Loss of Prkar1a leads to Bcl-2 family protein induction and cachexia in mice

被引：13

作者：

Gangoda, L. ^{[1
]}

Doerflinger, M. ^{[1
]}

Srivastava, R. ^{[1
]}

Narayan, N. ^{[2
]}

Edgington, L. E. ^{[1
]}

Orian, J. ^{[1
]}

Hawkins, C. ^{[1
]}

O'Reilly, L. A. ^{[2
,3
]}

Gu, H. ^{[4
,5
]}

Bogyo, M. ^{[6
]}

Ekert, P. ^{[2
]}

Strasser, A. ^{[2
,3
]}

Puthalakath, H. ^{[1
]}

机构：

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

[2] Walter & Eliza Hall Inst Med Res, Melbourne, Vic, Australia

[3] Univ Melbourne, Dept Med Biol, Melbourne, Vic, Australia

[4] Univ Montreal, Dept Microbiol & Immunol, Inst Rech Clin Montreal, Montreal, PQ H3C 3J7, Canada

[5] McGill Univ, Div Expt Med, Montreal, PQ, Canada

[6] Stanford Sch Med, Dept Pathol, Canc Biol Program, Stanford, CA USA

来源：

CELL DEATH AND DIFFERENTIATION | 2014年 / 21卷 / 11期

基金：

澳大利亚研究理事会;

关键词：

KINASE-A PKA; CARNEY COMPLEX; REGULATORY SUBUNIT; MEDIATED PHOSPHORYLATION; APOPTOTIC RESPONSES; CARDIAC MYXOMAS; ACTIVATION; MUTATIONS; DIFFERENTIATION; TUMORS;

D O I：

10.1038/cdd.2014.98

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：

Loss of function mutations in the Prkar1a gene are the cause of most cases of Carney complex disorder. Defects in Prkar1a are thought to cause hyper-activation of PKA signalling, which drives neoplastic transformation, and Prkar1a is therefore considered to be a tumour suppressor. Here we show that loss of Prkar1a in genetically modified mice caused transcriptional activation of several proapoptotic Bcl-2 family members and thereby caused cell death. Interestingly, combined loss of Bim and Prkar1a increased colony formation of fibroblasts in culture and promoted their growth as tumours in immune-deficient mice. Apart from inducing apoptosis, systemic deletion of Prkar1a caused cachexia with muscle loss, macrophage activation and increased lipolysis as well as serum triglyceride levels. Loss of single allele of Prkar1a did not enhance tumour development in a skin cancer model, but surprisingly, when combined with the loss of Bim, caused a significant delay in tumorigenesis and this was associated with upregulation of other BH3-only proteins, PUMA and NOXA. These results show that loss of Prkar1a can only promote tumorigenesis when Prkar1a-mediated apoptosis is somehow countered.

引用

页码：1815 / 1824

页数：10

共 44 条

[21] Mutations of the gene encoding the protein kinase A type I-α regulatory subunit in patients with the Carney complex [J].