Independent regulation of JNK/p38 mitogen-activated protein kinases by metabolic oxidative stress in the liver

AUTOR(ES)

Mendelson, Kim G.

FONTE

The National Academy of Sciences of the USA

RESUMO

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.

Documentos Relacionados

• Phosphorylation of NFATc4 by p38 Mitogen-Activated Protein Kinases
• Role of p38 and JNK mitogen-activated protein kinases in the activation of ternary complex factors.
• Targeting of p38 Mitogen-Activated Protein Kinases to MEF2 Transcription Factors
• ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis
• Opposing Effects of Jun Kinase and p38 Mitogen-Activated Protein Kinases on Cardiomyocyte Hypertrophy