This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Griffin, K. J. Articles by Stratakis, C. A. Search for Related Content PubMed PubMed Citation Articles by Griffin, K. J. Articles by Stratakis, C. A.

Down-Regulation of Regulatory Subunit Type 1A of Protein Kinase A Leads to Endocrine and Other Tumors

¹ Section on Genetics and Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development; and ² Cellular Biochemistry Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Mutations of the human type I regulatory subunit (RI) 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 RIIß protein levels. This mouse provides a novel, useful tool for the investigation of cyclic AMP, RI, and PKA functions and confirms the critical role of Prkar1a in tumorigenesis in endocrine and other tissues.

This article has been cited by other articles:

				A. J. Robinson-White, I. Bossis, H.-P. Hsiao, M. Nesterova, W. W. Leitner, and C. A. Stratakis 8-Cl-Adenosine Inhibits Proliferation and Causes Apoptosis in B-Lymphocytes via Protein Kinase A-Dependent and Independent Effects: Implications for Treatment of Carney Complex-Associated Tumors J. Clin. Endocrinol. Metab., October 1, 2009; 94(10): 4061 - 4069. [Abstract] [Full Text] [PDF]

				L. S Kirschner, Z. Yin, G. N Jones, and E. Mahoney Mouse models of altered protein kinase A signaling Endocr. Relat. Cancer, September 1, 2009; 16(3): 773 - 793. [Abstract] [Full Text] [PDF]

				D. Chaturvedi, M. S. Cohen, J. Taunton, and T. B. Patel The PKARI{alpha} Subunit of Protein Kinase A Modulates the Activation of p90RSK1 and Its Function J. Biol. Chem., August 28, 2009; 284(35): 23670 - 23681. [Abstract] [Full Text] [PDF]

				J. Bertherat, A. Horvath, L. Groussin, S. Grabar, S. Boikos, L. Cazabat, R. Libe, F. Rene-Corail, S. Stergiopoulos, I. Bourdeau, et al. Mutations in Regulatory Subunit Type 1A of Cyclic Adenosine 5'-Monophosphate-Dependent Protein Kinase (PRKAR1A): Phenotype Analysis in 353 Patients and 80 Different Genotypes J. Clin. Endocrinol. Metab., June 1, 2009; 94(6): 2085 - 2091. [Abstract] [Full Text] [PDF]

				E. Meoli, I. Bossis, L. Cazabat, M. Mavrakis, A. Horvath, S. Stergiopoulos, M. L. Shiferaw, G. Fumey, K. Perlemoine, M. Muchow, et al. Protein Kinase A Effects of an Expressed PRKAR1A Mutation Associated with Aggressive Tumors Cancer Res., May 1, 2008; 68(9): 3133 - 3141. [Abstract] [Full Text] [PDF]

				K. S. Nadella, G. N. Jones, A. Trimboli, C. A. Stratakis, G. Leone, and L. S. Kirschner Targeted Deletion of Prkar1a Reveals a Role for Protein Kinase A in Mesenchymal-to-Epithelial Transition Cancer Res., April 15, 2008; 68(8): 2671 - 2677. [Abstract] [Full Text] [PDF]

				E. Pavel, K. Nadella, W. H. Towns II, and L. S. Kirschner Mutation of Prkar1a Causes Osteoblast Neoplasia Driven by Dysregulation of Protein Kinase A Mol. Endocrinol., February 1, 2008; 22(2): 430 - 440. [Abstract] [Full Text] [PDF]

				M. Nesterova, I. Bossis, F. Wen, A. Horvath, L. Matyakhina, and C. A. Stratakis An Immortalized Human Cell Line Bearing a PRKAR1A-Inactivating Mutation: Effects of Overexpression of the Wild-Type Allele and Other Protein Kinase A Subunits J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 565 - 571. [Abstract] [Full Text] [PDF]

				M. Santoro, R. M. Melillo, and A. Fusco RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture. Eur. J. Endocrinol., November 1, 2006; 155(5): 645 - 653. [Abstract] [Full Text] [PDF]

				A. J. Robinson-White, W. W. Leitner, E. Aleem, P. Kaldis, I. Bossis, and C. A. Stratakis PRKAR1A Inactivation Leads to Increased Proliferation and Decreased Apoptosis in Human B Lymphocytes Cancer Res., November 1, 2006; 66(21): 10603 - 10612. [Abstract] [Full Text] [PDF]

				I. Bourdeau, L. Matyakhina, S. G. Stergiopoulos, F. Sandrini, S. Boikos, and C. A. Stratakis 17q22-24 Chromosomal Losses and Alterations of Protein Kinase A Subunit Expression and Activity in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3626 - 3632. [Abstract] [Full Text] [PDF]

				A. Robinson-White, E. Meoli, S. Stergiopoulos, A. Horvath, S. Boikos, I. Bossis, and C. A. Stratakis PRKAR1AMutations and Protein Kinase A Interactions with Other Signaling Pathways in the Adrenal Cortex J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2380 - 2388. [Abstract] [Full Text] [PDF]

				A. Horvath, L. Mathyakina, Q. Vong, V. Baxendale, A. L. Y. Pang, W.-Y. Chan, and C. A. Stratakis Serial Analysis of Gene Expression in Adrenocortical Hyperplasia Caused by a Germline PRKAR1A Mutation J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 584 - 596. [Abstract] [Full Text] [PDF]

				Y. Hibi, F. Kambe, Y. Tominaga, Y. Mizuno, H. Kobayashi, K. Iwase, T. Imai, and H. Seo Up-Regulation of the Gene Encoding Protein Kinase A Type I{alpha} Regulatory Subunit in Nodular Hyperplasia of Parathyroid Glands in Patients with Chronic Renal Failure J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 563 - 568. [Abstract] [Full Text] [PDF]

				A J Bauer and C A Stratakis The lentiginoses: cutaneous markers of systemic disease and a window to new aspects of tumourigenesis J. Med. Genet., November 1, 2005; 42(11): 801 - 810. [Abstract] [Full Text] [PDF]

				L. S. Kirschner, D. F. Kusewitt, L. Matyakhina, W. H. Towns II, J. A. Carney, H. Westphal, and C. A. Stratakis A Mouse Model for the Carney Complex Tumor Syndrome Develops Neoplasia in Cyclic AMP-Responsive Tissues Cancer Res., June 1, 2005; 65(11): 4506 - 4514. [Abstract] [Full Text] [PDF]