Stem cells are a source of differentiated cells in Multiple tissues. If genetic alterations occur in stem cells, the problem persists and malignant cancers may arise. Delta Np63 alpha-a homologue of the tumor suppressor p53-is exclusively expressed in proliferating undifferentiated epithelial cells and cancer cells of epidermal origin. Here, we show that Delta Np63 alpha antagonizes DNA damage-induced apoptosis in a p53-independent manner. We found that upon cellular injury, Delta Np63 alpha must be downregulated before apoptotic program can be activated. The 5637 cell line has abundant levels of Delta Np63 alpha and mutant p53, and it is resistant to DNA damage-induced apoptosis. The knockdown of Delta Np63 alpha by RNA interference sensitized these cells to apoptosis upon genotoxic insult. This suggests that Delta Np63 alpha plays an anti-apoptotic role regardless of the p53 status. Considering the frequent mutations of p53 in tumor cells, our results provide important implications for the treatment of cancers in which p63 is amplified. (c) 2006 Elsevier Inc. All rights reserved.