GADD45 family proteins suppress JNK signaling by targeting MKK7

Growth arrest and DNA damage-inducible 45 (GADD45) family genes encode related proteins, including GADD45 alpha, GADD45 beta, and GADD45 gamma. In HeLa cells, expression of GADD45 members is differentially regulated under a variety of environmental conditions, but thermal and genotoxic stresses induce the expression of all genes. The heat shock response of GADD45 beta is mediated by the heat shock transcription factor 1 (HSF1), and GADD45 beta is necessary for heat stress survival. Heat and genotoxic stress-induced activation of c-Jun N-terminal kinase (JNK) is suppressed by the expression of GADD45 proteins. GADD45 proteins bind the JNK kinase mitogen-activated protein kinase kinase 7 (MKK7) and inhibit its activity, even under normal physiological conditions. Our findings indicate that GADD45 essentially suppresses the MKK7-JNK pathway and suggest that differentially expressed GADD45 family members fine-tune stress-inducible JNK activity.