Controlled growth of endocrine tissues is essential for health, but little is known about the intrinsic cellular regulators that govern endocrine cell growth and differentiation. Mutations of the Men1 gene promote pathogenesis of type 1 multiple endocrine neoplasia (MEN1), and recent studies suggest that menin, the protein product of the Men1 gene, is a key regulator of endocrine cell proliferation and fates. Menin associates with other nuclear proteins and chromatin to promote specific covalent histone modifications that can activate or repress target gene expression. Identification of menin targets, menin functions in gene regulation, and signaling pathways that interact with menin should reveal crucial mechanisms in endocrine growth control and tumor suppression. The goal of experiments in this proposal is to elucidate the molecular and in vivo functions of menin in endocrine cell growth and neoplasia. Men1 inactivation in mice recapitulates some, but not all features of human MEN1 syndrome, indicating that additional unidentified changes accompany Men1 mutation to promote pathogenesis of endocrine neoplasias. In other conditions like pregnancy and obesity endocrine cells like pancreatic islets facultatively grow to meet changes in host physiologic needs, and our studies suggest that menin controls this adaptive proliferation. Menin associates with genes encoding growth regulators like c-Myc and represses their expression in pancreatic endocrine cells, but the mechanisms of repression are unknown. Experiments in this application will test the hypothesis that menin governs chromatin modifications to ensure normal levels and activity of c-Myc in the endocrine pancreas. This proposal's specific aims are to: (1) Use novel conditional-genetic methods to disrupt TGF-beta signaling in Me/77-deficient mice to test if TGF-beta pathways collaborate with menin in vivo to control gene expression, growth, and neoplastic progression in endocrine tumors. (2) Identify menin-dependent mechanisms of chromatin modification that repress expression of candidate target genes like c-Myc. (3) Identify mechanisms of menin-regulated adaptive islet cell growth. The analyses of menin proposed here will add substantially to our understanding of endocrine cell growth control and tumor suppression. Thus, these studies may lead to new diagnostic, prognostic, or therapeutic strategies for a broad range of human disorders stemming from dysregulated endocrine cell growth, including subsets of diabetes mellitus and endocrine neoplasias. ? ? ?
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