title: 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.
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.
authors.affiliation: Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice KennedyShriver, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. almeidamd@mail.nih.gov
authors.forename: Madson Q
authors.initials: MQ
authors.lastname: Almeida
authors.forename: Michael
authors.initials: M
authors.lastname: Muchow
authors.forename: Sosipatros
authors.initials: S
authors.lastname: Boikos
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bauer
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Griffin
authors.forename: Kit Man
authors.initials: KM
authors.lastname: Tsang
authors.forename: Chris
authors.initials: C
authors.lastname: Cheadle
authors.forename: Tonya
authors.initials: T
authors.lastname: Watkins
authors.forename: Feng
authors.initials: F
authors.lastname: Wen
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Starost
authors.forename: Ioannis
authors.initials: I
authors.lastname: Bossis
authors.forename: Maria
authors.initials: M
authors.lastname: Nesterova
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000818:Animals; D002453:Cell Cycle; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006238:Haploidy; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009385:Neoplastic Processes; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517835:Prkar1a protein, mouse; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins