Activation of transcription factor NF-kappaB and p38 mitogen-activated protein kinase is mediated by distinct and separate stress effector pathways.
Mitogen-activated protein (MAP) kinases are important mediators of the cellular stress response. Here, we investigated the relationship between activation of the MAP kinase p38 and transcription factor NF-kappaB. Different forms of cellular stress were found to preferentially trigger either p38 or NF-kappaB. Arsenite or osmotic stress potently activated p38 but were ineffective in inducing NF-kappaB activation. Tumor necrosis factor-alpha and hydrogen peroxide, in contrast, led to NF-kappaB activation but only modestly stimulated p38. The activation of NF-kappaB was strongly abolished by antioxidants, while the activity of p38 and transcription factor AP-1 were increased. Inhibition of small GTPases including Rac and Cdc42 prevented p38 and AP-1 activation without interfering with NF-kappaB. In addition, inhibition of p38 by a pharmacological inhibitor or a dominant-negative mutant of MAP kinase kinase-6, an activator of the p38 pathway, interfered with NF-kappaB-dependent gene expression but not its DNA binding activity. Our results indicate that activation of p38 and NF-kappaB are mediated by separate pathways, which may converge further downstream in the cell nucleus. Different forms of cellular stress, however, initially trigger distinct signaling cascades involving either oxidative stress or GTPase-coupled pathways.
Wesselborg
S
S
Institute of Biochemistry and Molecular Biology, Albert-Ludwigs-University, D-79104 Freiburg, Germany.
Bauer
M K
MK
Vogt
M
M
Schmitz
M L
ML
Schulze-Osthoff
K
K
D051698:Activating Transcription Factor 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D016350:Leucine Zippers; D048669:MAP Kinase Kinase 6; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D013379:Substrate Specificity; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; C093642:SB 203580