Induction of the SAPK activator MIG-6 by the alkylating agent methyl methanesulfonate.
The alkylating agent methylmethanesulfonate (MMS) activates the c-jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) and the p38 mitogen-activated protein kinase (p38MAPK) pathways via different mechanisms of action. Activation of p38MAPK by MMS involves the pp125 focal adhesion kinase-related tyrosine kinase RAFTK and the MAPK kinase 3. The way in which MMS can activate JNK/SAPK has not been elucidated. Here we describe the identification by differential display of human mitogen-activated gene-6 (MIG-6) as a novel MMS-inducible gene. Induction of MIG-6 by MMS was found in human diploid skin fibroblasts and in simian virus 40-transformed skin fibroblasts, indicating that the enhanced expression of MIG-6 after MMS-treatment did not require p53. The signal leading to activation of MIG-6 appeared to be independent of DNA damage. High MIG-6 expression was found in the liver, lung, and placenta. MIG-6 is an adapter protein that binds to the activated form of cdc42Hs and to 14-3-3 proteins, thereby activating JNK/SAPKs. Our results suggest that activation of JNK/SAPKs by MMS may involve the induction of MIG-6.
van Laar
T
T
Department of Radiation Genetics and Chemical Mutagenesis, Medical Genetics Centre Southwest Netherlands, Leiden University Medical Centre, Leiden, The Netherlands.
Schouten
T
T
van der Eb
A J
AJ
Terleth
C
C
D048868:Adaptor Proteins, Signal Transducing; D000477:Alkylating Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004249:DNA Damage; D018076:DNA, Complementary / Q000378:metabolism; D004171:Diploidy; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008741:Methyl Methanesulfonate / Q000494:pharmacology*; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013539:Simian virus 40 / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays
D048868:Adaptor Proteins, Signal Transducing; D000477:Alkylating Agents; D002352:Carrier Proteins; D018076:DNA, Complementary; C484017:ERRFI1 protein, human; D025521:Tumor Suppressor Proteins; D008741:Methyl Methanesulfonate; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases