Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor (TNF) exerts many actions through activation of the transcription factor NF-kappaB. NF-kappaB is sequestered in the cytosol by an inhibitory subunit IkappaB, which is inducibly phosphorylated by an IkappaB kinase complex and subsequently degraded. Sodium salicylate (NaSal) can block NF-kappaB activation by inhibiting IkappaBalpha phosphorylation. Recently, we used the specific p38 mitogen-activated protein (MAP) kinase inhibitor SB203580 to demonstrate that inhibition of TNF-induced IkappaBalpha phosphorylation requires NaSal-induced p38 activation. We demonstrate that NaSal similarly inhibits TNF-induced IkappaBbeta degradation in a p38-dependent manner. To further examine the role of p38, we determined whether other agents that activate p38 can block TNF-induced IkappaB phosphorylation and degradation. Sorbitol, H(2)O(2), and arsenite each blocked IkappaBalpha phosphorylation induced by TNF, and SB203580 reversed the inhibitory effects of sorbitol and H(2)O(2), but not arsenite. In addition, sorbitol and H(2)O(2) blocked TNF-induced but not interleukin-1-induced IkappaBalpha phosphorylation, whereas arsenite inhibited IkappaBalpha phosphorylation induced by TNF and interleukin-1. Transient expression of MAP kinase kinase (MKK) 6b(E), a constitutive activator of p38, reduced both TNF-induced phosphorylation of IkappaBalpha and NF-kappaB-dependent reporter activity. However, MKK7(D), a constitutive activator of c-Jun N-terminal kinases, failed to inhibit these TNF actions. Thus, sustained p38 activation by various stimuli inhibits TNF-induced IkappaB phosphorylation and NF-kappaB activation.
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PMID:Cell stress and MKK6b-mediated p38 MAP kinase activation inhibit tumor necrosis factor-induced IkappaB phosphorylation and NF-kappaB activation. 1042 82