MLH1- and ATM-dependent MAPK signaling is activated through c-Abl in response to the alkylator N-methyl-N'-nitro-N'-nitrosoguanidine.
N-Methyl-N'-nitro-N'-nitrosoguanidine (MNNG) is a DNA-methylating agent, and deficiency in mismatch repair (MMR) results in lack of sensitivity to this genotoxin (termed alkylation tolerance). A number of DNA damage response pathways are activated in a MMR-dependent manner following MNNG, and several also require ATM kinase activity. Here we show that activation of the transcription factor c-Jun is dependent upon both the MMR component MLH1 and ATM, but not ATR, in response to MNNG. In addition to c-Jun, the upstream MAPKs JNK and MKK4 are also activated in a MLH1- and ATM-dependent manner. We document that c-Jun activation is dependent on the MAPK kinase kinase MEKK1. Additionally, the tyrosine kinase c-Abl is required to activate this signaling cascade and forms a complex with MEKK1 and MLH1. This study indicates that an arm of DNA damage-activated MAPK signaling is activated in an MLH1- and ATM-dependent manner in response to MNNG and perhaps suggests that dysregulation of this signaling is responsible, in part, for alkylation tolerance.
Kim
Wan-Ju
WJ
Department of Biochemistry and Molecular Biology and the University of Florida Shands Cancer Center, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
Rajasekaran
Baskaran
B
Brown
Kevin D
KD
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology*; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism