PATHOPHYSIOLOGY OF MULTIPLE ENDOCRINE NEOPLASIA TYPE 1

1 型多发性内分泌肿瘤的病理生理学

• 批准号: 6161975
• 负责人: S J MARX
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6161975
• 关键词: Escherichia coli; Insecta; clinical research; family genetics; gene expression; human subject; human tissue; hyperparathyroidism; immunoprecipitation; loss of heterozygosity; molecular cloning; multiple endocrine neoplasia; neoplasm /cancer genetics; parathyroid neoplasms; point mutation; tissue /cell culture; transfection /expression vector; tumor suppressor genes; tumor suppressor proteins; yeast two hybrid system

The MEN1 gene is a likely tumor suppressor gene because tumors in multiple endocrine neoplasia type 1 (MEN1) show loss of heterozygosity (LOH) at this locus and because sporadic tumors of the same tissues also show 11q13 LOH implicating this gene through a similar mechanism. We have contributed to an intramural NIH collaboration that has cloned the MEN1 gene. We are continuing to explore its clinical and its basic implications. We find germline mutations in 90-95% of probands with familial MEN1 or with sporadic MEN1. In contrast, probands with familial isolated hyperparathyroidism have not shown MEN1 mutations. We will continue to explore these and other states for germline MEN1 mutations. We have also found somatic MEN1 mutation in 20% of parathyroid tumors not associated with MEN1. We will also determine the spectrum of pathologic states that MEN1 gene contributers to through mutation and other mechanisms. We have also initiated studies on the expression and actions of the encoded menin RNA and protein. The gene has been expressed in E. Coli and mammalian cells and will be overexpressed in insect cells. And vector constructs are being developed to express mutant forms. Its interactions with other proteins are being studied by immunoprecipitation and by the yeast 2-hybrid system. These studies should help identify its biochemical activities.

MEN1 基因可能是一种肿瘤抑制基因，因为肿瘤存在于 1 型多发性内分泌肿瘤 (MEN1) 显示杂合性缺失 （LOH）在这个位点，并且因为相同组织的散发性肿瘤也 显示 11q13 LOH 通过类似的机制暗示该基因。 我们 为 NIH 的校内合作做出了贡献，该合作克隆了 MEN1 基因。 我们正在继续探索其临床和基础 影响。 我们发现 90-95% 的先证者存在种系突变 家族性 MEN1 或散发性 MEN1。 相反，先证者 家族性孤立性甲状旁腺功能亢进症未表现出 MEN1 突变。 我们将继续探索种系 MEN1 的这些和其他状态 突变。 我们还发现 20% 的人存在体细胞 MEN1 突变 甲状旁腺肿瘤与 MEN1 无关。 我们还将确定 MEN1 基因促成的一系列病理状态 突变和其他机制。 我们还启动了相关研究 编码的 menin RNA 和蛋白质的表达和作用。 基因 已在大肠杆菌和哺乳动物细胞中表达，并将 在昆虫细胞中过度表达。载体构建体正在开发中 表达突变形式。 它与其他蛋白质的相互作用正在被 通过免疫沉淀和酵母2-杂交系统进行研究。 这些 研究应有助于确定其生化活性。