text: Inactivation of BAD by IKK inhibits TNFα-induced apoptosis independently of NF-κB activation.
  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.
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entities.type: GENE-N GENE-N GENE-Y GENE-N GENE-N GENE-Y GENE-N GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-N GENE-N GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-N CHEMICAL GENE-Y GENE-N GENE-Y GENE-N CHEMICAL GENE-N GENE-Y GENE-N GENE-N GENE-N GENE-N
entities.text: JNK BH3 BAD IKK NF-κB TNFα IκB kinase TNFα Ikkβ RelA serine cRel BAD IKK IKK BAD BAD TNFα IKK TNFα NF-κB Ser BAD IKK TNFα NF-κB Ser BH3 BAD IKK NF-κB caspases IKK