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

Research output: Contribution to journalArticle

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+/- back-grounds, 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 acti-vation and cell cycle dysregulation, consistent with studies in human neoplasms carrying PRKAR1A defects.

Original languageEnglish (US)
Article numberddq014
Pages (from-to)1387-1398
Number of pages12
JournalHuman Molecular Genetics
Volume19
Issue number8
DOIs
StatePublished - Jan 15 2010

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Haploinsufficiency
Papilloma
Cell Cycle
Skin
Carney Complex
Neoplasms
Cell Cycle Resting Phase
Wild Animals
G1 Phase
Pituitary Neoplasms
Gene Expression Profiling
Tumor Suppressor Genes
Sarcoma
Small Interfering RNA
Thyroid Gland
Carcinogenesis
Down-Regulation
Fibroblasts
Immunohistochemistry
Genome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

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

In: Human Molecular Genetics, Vol. 19, No. 8, ddq014, 15.01.2010, p. 1387-1398.

Research output: Contribution to journalArticle

Almeida, MQ, Muchow, M, Boikos, S, Bauer, AJ, Griffin, KJ, Tsang, KM, Cheadle, C, Watkins, T, Wen, F, Starost, MF, Bossis, I, Nesterova, M & Stratakis, CA 2010, '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', Human Molecular Genetics, vol. 19, no. 8, ddq014, pp. 1387-1398. https://doi.org/10.1093/hmg/ddq014
Almeida, Madson Q. ; Muchow, Michael ; Boikos, Sosipatros ; Bauer, Andrew J. ; Griffin, Kurt J. ; Tsang, Kit Man ; Cheadle, Chris ; Watkins, Tonya ; Wen, Feng ; Starost, Matthew F. ; Bossis, Ioannis ; Nesterova, Maria ; Stratakis, Constantine A. / 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. In: Human Molecular Genetics. 2010 ; Vol. 19, No. 8. pp. 1387-1398.
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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+/- back-grounds, 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 acti-vation and cell cycle dysregulation, consistent with studies in human neoplasms carrying PRKAR1A defects.",
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AU - Almeida, Madson Q.

AU - Muchow, Michael

AU - Boikos, Sosipatros

AU - Bauer, Andrew J.

AU - Griffin, Kurt J.

AU - Tsang, Kit Man

AU - Cheadle, Chris

AU - Watkins, Tonya

AU - Wen, Feng

AU - Starost, Matthew F.

AU - Bossis, Ioannis

AU - Nesterova, Maria

AU - Stratakis, Constantine A.

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