Widmann C, Gerwins P, Johnson N L, Jarpe M B, Johnson G L
Division of Basic Sciences, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206, USA.
Mol Cell Biol. 1998 Apr;18(4):2416-29. doi: 10.1128/MCB.18.4.2416.
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.
丝裂原活化蛋白激酶激酶1（MEKK1）是一种196千道尔顿的蛋白质，在受到基因毒性试剂刺激后，它会发生磷酸化依赖性激活。激酶失活的MEKK1的表达抑制了基因毒素诱导的细胞凋亡。在被基因毒素激活后，MEKK1以半胱天冬酶依赖性方式裂解为活性91千道尔顿的激酶片段。MEKK1的表达刺激了DEVD定向的半胱天冬酶活性并诱导了细胞凋亡。MEKK1本身是CPP32（半胱天冬酶-3）的底物。一种对半胱天冬酶裂解具有抗性的突变型MEKK1诱导细胞凋亡的能力受损。这些发现表明，MEKK1参与了对基因毒素的凋亡反应。基因毒素对MEKK1的调节涉及其激活，这可能是生存途径的一部分，随后是其裂解，这会产生一个能够激活半胱天冬酶的促凋亡激酶片段。预计MEKK1和半胱天冬酶是凋亡过程中增加半胱天冬酶活性的放大环的一部分。
