Carney Complex: A Model for PKA-Mediated Tumorigenesis

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DESCRIPTION (provided by applicant): 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.