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Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalpha 总被引:1,自引:0,他引:1
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Heissmeyer V Krappmann D Hatada EN Scheidereit C 《Molecular and cellular biology》2001,21(4):1024-1035
p105 (NFKB1) acts in a dual way as a cytoplasmic IkappaB molecule and as the source of the NF-kappaB p50 subunit upon processing. p105 can form various heterodimers with other NF-kappaB subunits, including its own processing product, p50, and these complexes are signal responsive. Signaling through the IkappaB kinase (IKK) complex invokes p105 degradation and p50 homodimer formation, involving p105 phosphorylation at a C-terminal destruction box. We show here that IKKbeta phosphorylation of p105 is direct and does not require kinases downstream of IKK. p105 contains an IKK docking site located in a death domain, which is separate from the substrate site. The substrate residues were identified as serines 923 and 927, the latter of which was previously assumed to be a threonine. S927 is part of a conserved DSGPsi motif and is functionally most critical. The region containing both serines is homologous to the N-terminal destruction box of IkappaBalpha, -beta, and -epsilon. Upon phosphorylation by IKK, p105 attracts the SCF E3 ubiquitin ligase substrate recognition molecules betaTrCP1 and betaTrCP2, resulting in polyubiquitination and complete degradation by the proteasome. However, processing of p105 is independent of IKK signaling. In line with this and as a physiologically relevant model, lipopolysaccharide (LPS) induced degradation of endogenous p105 and p50 homodimer formation, but not processing in pre-B cells. In mutant pre-B cells lacking IKKgamma, processing was unaffected, but LPS-induced p105 degradation was abolished. Thus, a functional endogenous IKK complex is required for signal-induced p105 degradation but not for processing. 相似文献
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Activation of NF-kappaB nuclear transcription factor by flow in human endothelial cells 总被引:3,自引:0,他引:3
Hay DC Beers C Cameron V Thomson L Flitney FW Hay RT 《Biochimica et biophysica acta》2003,1642(1-2):33-44
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The 'classical' NF-kappaB activation pathway proceeds via IkappaB kinase (IKK)-beta/gamma-mediated phosphorylation, induced ubiquitination and the degradation of small IkappaBs. An alternative, NF-kappaB-inducing kinase and IKK-alpha-dependent pathway, which stimulates the processing of NF-kappaB2/p100, has recently been suggested. However, no physiological stimulus has been shown to trigger the activation of this pathway. Here we demonstrate that persistent stimulation with lymphotoxin beta (LT-beta) receptor agonists or lipopolysaccharide (LPS), but not with interleukin-1beta, tumour necrosis factor-alpha or 12-O-tetradecanoylphorbol-13-acetate, induces the generation of p52 DNA-binding complexes by activating the processing of the p100 precursor. Induction of p52 DNA-binding activity is delayed in comparison with p50/p65 complexes and depends on de novo protein synthesis. p100 is constitutively and inducibly polyubiquitinated, and both ubiquitination and p52 generation are coupled to continuing p100 translation. Thus, both LT-beta receptor agonists and LPS induce NF-kappaB/p100 processing to p52 at the level of the ribosome. 相似文献
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Bcl-2 can suppress apoptosis by controlling genes that encode proteins required for programmed cell death and by interference with peroxidative damage. Overexpression of Bcl-2 in NIH3T3 cells can prevent GSNO-induced (S-nitrosoglutathione-induced) apoptosis. The experimental results indicated that activation of NF-kappaB by GSNO is involved in inducing apoptosis. Surprisingly, we found that Bcl-2 delayed the release of IkB by formation of a Bcl-2-NF-kappaB complex (p50-p65-IkappaB) in the cytoplasm during cell apoptosis. Furthermore, a novel Bcl-2-p50 complex was found in the nucleus. These features were only observed in Bcl-2-transfected cells but not in the parental NIH3T3 cells. Overexpression of Bcl-2 suppressed the levels of c-myc, a target gene of NF-kappaB, and influenced the DNA-binding activity of NF-kappaB during GSNOinduced apoptosis. We suggest that the Bcl-2-p50 complex inhibits NF-kappaB DNA-binding activity by competing with the p65-p50 heterodimer for the DNA-binding site in the nucleus. Finally, it has been demonstrated that the anti-apoptotic potential of Bcl-2 may be attributed to its complexing with p50 in the nucleus that leads to blockage of nuclear gene expression. 相似文献
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Interleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclear factor kappaB DNA binding. 总被引:30,自引:0,他引:30
A J Schottelius M W Mayo R B Sartor A S Baldwin 《The Journal of biological chemistry》1999,274(45):31868-31874
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PTEN blocks tumor necrosis factor-induced NF-kappa B-dependent transcription by inhibiting the transactivation potential of the p65 subunit. 总被引:4,自引:0,他引:4
Marty W Mayo Lee V Madrid Sandy D Westerheide David R Jones Xiu-Juan Yuan Albert S Baldwin Young E Whang 《The Journal of biological chemistry》2002,277(13):11116-11125
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Inhibition of NF-kappa B by S-nitrosylation 总被引:8,自引:0,他引:8