title: A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours: comparison with Carney complex and other PRKAR1A induced lesions.
abstract: BACKGROUND
  Inactivation of the human type Ialpha regulatory subunit (RIalpha) of cyclic AMP dependent protein kinase (PKA) (PRKAR1A) leads to altered kinase activity, primary pigmented nodular adrenocortical disease (PPNAD), and sporadic adrenal and other tumours.
  
  
  RESULTS
  A transgenic mouse carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline responsive promoter (the Tg(Prkar1a*x2as)1Stra, Tg(tTAhCMV)3Uh or tTA/X2AS line) developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia and other features reminiscent of PPNAD, including late onset weight gain, visceral adiposity, and non-dexamethasone suppressible hypercorticosteronaemia, with histiocytic, epithelial hyperplasias, lymphomas, and other mesenchymal tumours. These lesions 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; the latter biochemical and protein changes were also documented in Carney complex tumours associated with PRKAR1A inactivating mutations and chromosome 17 PRKAR1A locus changes.
  
  
  CONCLUSIONS
  We conclude that the tTA/X2AS mouse line with a downregulated Prkar1a gene replicates several of the findings in Carney complex patients and their affected tissues, supporting the role of RIalpha as a candidate tumour suppressor gene.
authors.affiliation: Section on Genetics & Endocrinology, Developmental Endocrinology Branch (DEB), National Institute of Child Health & Human Development, Bethesda, MD 20892-1103, USA. griffiku@mail.nih.gov <griffiku@mail.nih.gov>
authors.forename: K J
authors.initials: KJ
authors.lastname: Griffin
authors.forename: L S
authors.initials: LS
authors.lastname: Kirschner
authors.forename: L
authors.initials: L
authors.lastname: Matyakhina
authors.forename: S G
authors.initials: SG
authors.lastname: Stergiopoulos
authors.forename: A
authors.initials: A
authors.lastname: Robinson-White
authors.forename: S M
authors.initials: SM
authors.lastname: Lenherr
authors.forename: F D
authors.initials: FD
authors.lastname: Weinberg
authors.forename: E S
authors.initials: ES
authors.lastname: Claflin
authors.forename: D
authors.initials: D
authors.lastname: Batista
authors.forename: I
authors.initials: I
authors.lastname: Bourdeau
authors.forename: A
authors.initials: A
authors.lastname: Voutetakis
authors.forename: F
authors.initials: F
authors.lastname: Sandrini
authors.forename: E M
authors.initials: EM
authors.lastname: Meoli
authors.forename: A J
authors.initials: AJ
authors.lastname: Bauer
authors.forename: Y S
authors.initials: YS
authors.lastname: Cho-Chung
authors.forename: S R
authors.initials: SR
authors.lastname: Bornstein
authors.forename: J A
authors.initials: JA
authors.lastname: Carney
authors.forename: C A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000303:Adrenal Cortex Diseases / Q000201:enzymology / Q000235:genetics; D000310:Adrenal Gland Neoplasms / Q000201:enzymology / Q000235:genetics; D000483:Alleles; D000818:Animals; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation; D004701:Endocrine Gland Neoplasms / Q000201:enzymology* / Q000235:genetics; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000201:enzymology / Q000235:genetics; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000235:genetics
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; C517835:Prkar1a protein, mouse; D011506:Proteins; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases