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 journalArticle

53 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)304-315
Number of pages12
JournalCell
Volume152
Issue number1-2
DOIs
StatePublished - Jan 7 2013

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Chemical activation
Apoptosis
Fibroblasts
Serine
Cells
Phosphorylation
Caspases
Cultured Cells
Cell Survival
Carcinogenesis
Animals
Proteins
Transcription Factors
Phosphotransferases
Genes
Inflammation
Mortality

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yan, J., Xiang, J., Lin, Y., Ma, J., Zhang, J., Zhang, H., ... Lin, A. (2013). Inactivation of BAD by IKK inhibits TNFα-induced apoptosis independently of NF-κB activation. Cell, 152(1-2), 304-315. https://doi.org/10.1016/j.cell.2012.12.021
Yan, Jie ; Xiang, Jialing ; Lin, Yutin ; Ma, Jingui ; Zhang, Jiyan ; Zhang, Hao ; Sun, Jisheng ; Danial, Nika N. ; Liu, Jing ; Lin, Anning. / Inactivation of BAD by IKK inhibits TNFα-induced apoptosis independently of NF-κB activation. In: Cell. 2013 ; Vol. 152, No. 1-2. pp. 304-315.
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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.",
author = "Jie Yan and Jialing Xiang and Yutin Lin and Jingui Ma and Jiyan Zhang and Hao Zhang and Jisheng Sun and Danial, {Nika N.} and Jing Liu and Anning Lin",
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Yan, J, Xiang, J, Lin, Y, Ma, J, Zhang, J, Zhang, H, Sun, J, Danial, NN, Liu, J & Lin, A 2013, 'Inactivation of BAD by IKK inhibits TNFα-induced apoptosis independently of NF-κB activation', Cell, vol. 152, no. 1-2, pp. 304-315. https://doi.org/10.1016/j.cell.2012.12.021

Inactivation of BAD by IKK inhibits TNFα-induced apoptosis independently of NF-κB activation. / Yan, Jie; Xiang, Jialing; Lin, Yutin; Ma, Jingui; Zhang, Jiyan; Zhang, Hao; Sun, Jisheng; Danial, Nika N.; Liu, Jing; Lin, Anning.

In: Cell, Vol. 152, No. 1-2, 07.01.2013, p. 304-315.

Research output: Contribution to journalArticle

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AU - Yan, Jie

AU - Xiang, Jialing

AU - Lin, Yutin

AU - Ma, Jingui

AU - Zhang, Jiyan

AU - Zhang, Hao

AU - Sun, Jisheng

AU - Danial, Nika N.

AU - Liu, Jing

AU - Lin, Anning

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N2 - 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.

AB - 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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