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TNFα induced noncanonical NF-κB activation is attenuated by RIP1 through stabilization of TRAF2.

Kim, JY; Morgan, M; Kim, DG; Lee, JY; Bai, L; Lin, Y; Liu, ZG; Kim, YS
Journal of cell science, 124(Pt 4):647-656, 2011
Journal Title
Journal of cell science
The current paradigm of noncanonical NF-κB signaling suggests that the loss of TRAF2, TRAF3 or cIAP1 and cIAP2 leads to stabilization of NF-κB-inducing kinase (NIK) to activate the noncanonical pathway. Although a crucial role of RIP1 in the TNFα-induced canonical NF-κB pathway has been well established, its involvement in noncanonical activation of NF-κB through the TNFR1 receptor, is unknown. Here we show that TNFα is capable of activating the noncanonical NF-κB pathway, but that activation of this pathway is negatively regulated by RIP1. In the absence of RIP1, TNFR1 stimulation leads to activation of the noncanonical NF-κB pathway through TRAF2 degradation, leading to NIK stabilization, IKKα phosphorylation and the processing of p100 to generate p52. Thus although RIP1(-/-) mouse embryonic fibroblasts are sensitive at early time points to cell death induced by TNFα, probably as a result of lack of canonical NF-κB activation, the late activation of the noncanonical NF-κB pathway protects the remaining cells from further cell death. The TNFR1-dependent noncanonical NF-κB activation in RIP1(-/-) cells suggests that there is functional interplay between the two NF-κB pathways during TNFR1 signaling, which might regulate the number and kinds of NF-κB transcription factors and thus finely control NF-κB-dependent gene transcription.
MeSH terms
AnimalsCell LineGTPase-Activating Proteins/genetics/*metabolismHumansMiceMice, KnockoutNF-kappa B/genetics/*metabolismProtein BindingProtein StabilitySignal TransductionTNF Receptor-Associated Factor 2/chemistry/genetics/*metabolismTumor Necrosis Factor-alpha/genetics/*metabolism
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Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
김, 유선
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