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

ABSTRACT

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.

ACKNOWLEDGMENTS

We thank Thomas Schlesinger for performing the experiment shown in Fig. 4A.

C.W. is the recipient of grant 823A-042980 from the Swiss National Science Foundation. P.G. is supported by the Fullbright Commission; the Wennergren Foundation; the Karolinska Institute; and the Swedish Medical Research Council, Cancer Foundation, Society of Medicine, and Institute. This work was supported by NIH grants DK37871, DK48845, CA58157, and GM30324.