p53 and Bcl2, which is associated with protection of animals from toxicity caused by high doses of DNA damage agents. Collectively, our work uncovers a novel functional interplay between p53 and Δ133p53 determining cell fate; survival or death in response to stress.