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J Biol Chem, Vol. 274, Issue 29, 20733-20737, July 16, 1999

Activation of p53 Function in Carcinoma Cells by the alpha 6beta 4 Integrin

Robin E. BachelderDagger , Alessandra Marchetti, Rita Falcioni, Silvia Soddu, and Arthur M. MercurioDagger

From the Dagger  Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215 and  Regina Elena Cancer Institute, Rome 00158, Italy

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 6beta 4 integrin induces apoptosis in carcinoma cells by stimulating p53 function. Specifically, we show that expression of alpha 6beta 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, bax. In addition, we report that alpha 6beta 4 triggers apoptosis in carcinoma cells that express wild-type but not mutant p53 and that these alpha 6beta 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 6beta 4 with a beta 4 integrin-specific antibody promotes p53-dependent apoptosis in cells that express both alpha 6beta 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 6beta 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 6beta 4 to promote carcinoma progression will be enhanced in tumor cells that express mutant, inactive forms of p53.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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