title: Inactivation of BAD by IKK inhibits TNFα-induced apoptosis independently of NF-κB activation.
abstract: The IκB kinase complex (IKK) is a key regulator of immune responses, inflammation, cell survival, and tumorigenesis. The prosurvival function of IKK centers on activation of the transcription factor NF-κB, whose target gene products inhibit caspases and prevent prolonged JNK activation. Here, we report that inactivation of the BH3-only protein BAD by IKK independently of NF-κB activation suppresses TNFα-induced apoptosis. TNFα-treated Ikkβ(-/-) mouse embryonic fibroblasts (MEFs) undergo apoptosis significantly faster than MEFs deficient in both RelA and cRel due to lack of inhibition of BAD by IKK. IKK phosphorylates BAD at serine-26 (Ser26) and primes it for inactivation. Elimination of Ser26 phosphorylation promotes BAD proapoptotic activity, thereby accelerating TNFα-induced apoptosis in cultured cells and increasing mortality in animals. Our results reveal that IKK inhibits TNFα-induced apoptosis through two distinct but cooperative mechanisms: activation of the survival factor NF-κB and inactivation of the proapoptotic BH3-only BAD protein.
authors: Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
authors: Jie
authors: J
authors: Yan
authors: Jialing
authors: J
authors: Xiang
authors: Yutin
authors: Y
authors: Lin
authors: Jingui
authors: J
authors: Ma
authors: Jiyan
authors: J
authors: Zhang
authors: Hao
authors: H
authors: Zhang
authors: Jisheng
authors: J
authors: Sun
authors: Nika N
authors: NN
authors: Danial
authors: Jing
authors: J
authors: Liu
authors: Anning
authors: A
authors: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis; D005347:Fibroblasts / Q000166:cytology; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D051025:bcl-Associated Death Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494820:Bad protein, mouse; C494812:Bcl2l1 protein, mouse; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D012694:Serine; D051550:I-kappa B Kinase