BRCA1-IRIS overexpression abrogates UV-induced p38MAPK/p53 and promotes proliferation of damaged cells

Abstract

Cells ability to evade cell death and to proliferate post geno-/cell-toxic stresses likely leads to formation of cancer. Activation of p38MAPK and p53 following these stresses helps protect cells against cancer development by initiating apoptosis. The duration of p38MAPK and p53 activation is regulated by the WIP1 phosphatase. BRCA1-IRIS triggers WIP1 expression in a p53-dependent and-independent manner. BRCA1-IRIS triggers the expression and cytoplasmic localization of the mRNA stabilization and translation inducer, HuR, that binds p53 and PPM1D mRNA. Hence, BRCA1-IRIS overexpression inactivates p38MAPK and/or p53 by upregulating WIP1 expression. BRCA1-IRIS abrogation of the homeostatic balance maintained by the p38MAPK-p53-WIP1 pathway suppressed cell death induced by a lethal dose of short-wavelength UV light, and high dosage of etoposide or H2O2, and allowed cells to survive and proliferate post geno-/cell-toxic stresses. This mechanism represents a new link between geno-/cell-toxic stress and aggressive breast cancer formation in p53 wild-type cells. © 2010 Macmillan Publishers Limited All rights reserved.