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

Hum Mol Genet. 2010 Apr 15;19(8):1387-98. doi: 10.1093/hmg/ddq014. Epub 2010 Jan 15.

Abstract

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 < 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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cell Cycle*
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / genetics*
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / metabolism
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation, Neoplastic
  • Haploidy
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Neoplasms / physiopathology
  • Neoplastic Processes
  • Papilloma / chemically induced
  • Papilloma / genetics
  • Papilloma / metabolism
  • Papilloma / physiopathology
  • Retinoblastoma Protein / genetics*
  • Retinoblastoma Protein / metabolism
  • Signal Transduction*
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / physiopathology
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*

Substances

  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
  • Prkar1a protein, mouse
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53
  • Wnt Proteins