P53 promotes cellular survival in a context-dependent manner by directly inducing the expression of haeme-oxygenase-1

Abstract

A variety of cellular insults activate the tumour suppressor p53, leading generally to cell-cycle arrest or apoptosis. However, it is not inconceivable that cellular protective mechanisms may be required to keep cells alive while cell-fate decisions are made. In this respect, p53 has been suggested to perform functions that allow cells to survive, by halting of the cell-cycle, and thus preventing immediate cell death. Nonetheless, the existence of direct pro-survival p53 target genes regulating cellular survival is lacking. We show here evidence for p53-dependent cellular survival in a context-dependent manner. Both mouse and human cells lacking p53 are hypersensitive to hydrogen peroxide (H 2 O 2)-induced cell death compared with their isogenic wild-type counterparts. By contrast, p53/cells are expectedly resistant to cell death upon exposure to DNA-damaging agents such as cisplatin (CDDP) and etoposide. Although p53 and its classical targets such as p21 and Mdm2 are activated by both H 2 O 2 and CDDP, we found that the expression of haeme-oxygenase-1 (HO-1)an antioxidant and antiapoptotic proteinwas directly induced only upon H 2 O 2 treatment in a p53-dependent manner. Consistently, p53, but not its homologue p73, activated HO-1 expression and was bound to the HO-1 promoter specifically only upon H 2 O 2 treatment. Moreover, silencing HO-1 expression enhanced cell death upon H 2 O 2 treatment only in p53-proficient cells. Finally, H 2 O 2-mediated cell death was rescued significantly in p53-deficient cells by antioxidant treatment, as well as by bilirubin, a by-product of HO-1 metabolism. Taken together, these data demonstrate a direct role for p53 in promoting cellular survival in a context-specific manner through the activation of a direct transcriptional target, HO-1. © 2011 Macmillan Publishers Limited All rights reserved.