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

K J Griffin¹, L S Kirschner^1,*, L Matyakhina¹, S G Stergiopoulos¹, A Robinson-White¹, S M Lenherr¹, F D Weinberg¹, E S Claflin¹, D Batista¹, I Bourdeau¹, A Voutetakis¹, F Sandrini¹, E M Meoli¹, A J Bauer¹, Y S Cho-Chung², S R Bornstein³, J A Carney⁴, C A Stratakis¹

¹ Section on Genetics & Endocrinology, Developmental Endocrinology Branch (DEB), National Institute of Child Health & Human Development, Bethesda, MD 20892-1103, USA
² Cellular Biochemistry Section, BRL, CCR, National Cancer Institute, Bethesda, MD 20892-1750, USA
³ Department of Internal Medicine, Division of Endocrinology, University of Düsseldorf, 40225 Düsseldorf, Germany Present address: Department of Medicine, University of Dresden, 01307 Dresden, Germany
⁴ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA

Correspondence to:
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; griffiku{at}mail.nih.gov or stratakc{at}mail.nih.gov

Background: Inactivation of the human type I regulatory subunit (RI) 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 RI as a candidate tumour suppressor gene.

Abbreviations: 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

Keywords: Carney complex; PRKAR1A; endocrine tumours; protein kinase A; transgenic mouse

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Robinson-White, A. J., Bossis, I., Hsiao, H.-P., Nesterova, M., Leitner, W. W., Stratakis, C. A. (2009). 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. 94: 4061-4069 [Abstract] [Full Text]  
• Ragazzon, B., Cazabat, L., Rizk-Rabin, M., Assie, G., Groussin, L., Fierrard, H., Perlemoine, K., Martinez, A., Bertherat, J. (2009). Inactivation of the Carney Complex Gene 1 (Protein Kinase A Regulatory Subunit 1A) Inhibits SMAD3 Expression and TGF{beta}-Stimulated Apoptosis in Adrenocortical Cells. Cancer Res. 69: 7278-7284 [Abstract] [Full Text]  
• Kirschner, L. S, Yin, Z., Jones, G. N, Mahoney, E. (2009). Mouse models of altered protein kinase A signaling. Endocr Relat Cancer 16: 773-793 [Abstract] [Full Text]  
• Louiset, E., Stratakis, C. A., Perraudin, V., Griffin, K. J., Libe, R., Cabrol, S., Feve, B., Young, J., Groussin, L., Bertherat, J., Lefebvre, H. (2009). The Paradoxical Increase in Cortisol Secretion Induced by Dexamethasone in Primary Pigmented Nodular Adrenocortical Disease Involves a Glucocorticoid Receptor-Mediated Effect of Dexamethasone on Protein Kinase A Catalytic Subunits. J. Clin. Endocrinol. Metab. 94: 2406-2413 [Abstract] [Full Text]  
• Bertherat, J., Horvath, A., Groussin, L., Grabar, S., Boikos, S., Cazabat, L., Libe, R., Rene-Corail, F., Stergiopoulos, S., Bourdeau, I., Bei, T., Clauser, E., Calender, A., Kirschner, L. S., Bertagna, X., Carney, J. A., Stratakis, C. A. (2009). 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. 94: 2085-2091 [Abstract] [Full Text]  
• Meoli, E., Bossis, I., Cazabat, L., Mavrakis, M., Horvath, A., Stergiopoulos, S., Shiferaw, M. L., Fumey, G., Perlemoine, K., Muchow, M., Robinson-White, A., Weinberg, F., Nesterova, M., Patronas, Y., Groussin, L., Bertherat, J., Stratakis, C. A. (2008). Protein Kinase A Effects of an Expressed PRKAR1A Mutation Associated with Aggressive Tumors. Cancer Res. 68: 3133-3141 [Abstract] [Full Text]  
• Pavel, E., Nadella, K., Towns, W. H. II, Kirschner, L. S. (2008). Mutation of Prkar1a Causes Osteoblast Neoplasia Driven by Dysregulation of Protein Kinase A. Mol. Endocrinol. 22: 430-440 [Abstract] [Full Text]  
• Nesterova, M., Bossis, I., Wen, F., Horvath, A., Matyakhina, L., Stratakis, C. A. (2008). 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. 93: 565-571 [Abstract] [Full Text]  
• Boikos, S. A., Stratakis, C. A. (2007). Molecular genetics of the cAMP-dependent protein kinase pathway and of sporadic pituitary tumorigenesis. Hum Mol Genet 16: R80-R87 [Abstract] [Full Text]  
• Robinson-White, A. J., Leitner, W. W., Aleem, E., Kaldis, P., Bossis, I., Stratakis, C. A. (2006). PRKAR1A Inactivation Leads to Increased Proliferation and Decreased Apoptosis in Human B Lymphocytes. Cancer Res. 66: 10603-10612 [Abstract] [Full Text]  
• Bourdeau, I., Matyakhina, L., Stergiopoulos, S. G., Sandrini, F., Boikos, S., Stratakis, C. A. (2006). 17q22-24 Chromosomal Losses and Alterations of Protein Kinase A Subunit Expression and Activity in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia. J. Clin. Endocrinol. Metab. 91: 3626-3632 [Abstract] [Full Text]  
• Robinson-White, A., Meoli, E., Stergiopoulos, S., Horvath, A., Boikos, S., Bossis, I., Stratakis, C. A. (2006). PRKAR1AMutations and Protein Kinase A Interactions with Other Signaling Pathways in the Adrenal Cortex. J. Clin. Endocrinol. Metab. 91: 2380-2388 [Abstract] [Full Text]  
• Horvath, A., Mathyakina, L., Vong, Q., Baxendale, V., Pang, A. L. Y., Chan, W.-Y., Stratakis, C. A. (2006). Serial Analysis of Gene Expression in Adrenocortical Hyperplasia Caused by a Germline PRKAR1A Mutation. J. Clin. Endocrinol. Metab. 91: 584-596 [Abstract] [Full Text]  
• Bauer, A J, Stratakis, C A (2005). The lentiginoses: cutaneous markers of systemic disease and a window to new aspects of tumourigenesis. J. Med. Genet. 42: 801-810 [Abstract] [Full Text]  
• Kirschner, L. S., Kusewitt, D. F., Matyakhina, L., Towns, W. H. II, Carney, J. A., Westphal, H., Stratakis, C. A. (2005). A Mouse Model for the Carney Complex Tumor Syndrome Develops Neoplasia in Cyclic AMP-Responsive Tissues. Cancer Res. 65: 4506-4514 [Abstract] [Full Text]