gadd45 Is Not Required for Activation of c-Jun N-terminal Kinase or p38 during Acute Stress

Using embryo fibroblasts from gadd45-null mice, we have addressed the requirement for Gadd45 in mediating Jun N-terminal kinase /p38 activation during acute stress

Xiantao Wang; Myriam Gorospe; Nikki J. Holbrook


Scholarcy highlights

  • Additional experiments demonstrated that the Gadd45-related proteins were capable of enhancing MTK1 activity in vitro and that their overexpression led to activation of Jun N-terminal kinase and p38
  • Activation of JNK and p38 in gadd45ϩ/ϩ and gadd45Ϫ/Ϫ MEF—To determine whether Gadd45 was necessary for JNK activation during stress, we examined the relative activation of JNK occurring in response to a panel of stresses in primary embryo fibroblasts obtained from wild type and gadd45null mice
  • The kinetics of activation varied for the different stresses, in all cases JNK activation was apparent at the earliest time point examined and occurred in the absence of detectable gadd45 expression
  • General Discussion—The recent finding that Gadd45 and the Gadd45-related proteins, MyD118/Gadd45␤ and CR6/ Gadd45␥, can bind directly to MTK1 and enhance its kinase activity has implicated these proteins in the early signaling events leading to JNK and p38 activation
  • It was proposed that DNA damage and other environmental stresses result in the induction of Gadd45-related proteins, which in turn activate MTK1 leading to activation of JNK and p38
  • Our observation that JNK and p38 activation in response to environmental stresses clearly precedes induction of all three gadd45-related genes argues strongly against the hypothesis that stress-induced levels of the Gadd45-related proteins are involved in the acute activation of JNK and p38
  • It is possible that the Gadd45-related proteins serve a role in regulating MTK1 activity that can be satisfied by basal levels of the proteins, but that MTK1 activation in cells requires some additional factor(s) that is influenced by stress

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