Activation of c-Jun N-terminal kinase (JNK) by widely used specific p38 MAPK inhibitors SB202190 and SB203580: a MLK-3-MKK7-dependent mechanism.
Mitogen-activated protein kinases (MAPKs) are key signaling molecules that respond to mitogenic stimulation or environmental stress, resulting in the expression of target proteins. c-Jun N-terminal kinase (JNK) and p38 MAPKs are activated by inflammatory cytokines or environmental stress. Specific p38 MAPK inhibitors, such as SB202190 or SB203580, are widely used to dissect p38 MAPK-related signal transduction mechanisms. While using SB202190 to inhibit p38 MAPK-related signaling, we observed that SB202190 treatment could activate JNK. Further experiments showed that treatment of cells with SB202190 could phosphorylate JNK and activating transcription factor 2 (ATF-2), and increased AP-1 DNA binding. Using multiple cell lines and primary endothelial cells, we demonstrated that specific p38 MAPK inhibitors SB202190 or SB203580 induces the activation of the JNK pathway. Further, using with RNA interference and kinase-inactive expression of intermediates of the JNK pathway, we demonstrated SB202190- or SB203580-induced JNK activation is dependent on the MLK-3-MKK4/MKK7-dependent signal transduction pathway. Finally, we demonstrate that treatment of cells with SB202190 or SB203580 induces the phosphorylation and activation of MLK3.
Muniyappa
Harish
H
Department of Pathology and the Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, 4301 West Markham, Slot # 845, Little Rock, AR 72205, United States.
Das
Kumuda C
KC
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048688:MAP Kinase Kinase 7 / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D051698:Activating Transcription Factor 2; D020536:Enzyme Activators; D007093:Imidazoles; D048031:JNK Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; D020930:MAP Kinase Kinase Kinases; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D011725:Pyridines; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C497105:ATF2 protein, human; C482569:MAP2K7 protein, human; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole