title: Down-regulation of regulatory subunit type 1A of protein kinase A leads to endocrine and other tumors.
abstract: Mutations of the human type Ialpha regulatory subunit (RIalpha) of cyclic AMP-dependent protein kinase (PKA; PRKAR1A) lead to altered kinase activity, primary pigmented nodular adrenocortical disease, and tumors of the thyroid and other tissues. To bypass the early embryonic lethality of Prkar1a(-/-) mice, we established transgenic mice carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline-responsive promoter. Down-regulation of Prkar1a by up to 70% was achieved in transgenic mouse tissues and embryonic fibroblasts, with concomitant changes in kinase activity and increased cell proliferation, respectively. Mice developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia, and other features reminiscent of primary pigmented nodular adrenocortical disease, histiocytic and epithelial hyperplasias, lymphomas, and other mesenchymal tumors. These were associated with allelic losses of the mouse chromosome 11 Prkar1a locus, an increase in total type II PKA activity, and higher RIIbeta protein levels. This mouse provides a novel, useful tool for the investigation of cyclic AMP, RIalpha, and PKA functions and confirms the critical role of Prkar1a in tumorigenesis in endocrine and other tissues.
authors.affiliation: Section on Genetics and Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Griffin
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Kirschner
authors.forename: Ludmila
authors.initials: L
authors.lastname: Matyakhina
authors.forename: Sotirios
authors.initials: S
authors.lastname: Stergiopoulos
authors.forename: Audrey
authors.initials: A
authors.lastname: Robinson-White
authors.forename: Sara
authors.initials: S
authors.lastname: Lenherr
authors.forename: Frank D
authors.initials: FD
authors.lastname: Weinberg
authors.forename: Edward
authors.initials: E
authors.lastname: Claflin
authors.forename: Elise
authors.initials: E
authors.lastname: Meoli
authors.forename: Yoon S
authors.initials: YS
authors.lastname: Cho-Chung
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000236:Adenoma / Q000201:enzymology / Q000235:genetics; D000306:Adrenal Cortex Neoplasms / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D016373:DNA, Antisense / Q000235:genetics; D015536:Down-Regulation; D005091:Exons; D005260:Female; D008232:Lymphoproliferative Disorders / Q000201:enzymology* / Q000235:genetics; D008648:Mesoderm / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D013752:Tetracycline / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000201:enzymology* / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D016373:DNA, Antisense; C517834:PRKAR1A protein, human; C517835:Prkar1a protein, mouse; D011506:Proteins; D015534:Trans-Activators; D013752:Tetracycline