gadd45 is not required for activation of c-Jun N-terminal kinase or p38 during acute stress

Cells respond to environmental stress with activation of c-Jun N-terminal k inase (JNK) and p38. Recent studies have implicated Gadd45 and two related proteins, MyD118/Gadd45 beta and CR6/Gadd45 gamma, as initiators of JNK/p38 signaling via their interaction with an upstream kinase MTK1. It was propo sed that stress-induced expression of the Gadd45-related proteins leads to MTK1 activation and subsequent JNK/p38 activation. Using embryo fibroblasts from gadd45-null mice, we have addressed the requirement for Gadd45 in med iating JNK/p38 activation during acute stress. Comparison of JNH/p38 activi ties in response to methyl methanesulfonate, hydrogen peroxide, WC irradiat ion, sorbitol, and anisomycin treatment of gadd45(+/+) and gadd45(-/-) fibr oblasts revealed no deficiency in JNK/p38 activation in gadd45(-/-) fibrobl asts. In addition, in wild type cells, JNK and p38 activation significantly preceded gadd45 induction with all stresses. Examination of myd118/ gadd45 beta and cr6/gadd45 gamma expression in gadd45(+/+) and gadd45(-/-) fibrob lasts revealed similar induction patterns in the two cell types, which, lik e gadd45 expression, was delayed relative to JNK/p38 activation. We conclud e that gadd45 expression is not required for activation of JNK/p38 by envir onmental stresses, nor are stress-induced increases in myd118/gadd45 beta a nd cr6/ gadd45 gamma expression necessary for kinase activation in response to such insults.