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Inactivation of BAD by IKK inhibits TNF?-induced apoptosis independently of NF-?B activation.

ABSTRACT: The I?B 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-?B, 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-?B activation suppresses TNF?-induced apoptosis. TNF?-treated Ikk?(-/-) 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 TNF?-induced apoptosis in cultured cells and increasing mortality in animals. Our results reveal that IKK inhibits TNF?-induced apoptosis through two distinct but cooperative mechanisms: activation of the survival factor NF-?B and inactivation of the proapoptotic BH3-only BAD protein.

SUBMITTER: Yan J 

PROVIDER: S-EPMC3586589 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Inactivation of BAD by IKK inhibits TNFα-induced apoptosis independently of NF-κB activation.

Yan Jie J   Xiang Jialing J   Lin Yutin Y   Ma Jingui J   Zhang Jiyan J   Zhang Hao H   Sun Jisheng J   Danial Nika N NN   Liu Jing J   Lin Anning A  

Cell 20130101 1-2

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 apoptosi  ...[more]

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