Loss of Prkar1a leads to Bcl-2 family protein induction and cachexia in mice.
Details
Publication Year 2014-07-11, Volume 21, Issue #11, Page 1815-1824
Journal Title
Cell Death and Differentiation
Publication Type
JOURNAL ARTICLE
Abstract
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.Cell Death and Differentiation advance online publication, 11 July 2014; doi:10.1038/cdd.2014.98.
Publisher
NPG
WEHI Research Division(s)
Molecular Genetics Of Cancer
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2014-07-30 02:50:02
Last Modified: 0001-01-01 12:00:00
An error has occurred. This application may no longer respond until reloaded. Reload 🗙