title: Loss of Prkar1a leads to Bcl-2 family protein induction and cachexia in mice.
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.
authors.affiliation: Department of Biochemistry, La Trobe Institute of Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Gangoda
authors.affiliation: Department of Biochemistry, La Trobe Institute of Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Doerflinger
authors.affiliation: Department of Biochemistry, La Trobe Institute of Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Srivastava
authors.affiliation: The Walter and Eliza Hall Institute, Melbourne, Victoria, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Narayan
authors.affiliation: Department of Biochemistry, La Trobe Institute of Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: L E
authors.initials: LE
authors.lastname: Edgington
authors.affiliation: Department of Biochemistry, La Trobe Institute of Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Orian
authors.affiliation: Department of Biochemistry, La Trobe Institute of Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Hawkins
authors.affiliation: 1] The Walter and Eliza Hall Institute, Melbourne, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: L A
authors.initials: LA
authors.lastname: O'Reilly
authors.affiliation: Institut de Recherches Cliniques de Montréal (IRCM) Department of Microbiology and Immunology, University of Montreal and Division of Experimental Medicine, McGill University Montreal, Montreal, Quebec, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Gu
authors.affiliation: Cancer Biology Program, Department of Pathology, Stanford School of Medicine, Stanford, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bogyo
authors.affiliation: The Walter and Eliza Hall Institute, Melbourne, Victoria, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Ekert
authors.affiliation: 1] The Walter and Eliza Hall Institute, Melbourne, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Strasser
authors.affiliation: Department of Biochemistry, La Trobe Institute of Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Puthalakath
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002100:Cachexia / Q000235:genetics*; D063646:Carcinogenesis; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517835:Prkar1a protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2