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 language | English (US) |
|---|---|
| Pages (from-to) | 304-315 |
| Number of pages | 12 |
| Journal | Cell |
| Volume | 152 |
| Issue number | 1-2 |
| DOIs | |
| State | Published - Jan 7 2013 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
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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 journal › Article
TY - JOUR
T1 - Inactivation of BAD by IKK inhibits TNFα-induced apoptosis independently of NF-κB activation
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
PY - 2013/1/7
Y1 - 2013/1/7
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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UR - http://www.scopus.com/inward/citedby.url?scp=84872587266&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2012.12.021
DO - 10.1016/j.cell.2012.12.021
M3 - Article
VL - 152
SP - 304
EP - 315
JO - Cell
JF - Cell
SN - 0092-8674
IS - 1-2
ER -