Open AccessIndependent regulation of JNK/p38 mitogen-activated protein kinases by metabolic oxidative stress in the liver
Author(s) -
Mendelson Kg,
Contois Lr,
Tevosian Sg,
RJ Davis,
Paulson Ke
Publication year - 1996
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.93.23.12908
Subject(s) - junb , p38 mitogen activated protein kinases , kinase , microbiology and biotechnology , dephosphorylation , phosphatase , protein kinase a , ask1 , phosphorylation , oxidative stress , signal transduction , mitogen activated protein kinase , biology , chemistry , biochemistry , mitogen activated protein kinase kinase , transcription factor , gene
The stress-activated protein kinases JNK and p38 mediate increased gene expression and are activated by environmental stresses and proinflammatory cytokines. Using anin 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.