c-Jun NH2-terminal kinase promotes apoptosis by down-regulating the transcriptional co-repressor CtBP.
Genetic knock out of the transcriptional co-repressor carboxyl-terminal-binding protein (CtBP) in mouse embryonic fibroblasts results in up-regulation of several genes involved in apoptosis. We predicted, therefore, that a propensity toward apoptosis might be regulated through changes in cellular CtBP levels. Previously, we have identified the homeodomain-interacting protein kinase 2 as such a regulator and demonstrated that HIPK2 activation causes Ser-422 phosphorylation and degradation of CtBP. In this study, we found that c-Jun NH2-terminal kinase 1 activation triggered CtBP phosphorylation on Ser-422 and subsequent degradation, inducing p53-independent apoptosis in human lung cancer cells. JNK1 has previously been linked to UV-directed apoptosis. Expression of MKK7-JNK1 or exposure to UV irradiation reduced cellular levels of CtBP via a proteasome-mediated pathway. This effect was prevented by JNK1 deficiency. In addition, sustained activation of the JNK1 pathway by cisplatin similarly triggered CtBP degradation. These findings provide a novel target for chemotherapy in cancers lacking p53.
Wang
Su-Yan
SY
Vollum Institute and Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon 97239, USA.
Iordanov
Mihail
M
Zhang
Qinghong
Q
D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D002945:Cisplatin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D005347:Fibroblasts; D017353:Gene Deletion; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048688:MAP Kinase Kinase 7 / Q000378:metabolism; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014466:Ultraviolet Rays
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D048688:MAP Kinase Kinase 7; C482569:MAP2K7 protein, human; D002945:Cisplatin