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

Jie Yan, Jialing Xiang, Yutin Lin, Jingui Ma, Jiyan Zhang, Hao Zhang, Jisheng Sun, Nika N. Danial, Jing Liu, Anning Lin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)304-315
Number of pages12
Issue number1-2
StatePublished - Jan 7 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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