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. 2004 Dec;41(12):923–931. doi: 10.1136/jmg.2004.028043

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

K Griffin 1, L Kirschner 1, L Matyakhina 1, S Stergiopoulos 1, A Robinson-White 1, S Lenherr 1, F Weinberg 1, E Claflin 1, D Batista 1, I Bourdeau 1, A Voutetakis 1, F Sandrini 1, E Meoli 1, A Bauer 1, Y Cho-Chung 1, S Bornstein 1, J Carney 1, C Stratakis 1
PMCID: PMC1735656  PMID: 15591278

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 RIIß 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.

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Selected References

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  1. Amieux P. S., Cummings D. E., Motamed K., Brandon E. P., Wailes L. A., Le K., Idzerda R. L., McKnight G. S. Compensatory regulation of RIalpha protein levels in protein kinase A mutant mice. J Biol Chem. 1997 Feb 14;272(7):3993–3998. doi: 10.1074/jbc.272.7.3993. [DOI] [PubMed] [Google Scholar]
  2. Amieux Paul S., Howe Douglas G., Knickerbocker Heidi, Lee David C., Su Thomas, Laszlo George S., Idzerda Rejean L., McKnight G. Stanley. Increased basal cAMP-dependent protein kinase activity inhibits the formation of mesoderm-derived structures in the developing mouse embryo. J Biol Chem. 2002 May 9;277(30):27294–27304. doi: 10.1074/jbc.M200302200. [DOI] [PubMed] [Google Scholar]
  3. Amieux Paul S., McKnight G. Stanley. The essential role of RI alpha in the maintenance of regulated PKA activity. Ann N Y Acad Sci. 2002 Jun;968:75–95. doi: 10.1111/j.1749-6632.2002.tb04328.x. [DOI] [PubMed] [Google Scholar]
  4. Bertherat Jerome, Groussin Lionel, Sandrini Fabiano, Matyakhina Ludmila, Bei Thalia, Stergiopoulos Sotirios, Papageorgiou Theocharis, Bourdeau Isabelle, Kirschner Lawrence S., Vincent-Dejean Caroline. Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity. Cancer Res. 2003 Sep 1;63(17):5308–5319. [PubMed] [Google Scholar]
  5. Bossis I., Voutetakis A., Bei T., Sandrini F., Griffin K. J., Stratakis C. A. Protein kinase A and its role in human neoplasia: the Carney complex paradigm. Endocr Relat Cancer. 2004 Jun;11(2):265–280. doi: 10.1677/erc.0.0110265. [DOI] [PubMed] [Google Scholar]
  6. Carney J. A. Carney complex: the complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas. Semin Dermatol. 1995 Jun;14(2):90–98. doi: 10.1016/s1085-5629(05)80003-3. [DOI] [PubMed] [Google Scholar]
  7. Carney J. A., Stratakis C. A. Ductal adenoma of the breast and the Carney complex. Am J Surg Pathol. 1996 Sep;20(9):1154–1155. doi: 10.1097/00000478-199609000-00014. [DOI] [PubMed] [Google Scholar]
  8. Cho-Chung Y. S., Nesterova M., Pepe S., Lee G. R., Noguchi K., Srivastava R. K., Srivastava A. R., Alper O., Park Y. G., Lee Y. N. Antisense DNA-targeting protein kinase A-RIA subunit: a novel approach to cancer treatment. Front Biosci. 1999 Dec 1;4:D898–D907. doi: 10.2741/cho-chung. [DOI] [PubMed] [Google Scholar]
  9. Cho-Chung Y. S., Pepe S., Clair T., Budillon A., Nesterova M. cAMP-dependent protein kinase: role in normal and malignant growth. Crit Rev Oncol Hematol. 1995 Nov;21(1-3):33–61. doi: 10.1016/1040-8428(94)00166-9. [DOI] [PubMed] [Google Scholar]
  10. Donehower L. A., Harvey M., Slagle B. L., McArthur M. J., Montgomery C. A., Jr, Butel J. S., Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992 Mar 19;356(6366):215–221. doi: 10.1038/356215a0. [DOI] [PubMed] [Google Scholar]
  11. Gottesman M. M., Fleischmann R. D. The role of cAMP in regulating tumour cell growth. Cancer Surv. 1986;5(2):291–308. [PubMed] [Google Scholar]
  12. Gottesman M. M., Fleischmann R., Abraham I. Molecular genetic analysis of cAMP-dependent protein kinase. Ann N Y Acad Sci. 1986;478:162–174. doi: 10.1111/j.1749-6632.1986.tb15529.x. [DOI] [PubMed] [Google Scholar]
  13. Groussin Lionel, Jullian Eric, Perlemoine Karine, Louvel Albert, Leheup Bruno, Luton Jean Pierre, Bertagna Xavier, Bertherat Jérôme. Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease. J Clin Endocrinol Metab. 2002 Sep;87(9):4324–4329. doi: 10.1210/jc.2002-020592. [DOI] [PubMed] [Google Scholar]
  14. Hanson J. A., Sohaib S. A., Newell-Price J., Islam N., Monson J. P., Trainer P. J., Grossman A., Besser G. M., Reznek R. H. Computed tomography appearance of the thymus and anterior mediastinum in active Cushing's syndrome. J Clin Endocrinol Metab. 1999 Feb;84(2):602–605. doi: 10.1210/jcem.84.2.5501. [DOI] [PubMed] [Google Scholar]
  15. Keegan Catherine E., Hammer Gary D. Recent insights into organogenesis of the adrenal cortex. Trends Endocrinol Metab. 2002 Jul;13(5):200–208. doi: 10.1016/s1043-2760(02)00602-1. [DOI] [PubMed] [Google Scholar]
  16. Khariwala S. S., Nicollas R., Triglia J. M., Garabedian E. N., Marianowski R., Van Den Abbeele T., April M., Ward R., Koltai P. J. Cervical presentations of thymic anomalies in children. Int J Pediatr Otorhinolaryngol. 2004 Jul;68(7):909–914. doi: 10.1016/j.ijporl.2004.02.012. [DOI] [PubMed] [Google Scholar]
  17. Kim S. N., Kim S. G., Park S. D., Cho-Chung Y. S., Hong S. H. Participation of type II protein kinase A in the retinoic acid-induced growth inhibition of SH-SY5Y human neuroblastoma cells. J Cell Physiol. 2000 Mar;182(3):421–428. doi: 10.1002/(SICI)1097-4652(200003)182:3<421::AID-JCP13>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  18. Kirschner L. S., Carney J. A., Pack S. D., Taymans S. E., Giatzakis C., Cho Y. S., Cho-Chung Y. S., Stratakis C. A. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet. 2000 Sep;26(1):89–92. doi: 10.1038/79238. [DOI] [PubMed] [Google Scholar]
  19. Kirschner L. S., Sandrini F., Monbo J., Lin J. P., Carney J. A., Stratakis C. A. Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the carney complex. Hum Mol Genet. 2000 Dec 12;9(20):3037–3046. doi: 10.1093/hmg/9.20.3037. [DOI] [PubMed] [Google Scholar]
  20. McKnight G. S., Clegg C. H., Uhler M. D., Chrivia J. C., Cadd G. G., Correll L. A., Otten A. D. Analysis of the cAMP-dependent protein kinase system using molecular genetic approaches. Recent Prog Horm Res. 1988;44:307–335. doi: 10.1016/b978-0-12-571144-9.50014-4. [DOI] [PubMed] [Google Scholar]
  21. McKnight G. S., Cummings D. E., Amieux P. S., Sikorski M. A., Brandon E. P., Planas J. V., Motamed K., Idzerda R. L. Cyclic AMP, PKA, and the physiological regulation of adiposity. Recent Prog Horm Res. 1998;53:139–161. [PubMed] [Google Scholar]
  22. Rangarajan Annapoorni, Weinberg Robert A. Opinion: Comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer. 2003 Dec;3(12):952–959. doi: 10.1038/nrc1235. [DOI] [PubMed] [Google Scholar]
  23. Sandrini Fabiano, Matyakhina Ludmila, Sarlis Nicholas J., Kirschner Lawrence S., Farmakidis Constantine, Gimm Oliver, Stratakis Constantine A. Regulatory subunit type I-alpha of protein kinase A (PRKAR1A): a tumor-suppressor gene for sporadic thyroid cancer. Genes Chromosomes Cancer. 2002 Oct;35(2):182–192. doi: 10.1002/gcc.10112. [DOI] [PubMed] [Google Scholar]
  24. Scott J. D. Cyclic nucleotide-dependent protein kinases. Pharmacol Ther. 1991;50(1):123–145. doi: 10.1016/0163-7258(91)90075-w. [DOI] [PubMed] [Google Scholar]
  25. Stratakis C. A., Courcoutsakis N. A., Abati A., Filie A., Doppman J. L., Carney J. A., Shawker T. Thyroid gland abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas (Carney complex) J Clin Endocrinol Metab. 1997 Jul;82(7):2037–2043. doi: 10.1210/jcem.82.7.4079. [DOI] [PubMed] [Google Scholar]
  26. Stratakis C. A., Kirschner L. S., Carney J. A. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab. 2001 Sep;86(9):4041–4046. doi: 10.1210/jcem.86.9.7903. [DOI] [PubMed] [Google Scholar]
  27. Stratakis C. A., Sarlis N., Kirschner L. S., Carney J. A., Doppman J. L., Nieman L. K., Chrousos G. P., Papanicolaou D. A. Paradoxical response to dexamethasone in the diagnosis of primary pigmented nodular adrenocortical disease. Ann Intern Med. 1999 Oct 19;131(8):585–591. doi: 10.7326/0003-4819-131-8-199910190-00006. [DOI] [PubMed] [Google Scholar]
  28. Taimi M., Breitman T. R., Takahashi N. Cyclic AMP-dependent protein kinase isoenzymes in human myeloid leukemia (HL60) and breast tumor (MCF-7) cells. Arch Biochem Biophys. 2001 Aug 1;392(1):137–144. doi: 10.1006/abbi.2001.2443. [DOI] [PubMed] [Google Scholar]

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