CHROMOGRANINS IN NEUROENDOCRINE TUMOR CELLS

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The granins are a family of immunologically distinct, secretory proteins that are expressed only in endocrine and neuronal cells that concentrate their secretory products in storage granules and release it upon stimulation. In these cells the granins are integral to the formation of the dense-core matrix which forms in the Golgi prior to packaging of the secretory products. The granins also possess a number of proteolytic processing sites and peptides derived from granin precursors have been shown to have important autocrine regulatory activity. The granins are secreted at high rates by endocrine neoplasms and their immunocytochemical detection in tumoral tissue is considered diagnostic of the presence of tissue of neuroendocrine origin. Despite these and other studies on granin structure and function, the molecular basis for tissue-specific expression of the granins has yet to be studied. The present study is designed to investigate in detail the expression of a single member of the granin family, secretogranin II (SgII), in the rat anterior pituitary gland and to use the rat PC12 and GH4C1 neuroendocrine cell lines as models to study the molecular basis of SgII expression. These results of these studies will establish where, when and how SgII is expressed in neuroendocrine cells. The following specific questions will be answered by these studies: 1. Which cells in the anterior pituitary gland express SgII? 2. Is SgII a marker for early pituitary differentiation or granulation in the developing pituitary gland? 3. Which cis-acting elements in the SgII promoter mediate tissue-specific expression of SgII in neuroendocrine cells and can specific trans-acting factors be identified which mediate neuroendocrine-specific expression? 4. Which cis-acting elements mediate negative regulation of SgII expression by cyclic AMP in PC12 cells and can specific trans-acting factors be identified which mediate this regulation? The results of these studies will provide the first analysis of the molecular mechanism for expression of SgII in neuroendocrine cells.