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
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
收藏
页码:77 / 83
页数:7
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