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J. Cell Biol. 147 (5): 1063-1072

Copyright © 1999 by the Rockefeller University Press.

Original Article

P53 Inhibits {alpha}6β4 Integrin Survival Signaling by Promoting the Caspase 3–Dependent Cleavage of Akt/PKB

Robin E. Bacheldera,b, Mark J. Ribicka,b, Alessandra Marchettib, Rita Falcionic, Silvia Sodduc, Kathryn R. Davisa,b, , and Arthur M. Mercurioa

a Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center
b Harvard Medical School, Boston, Massachusetts 02215
c Regina Elena Cancer Institute, Rome, 00158 Italy
Beth Israel Deaconess Medical Center, Research North, 330 Brookline Avenue, Boston, MA 02215.(617) 975-5531(617) 667-7714


Abstract: Although the interaction of matrix proteins with integrins is known to initiate signaling pathways that are essential for cell survival, a role for tumor suppressors in the regulation of these pathways has not been established. We demonstrate here that p53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase AKT/PKB. Specifically, we show that the {alpha}6β4 integrin promotes the survival of p53-deficient carcinoma cells by activating AKT/PKB. In contrast, this integrin does not activate AKT/PKB in carcinoma cells that express wild-type p53 and it actually stimulates their apoptosis, in agreement with our previous findings (Bachelder, R.E., A. Marchetti, R. Falcioni, S. Soddu, and A.M. Mercurio. 1999. J. Biol. Chem. 274:20733–20737). Interestingly, we observed reduced levels of AKT/PKB protein after antibody clustering of {alpha}6β4 in carcinoma cells that express wild-type p53. In contrast, {alpha}6β4 clustering did not reduce the level of AKT/PKB in carcinoma cells that lack functional p53. The involvement of caspase 3 in AKT/PKB regulation was indicated by the ability of Z-DEVD-FMK, a caspase 3 inhibitor, to block the {alpha}6β4-associated reduction in AKT/PKB levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of AKT/PKB in vitro. In addition, the ability of {alpha}6β4 to activate AKT/PKB could be restored in p53 wild-type carcinoma cells by inhibiting caspase 3 activity. These studies demonstrate that the p53 tumor suppressor can inhibit integrin-associated survival signaling pathways.

Key Words: p53 • integrin • AKT/PKB • survival • caspase

Abbreviations used in this paper: CAD, caspase-activated deoxyribonuclease; dnAKT, dominant negative AKT; dnp53, dominant negative p53; GFP, green fluorescent protein; HA, hemagglutinin; tsp53, temperature-sensitive p53.

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