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  • 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

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Original article
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
  1. K J Griffin1,
  2. L S Kirschner1,*,
  3. L Matyakhina1,
  4. S G Stergiopoulos1,
  5. A Robinson-White1,
  6. S M Lenherr1,
  7. F D Weinberg1,
  8. E S Claflin1,
  9. D Batista1,
  10. I Bourdeau1,
  11. A Voutetakis1,
  12. F Sandrini1,
  13. E M Meoli1,
  14. A J Bauer1,
  15. Y S Cho-Chung2,
  16. S R Bornstein3,
  17. J A Carney4,
  18. C A Stratakis1
  1. 1Section on Genetics & Endocrinology, Developmental Endocrinology Branch (DEB), National Institute of Child Health & Human Development, Bethesda, MD 20892-1103, USA
  2. 2Cellular Biochemistry Section, BRL, CCR, National Cancer Institute, Bethesda, MD 20892-1750, USA
  3. 3Department of Internal Medicine, Division of Endocrinology, University of Düsseldorf, 40225 Düsseldorf, Germany Present address: Department of Medicine, University of Dresden, 01307 Dresden, Germany
  4. 4Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
  1. Correspondence to:
 Dr K Griffin or Dr C Stratakis
 at the Section on Genetics & Endocrinology (SEGEN), DEB, National Institute of Child Health and Human Development (NICHD), NIH, CRC, 1-3330, MSC1103, 10 Center Drive, Bethesda, MD 20892-1103, USA; griffikumail.nih.gov or stratakcmail.nih.gov

Abstract

Background: Inactivation of the human type Iα regulatory subunit (RIα) 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.

Methods and 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 RIIβ 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.

Conclusion: 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 RIα as a candidate tumour suppressor gene.

  • ACTH, adrenocorticotrophic hormone
  • BAC, bacterial artificial chromosome
  • bw, bodyweight
  • CNC, Carney complex
  • FISH, fluorescent in situ hybridisation
  • NIH, National Institutes of Health (USA)
  • PKA, protein kinase A
  • PPNAD, primary pigmented nodular adrenocortical disease
  • Carney complex
  • PRKAR1A
  • endocrine tumours
  • protein kinase A
  • transgenic mouse

https://doi.org/10.1136/jmg.2004.028043

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    Footnotes

    • ↵* Present address: Department of Internal Medicine, Divisions of Human Cancer Genetics and Endocrinology, Ohio State University, 544 TMRF, 420 West 12th Street, Columbus, OH 43210, USA

    • Competing interests: there are no competing interests.