Independent regulation of JNK/p38 mitogen-activated protein kinases by metabolic oxidative stress in the liver.
The stress-activated protein kinases JNK and p38 mediate increased gene expression and are activated by environmental stresses and proinflammatory cytokines. Using an in vivo model in which oxidative stress is generated in the liver by intracellular metabolism, rapid protein-DNA complex formation on stress-activated AP-1 target genes was observed. Analysis of the induced binding complexes indicates that c-fos, c-jun, and ATF-2 were present, but also two additional jun family members, JunB and JunD. Activation of JNK precedes increased AP-1 DNA binding. Furthermore, JunB was shown to be a substrate for JNK, and phosphorylation requires the N-terminal activation domain. Unexpectedly, p38 activity was found to be constitutively active in the liver and was down-regulated through selective dephosphorylation following oxidative stress. One potential mechanism for p38 dephosphorylation is the rapid stress-induced activation of the phosphatase MKP-1, which has high affinity for phosphorylated p38 as a substrate. These data demonstrate that there are mechanisms for independent regulation of the JNK and p38 mitogen-activated protein kinase signal transduction pathways after metabolic oxidative stress in the liver.
Mendelson
K G
KG
Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111, USA.
Contois
L R
LR
Tevosian
S G
SG
Davis
R J
RJ
Paulson
K E
KE
D000818:Animals; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002455:Cell Division; D004247:DNA / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D017874:Immediate-Early Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases; D008954:Models, Biological; D018384:Oxidative Stress; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D013379:Substrate Specificity; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D018808:Transcription Factor AP-1; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases