Abstract 3105: Expression of Wip1, a homeostatic regulator, is competitively controlled by c-Jun and p53 in response to UV irradiation

Abstract

Wild-type p53-induced phosphatase (Wip1) is induced by p53 in response to various stresses, resulting in the dephosphorylation of proteins (i.e., p38 MAPK, p53, and uracil DNA glycosylase) involved in DNA repair and cell cycle checkpoint pathways. The p38 MAPK-p53 pathway has been a unique way for Wip1 induction as a stress responder. Here, we show that c-Jun directly binds to and activates the Wip1 promoter in response to UV irradiation. Mutation of the p53 response element (p53RE) or c-Jun consensus sites reduced promoter activities in both non-stressed and stressed A549 cells. Intriguingly, overexpression of p53 significantly decreased Wip1 expression in HCT116 p53+/+ cells but increased Wip1 expression in HCT116 p53−/− cells. Adenovirus-mediated p53 overexpression greatly decreased JNK activity. Up-regulation of Wip1 via the p38 MAPK-p53 and JNK-c-Jun pathways is specific, as demonstrated by our findings that p38 MAPK and JNK inhibitors affected the expression of Wip1 protein, whereas an ERK inhibitor did not. The JNK-c-Jun and p38 MAPK-p53 pathways were activated concomitantly in A549 cells; however, c-Jun activation occurred much more quickly, and to a greater extent, in A549-E6 cells, with delayed but fully induced Wip1 expression. Collectively, these data indicate that Wip1 is activated via both the JNK-c-Jun and p38 MAPK-p53 signaling pathways and that temporal induction of Wip1 largely depends on the balance between c-Jun and p53, because of their competition for JNK binding. Moreover, our results suggest that JNK-c-Jun-mediated Wip1 induction could serve as a major signaling pathway in human tumors, because of frequent p53 mutation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3105.