Cyclic-AMP-dependent protein kinase A regulates apoptosis by stabilizing the BH3-only protein Bim

被引：53

作者：

Moujalled, Diane ^{[1
,2
]}

Weston, Ross ^{[1
]}

Anderton, Holly ^{[1
]}

Ninnis, Robert ^{[1
]}

Goel, Pranay ^{[1
]}

Coley, Andrew ^{[1
,2
]}

Huang, David C. S. ^{[3
]}

Wu, Li ^{[3
]}

Strasser, Andreas ^{[3
]}

Puthalakath, Hamsa ^{[1
,2
]}

机构：

[1] La Trobe Univ, Dept Biochem, La Trobe Inst Mol Sci, Bundoora, Vic 3086, Australia

[2] La Trobe Univ, Cooperat Res Ctr Biomarker Translat, Dept Biochem, Bundoora, Vic 3086, Australia

[3] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia

来源：

EMBO REPORTS | 2011年 / 12卷 / 01期

基金：

澳大利亚研究理事会; 英国医学研究理事会;

关键词：

apoptosis; Bim; cAMP; PKA; PHOSPHORYLATION; ACTIVATION; EXPRESSION; CELLS; DEGRADATION; INHIBITION; RESISTANCE; LYMPHOMA; PRKAR1A; PATHWAY;

D O I：

10.1038/embor.2010.190

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 proapoptotic Bcl2 homology domain 3(BH3)-only protein Bim is controlled by stringent post-translational regulation, predominantly through alterations in phosphorylation status. To identify new kinases involved in its regulation, we carried out a yeast two-hybrid screen using a non-spliceable variant of the predominant isoform-Bim(EL)-as the bait and identified the regulatory subunit of cyclic-AMP-dependent protein kinase A-PRKAR1A-as an interacting partner. We also show that protein kinase A (PKA) is a Bim(EL) isoform-specific kinase that promotes its stabilization. Inhibition of PKA or mutation of the PKA phosphorylation site within Bim(EL) resulted in its accelerated proteasome-dependent degradation. These results might have implications for human diseases that are characterized by abnormally increased PKA activity, such as the Carney complex and dilated cardiomyopathy.

引用

页码：77 / 83

页数：7

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