Activation of p53 function in carcinoma cells by the α6β4 integrin

The interaction of integrins with extracellular matrix is known to promote cell survival by inhibiting apoptotic signaling. In contrast, we demonstrate here that the alpha(6)beta(4) integrin induces apoptosis in carcinoma cells by stimulating p53 function. Specifically, we show that expression of alpha(6)beta(4) 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, box, In addition, we report that alpha(6)beta(4) triggers apoptosis in carcinoma cells that express wild-type but not mutant p53 and that these alpha(6)beta(4) 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 alpha(6)beta(4) with a beta(4) integrin-specific antibody promotes p53-dependent apoptosis in cells that express both alpha(6)beta(4) 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 alpha(6)beta(4) 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 alpha(6)beta(4) to promote carcinoma progression will be enhanced in tumor cells that express mutant, inactive forms of p53.