POSITIONAL CLONING OF THE MEN1 GENE

MEN1 基因的定位克隆

• 批准号: 6988572
• 负责人: settara chandrasekharappa
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 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/6988572
• 关键词: Drosophilidae; biotechnology; cell differentiation; cell growth regulation; cell line; embryonic stem cell; gene mutation; genetic mapping; genetic markers; genetically modified animals; hematopoietic stem cells; human genetic material tag; laboratory mouse; molecular cloning; multiple endocrine neoplasia; neoplasm /cancer genetics; nuclear proteins; pancreatic islet neoplasm; parathyroid neoplasms; pituitary neoplasms; transcription factor

Multiple endocrine neoplasia type 1 (MEN1) is characterized by multiple tumors of the parathyroid, anterior pituitary and GI endocrine tissues. We have shown earlier that mutations in the MEN1 gene are responsible for the MEN1 syndrome. The MEN1 encoded nuclear protein, Menin, binds the transcription factors JunD and NFkB, and can repress JunD and NFkB-induced transcription. By expressing WT or mutant JunD in mouse fibroblast cell lines that are null for menin and JunD, we find that interaction with menin is required for the growth suppressor function(s) of JunD. We have developed both conventional and conditional mouse knockout models, which yield phenotypes that are remarkably similar to the human MEN1 disease, and have allowed us to delineate the stages in tumor development. In addition, we have developed tissue specific menin-inducible transgenic mouse models. Expression changes associated with presence or absence of menin in cell lines and during tumorigenesis, and specifically identification of the promoters of the genes with which menin is associated, are being studied to understand the biology of menin. The role of menin in differentiation of ES cells to pancreatic islet and hematopoietic lineages is being explored. In addition, tissue specific transgenic expression and knockout models for MEN1 are being developed in Drosophila. These models should help to understand the functional role(s) of menin and suggest possible therapeutic directions.

多发性内分泌腺瘤病1型(MEN1)的特点是 甲状旁腺、垂体前叶和胃肠道内分泌组织的肿瘤。 我们早些时候已经证明，MEN1基因的突变是 针对MEN1综合症。MEN1编码核蛋白，梅宁， 结合转录因子Jund和NFkB，并能抑制Jund和NFkB NFkB诱导转录。通过在MAND和JUND阴性的小鼠成纤维细胞系中表达WT或突变的JUND，我们发现JUND的生长抑制功能(S)需要与MENIN相互作用。我们开发了传统的和 有条件的小鼠基因敲除模型，其产生的表型是 与人类的MEN1疾病非常相似，并使我们能够 勾勒出肿瘤发展的各个阶段。此外，我们还有 开发了组织特异性薄荷素诱导的转基因小鼠模型。 在细胞系中和肿瘤发生过程中，与有无薄荷素相关的表达变化，特别是与薄荷素相关的基因启动子的鉴定，正在被研究，以了解薄荷素的生物学。脑膜素在ES细胞向胰岛和造血祖细胞分化中的作用正在探索中。此外，在果蝇中正在开发MEN1的组织特异性转基因表达和敲除模型。这些模型应该有助于理解薄荷素的功能作用(S)，并提出可能的治疗方向。