Men1 Control of Endocrine Cell Growth and Differentiation

描述(申请人提供)：内分泌组织的受控生长对健康是必不可少的，但对控制内分泌细胞生长和分化的内在细胞调节因子知之甚少。MEN1基因的突变促进了1型多发性内分泌肿瘤(MEN1)的发病机制，最近的研究表明，MEN1基因的蛋白产物Menin是内分泌细胞增殖和命运的关键调节因子。Menin与其他核蛋白和染色质结合，促进特定的共价组蛋白修饰，从而激活或抑制靶基因的表达。识别脑膜素靶点、脑膜素在基因调控中的功能，以及与脑膜素相互作用的信号通路，应该揭示内分泌生长控制和肿瘤抑制的关键机制。这项实验的目的是阐明脑膜素在内分泌细胞生长和肿瘤形成中的分子和体内功能。小鼠的MEN1失活概括了人类MEN1综合征的部分但不是全部特征，表明伴随MEN1突变的其他未知变化促进内分泌肿瘤的发病。在其他情况下，如怀孕和肥胖，内分泌细胞，如胰岛，可以兼性生长以满足宿主生理需求的变化，我们的研究表明，薄荷素控制这种适应性增殖。Menin与编码c-Myc等生长调节剂的基因相关，并抑制它们在胰腺内分泌细胞中的表达，但抑制机制尚不清楚。这一应用中的实验将检验这一假设，即薄荷素控制染色质修饰，以确保内分泌胰腺中c-Myc的正常水平和活性。这项建议的具体目的是：(1)使用新的条件遗传方法来干扰Me/77缺陷小鼠的转化生长因子-β信号转导，以测试转化生长因子-β途径是否与体内的薄荷素协同控制内分泌肿瘤的基因表达、生长和肿瘤进展。(2)明确抑制c-Myc等候选靶基因表达的染色质修饰的脑膜素依赖机制。(3)明确脑膜素调节适应性胰岛细胞生长的机制。在这里提出的薄荷素的分析将大大增加我们对内分泌细胞生长控制和肿瘤抑制的理解。因此，这些研究可能导致新的诊断、预后或治疗策略，用于治疗由内分泌细胞生长失调引起的广泛的人类疾病，包括糖尿病和内分泌肿瘤的亚型。

DESCRIPTION (provided by applicant): 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.