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PubMed · 20080939

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.

Madson Q Almeida·Michael Muchow·Sosipatros Boikos·Andrew J Bauer·Kurt J Griffin·Kit Man Tsang·Chris Cheadle·Tonya Watkins·Feng Wen·Matthew F Starost·Ioannis Bossis·Maria Nesterova·Constantine A Stratakis
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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.

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AnimalsCell CycleCyclic AMP-Dependent Protein Kinase RIalpha SubunitDisease Models, AnimalFemaleGene Expression Regulation, NeoplasticHaploidyHumansMaleMiceMice, Inbred C57BLNeoplasmsNeoplastic ProcessesPapillomaRetinoblastoma ProteinSignal TransductionSkin NeoplasmsTumor Suppressor Protein p53Wnt ProteinsJournal ArticleResearch Support, N.I.H., Intramural

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Madson Q Almeida, Michael Muchow, Sosipatros Boikos, Andrew J Bauer, Kurt J Griffin, Kit Man Tsang, Chris Cheadle, Tonya Watkins, Feng Wen, Matthew F Starost, Ioannis Bossis, Maria Nesterova, Constantine A Stratakis. 2010-01-15. 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.. https://doi.org/10.1093/hmg%2Fddq014

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