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PRKAR1A  inactivation leads to dysregulated cAMP signaling and Carney complex (CNC) in humans, a syndrome associated with skin, endocrine and other tumors. The CNC phenotype is not easily explained by the ubiquitous cAMP signaling defect; furthermore,  Prkar1a  +/−  mice did not develop skin and other CNC tumors. To identify whether a  Prkar1a  defect is truly a  generic  but  weak  tumorigenic signal that depends on tissue-specific or other factors, we investigated  Prkar1a  +/−  mice when bred within the  Rb1   +/−   or  Trp53   +/−   backgrounds, or treated with a two-step skin carcinogenesis protocol.  Prkar1a  +/−  Trp53  +/−  mice developed more sarcomas than  Trp53  +/−  mice ( P  &lt; 0.05) and  Prkar1a  +/−  Rb1  +/−  mice grew more (and larger) pituitary and thyroid tumors than  Rb1  +/−  mice. All mice with double heterozygosity had significantly reduced life-spans compared with their single-heterozygous counterparts.  Prkar1a  +/−  mice also developed more papillomas than wild-type animals. A whole-genome transcriptome profiling of tumors produced by all three models identified  Wnt  signaling as the main pathway activated by abnormal cAMP signaling, along with cell cycle abnormalities; all changes were confirmed by qRT–PCR array and immunohistochemistry. siRNA down-regulation of  Ctnnb1 ,  E2f1  or  Cdk4  inhibited proliferation of human adrenal cells bearing a  PRKAR1A -inactivating mutation and  Prkar1a   +/−   mouse embryonic fibroblasts and arrested both cell lines at the G0/G1 phase of the cell cycle. In conclusion,  Prkar1a  haploinsufficiency is a relatively weak tumorigenic signal that can act synergistically with other tumor suppressor gene defects or chemicals to induce tumors, mostly through  Wnt -signaling activation and cell cycle dysregulation, consistent with studies in human neoplasms carrying  PRKAR1A  defects.

human molecular genetics

Mouse  Prkar1a  haploinsufficiency leads to an increase in tumors in the  Trp53   +/−   or  Rb1   +/−   backgrounds and chemically induced skin papillomas by dysregulation of the cell cycle and  Wnt  signaling