Primary hyperparathyroidism is a common human endocrinopathy, and cyclin D1 (PRAD1) oncogene overexpression contributes to the pathogenesis of up to 40% of parathyroid adenomas. Numerous studies have led to the widely accepted paradigm that cyclin D1 functions in a biochemical pathway with cyclin- dependent kinase (cdk) 4 or 6, which it activates, and the retinoblastoma oncosuppressor protein pRB, considered the primary substrate of cyclin D1-activated cdk. These molecules have tremendous significance to neoplasia, being targeted by mutation or regulatory derangements in most or perhaps even all cancers. These concepts, however, may not fully reflect cyclin D1's true role when overexpressed in the complex in vivo process of tumorigenesis, and recent data indeed suggest other, non-cdk-dependent roles for cyclin D1. Such alternative mechanisms might be especially important in parathyroid tumors, possibly explaining why these cyclin D1-driven neoplasms are almost always benign in marked contrast with the malignant features of other cyclin D1-induced tumors, and may be relevant to the mechanism through which cyclin D1 leads to dysregulation of the serum calcium parathyroid hormone setpoint. Further, cyclin D1-induced parathyroid tumorigenesis may be modulated by key regulators, most notably vitamin D status, but direct in vivo experimental evidence is lacking. Hyperparathyroid-prone transgenic mice with parathyroid-targeted overexpression of cyclin D1 constitute an especially relevant system in which to test these hypotheses. The proposed studies are designed to address the mechanisms through which cyclin D1, directly and as modified by vitamin D status, contributes to parathyroid neoplasia. The studies will (a) examine whether overexpressed cyclin D1 may contribute to parathyroid tumorigenesis through mechanisms apart from activation of cdk4/6, by developing and characterizing transgenic mice bearing a parathyroid-targeted mutant cyclin D1 transgene unable to activate cdk4 or 6, and (b) examine whether vitamin D deficiency directly alters the growth of cyclin D1-induced parathyroid tumors and modulates the phenotype of primary hyperparathyroidism, by imposing nutritional vitamin D deficiency upon transgenic mice with parathyroid-targeted overexpression of cyclin D1. These results will carry important implications to the molecular pathogenesis of parathyroid neoplasia, are potentially relevant to a variety of cyclin D1-driven cancers, and may ultimately contribute to novel treatment strategies. This research will uncover important molecular mechanisms causing hyperparathyroidism, a common human endocrine disorder in which osteoporosis occurs, and will likely have strong relevance to a variety of malignancies also caused by the cyclin D1 cancer gene, such as breast cancer, B-cell lymphoma, myeloma, and squamous cell cancers. Further, the results may ultimately contribute to novel treatment strategies for these diseases. Finally, vitamin D nutritional status, a major problem in aging Americans and also rampant in underdeveloped nations, is considered an important potential influence on the vigor of parathyroid (and other forms of) tumorigenicity, and our model system provides unique advantages in which this hypothesis can be tested.
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