A FAMILY OF STRESS-INDUCIBLE GADD45-LIKE PROTEINS MEDIATE ACTIVATION OF THE STRESS-RESPONSIVE MTK1 MEKK4 MAPKKK/

The stress-responsive p38 and JNK MAPK pathways regulate cell cycle an d apoptosis. A human MAPKKK, MTK1 (= MEKK4), mediates activation of bo th p38 and JNK in response to environmental stresses. Using a yeast tw o-hybrid method, three related proteins, GADD45 alpha (= GADD45), GADD 45 beta (= MyD118), and GADD45 gamma, were identified that bound to an N-terminal domain of MTK1. These proteins activated MTK1 kinase activ ity, both in vivo and in vitro. The GADD45-like genes are induced by e nvironmental stresses, including MMS, UV, and gamma irradiation. Expre ssion of the GADD45-like genes induces p38/JNK activation and apoptosi s, which can be partially suppressed by coexpression of a dominant inh ibitory MTK1 mutant protein. We propose that the GADD45-like proteins mediate activation of the p38/JNK pathway, via MTK1/MEKK4, in response to environmental stresses.