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

Cell Death Differ. 2014 Nov;21(11):1815-24. doi: 10.1038/cdd.2014.98. Epub 2014 Jul 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / genetics*
  • Cachexia / genetics*
  • Carcinogenesis
  • Cell Transformation, Neoplastic / genetics
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / genetics*
  • Fibroblasts / metabolism
  • Gene Deletion
  • Genes, Tumor Suppressor
  • Mice
  • Proto-Oncogene Proteins c-bcl-2 / genetics

Substances

  • Apoptosis Regulatory Proteins
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
  • Prkar1a protein, mouse
  • Proto-Oncogene Proteins c-bcl-2