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Mol Cell Biol, April 1998, p. 2416-2429, Vol. 18, No. 4
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

MEK Kinase 1, a Substrate for DEVD-Directed Caspases, Is Involved in Genotoxin-Induced Apoptosis

Christian Widmann,1,2,* Pär Gerwins,1,2 Nancy Lassignal Johnson,1,2 Matthew B. Jarpe,1,2 and Gary L. Johnson1,2,3,*

Program in Molecular Signal Transduction1 and Division of Basic Sciences,2 National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206, and Department of Pharmacology, University of Colorado Medical School, Denver, Colorado 802623

Received 30 September 1997/Returned for modification 1 December 1997/Accepted 6 January 1998

MEK kinase 1 (MEKK1) is a 196-kDa protein that, in response to genotoxic agents, was found to undergo phosphorylation-dependent activation. The expression of kinase-inactive MEKK1 inhibited genotoxin-induced apoptosis. Following activation by genotoxins, MEKK1 was cleaved in a caspase-dependent manner into an active 91-kDa kinase fragment. Expression of MEKK1 stimulated DEVD-directed caspase activity and induced apoptosis. MEKK1 is itself a substrate for CPP32 (caspase-3). A mutant MEKK1 that is resistant to caspase cleavage was impaired in its ability to induce apoptosis. These findings demonstrate that MEKK1 contributes to the apoptotic response to genotoxins. The regulation of MEKK1 by genotoxins involves its activation, which may be part of survival pathways, followed by its cleavage, which generates a proapoptotic kinase fragment able to activate caspases. MEKK1 and caspases are predicted to be part of an amplification loop to increase caspase activity during apoptosis.

* Corresponding author. Mailing address for Christian Widmann: Division of Basic Sciences, National Jewish Center for Immunology and Respiratory Medicine, 1400 Jackson St., Denver, CO 80206. Phone: (303) 398-1772. Fax: (303) 398-1225. E-mail: johnsonlab{at}njc.org. Mailing address for Gary L. Johnson: Division of Basic Sciences, National Jewish Center for Immunology and Respiratory Medicine, 1400 Jackson St., Denver, CO 80206. Phone: (303) 398-1504. Fax: (303) 398-1225. E-mail: johnsonlab{at}njc.org.




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