Carney Complex (CNC) is an inherited syndrome comprised of spotty skin pigmentation, myxomas, pigmented schwannomas, and endocrine tumors. Examples of the latter include secretory tumors of the adrenal gland and pituitary, as well as non-secreting tumors of the thyroid, testes, ovaries, and breast. In research funded by an NIH K22 career development award, the investigator identified inactivating mutations in the PRKAR1A gene as responsible for the disease in approximately 50% of affected kindreds. This gene codes for the Type 1A regulatory subunit of the cyclic AMP-dependent protein kinase (Protein Kinase A, PKA), a key regulator of growth pathways in many endocrine and non-endocrine cell types. PKA is also a key second messenger system mediating hormone release in secretory cells from most endocrine organs. Loss of this regulatory subunit leads to dysregulation of PKA activity, which has been theorized to cause abnormal cell proliferation and tumorigenesis. As part of the prior research, the investigator created transgenic mice carrying a conditional or conventional null allele of the Prkar1a gene. In this proposal, we will use these gene-targeted mice to test the hypothesis that complete loss of Prkarla causes dysregulation of PKA signaling, leading to abnormal cell proliferation both in vitro and in vivo. The in vitro studies will comprise the generation of primary mouse embryonic fibroblasts (MEFs) that lack the Prkarla gene and an analysis of the biology of these immortalized cells. Studies in intact mice will include gross and molecular phenotyping of Prkarla heterozygous null mice as a genetic model for CNC, as well a characterization of tissue-specific null mice. Although CNC is itself a rare syndrome, PKA's central role in growth control and other cellular processes makes this human disease an attractive model for use in understanding the means by which PKA exerts its wide variety of intracellular effects, and holds the promise that understanding PKA's role in the cell may eventually lead to the development of new therapies aimed at treating human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112268-04
Application #
7246583
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Ault, Grace S
Project Start
2004-09-29
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$261,534
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Zhang, Mei; Mahoney, Emilia; Zuo, Tao et al. (2014) Protein kinase A activation enhances ?-catenin transcriptional activity through nuclear localization to PML bodies. PLoS One 9:e109523
Pringle, Daphne R; Vasko, Vasily V; Yu, Lianbo et al. (2014) Follicular thyroid cancers demonstrate dual activation of PKA and mTOR as modeled by thyroid-specific deletion of Prkar1a and Pten in mice. J Clin Endocrinol Metab 99:E804-12
Zhang, Mei; Manchanda, Parmeet K; Wu, Dayong et al. (2014) Knockdown of PRKAR1A, the gene responsible for Carney complex, interferes with differentiation in osteoblastic cells. Mol Endocrinol 28:295-307
Manchanda, P K; Jones, G N; Lee, A A et al. (2013) Rac1 is required for Prkar1a-mediated Nf2 suppression in Schwann cell tumors. Oncogene 32:3491-9
Hussain, M A; Stratakis, C; Kirschner, L (2012) Prkar1a in the regulation of insulin secretion. Horm Metab Res 44:759-65
Pringle, Daphne R; Yin, Zhirong; Lee, Audrey A et al. (2012) Thyroid-specific ablation of the Carney complex gene, PRKAR1A, results in hyperthyroidism and follicular thyroid cancer. Endocr Relat Cancer 19:435-46
Yin, Zhirong; Pringle, Daphne R; Jones, Georgette N et al. (2011) Differential role of PKA catalytic subunits in mediating phenotypes caused by knockout of the Carney complex gene Prkar1a. Mol Endocrinol 25:1786-93
Song, Woo-Jin; Seshadri, Madhav; Ashraf, Uzair et al. (2011) Snapin mediates incretin action and augments glucose-dependent insulin secretion. Cell Metab 13:308-19
Kirschner, Lawrence S (2010) PRKAR1A and the evolution of pituitary tumors. Mol Cell Endocrinol 326:3-7
Jones, Georgette N; Manchanda, Parmeet K; Pringle, Daphne R et al. (2010) Mouse models of endocrine tumours. Best Pract Res Clin Endocrinol Metab 24:451-60

Showing the most recent 10 out of 20 publications