Inactivation of BAD by IKK Inhibits TNFα-Induced Apoptosis Independently of NF-κB Activation

被引：87
作者：
Yan, Jie [1 ]
Xiang, Jialing [2 ]
Lin, Yutin [2 ]
Ma, Jingui [1 ]
Zhang, Jiyan [1 ,3 ]
Zhang, Hao [4 ]
Sun, Jisheng [4 ]
Danial, Nika N. [5 ]
Liu, Jing [6 ]
Lin, Anning [1 ,4 ]
机构：
[1] Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA
[2] IIT, Dept Biol & Chem Sci, Chicago, IL 60616 USA
[3] Inst Basic Med Sci, Dept Mol Immunol, Beijing 100850, Peoples R China
[4] Chinese Acad Sci, Inst Biochem & Cell Biol, State Key Lab Cell Biol, Shanghai 200031, Peoples R China
[5] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA
[6] Northwestern Univ, Feinberg Sch Med, Div Pulm & Crit Care Med, Chicago, IL 60611 USA
来源：
CELL | 2013年 / 152卷 / 1-2期
基金：
美国国家卫生研究院; 中国国家自然科学基金;
关键词：
TUMOR-NECROSIS-FACTOR; SEVERE LIVER DEGENERATION; CELL-DEATH; TRANSCRIPTION FACTORS; SIGNAL-TRANSDUCTION; FEEDBACK INHIBITION; KINASE ACTIVATION; JNK ACTIVATION; DEFICIENT MICE; PHOSPHORYLATION;
D O I：
10.1016/j.cell.2012.12.021
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
The I kappa 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-kappa 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-kappa B activation suppresses TNF alpha-induced apoptosis. TNF alpha-treated Ikk beta(-/-) 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 alpha-induced apoptosis in cultured cells and increasing mortality in animals. Our results reveal that IKK inhibits TNF alpha-induced apoptosis through two distinct but cooperative mechanisms: activation of the survival facto r NF-kappa B and inactivation of the proapoptotic BH3-only BAD protein.
引用
收藏
页码：304 / 315
页数：12
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