The interaction of integrins with extracellular matrix is known to promote cell survival by inhibiting apoptotic signaling. In contrast, we demonstrate here that the α6β4 integrin induces apoptosis in carcinoma cells by stimulating p53 function. Specifically, we show that expression of α6β4 in carcinoma cells that lack this integrin stimulates an increase in the transactivating function of p53 as demonstrated by the ability of this integrin to up-regulate the expression of a p53-sensitive reporter gene as well as the endogenous p53 response gene, bax. In addition, we report that α6β4 triggers apoptosis in carcinoma cells that express wild-type but not mutant p53 and that these α6β4 functions are inhibited by a dominant negative p53 construct. Importantly, we provide a link between integrin signaling and p53 activation by demonstrating that the clustering of α6β4 with a β4 integrin-specific antibody promotes p53-dependent apoptosis in cells that express both α6β4 and wild-type p53. These studies are the first to demonstrate that a specific integrin can promote apoptosis by activating p53. Moreover, given the ability of α6β4 to stimulate invasion (Shaw, L. M., Rabinovitz, I., Wang, H. F., Toker, A., and Mercurio, A. M. (1997) Cell 91, 949-960), these studies suggest that the ability of α6β4 to promote carcinoma progression will be enhanced in tumor cells that express mutant, inactive forms of p53.
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