POSITIONAL CLONING OF MEN1 GENE

多发性内分泌瘤1型（MEN 1）的特征是甲状旁腺、垂体前叶和胃肠道内分泌组织的多发性肿瘤。 我们之前已经表明，MEN 1基因的突变是MEN 1综合征的原因，MEN 1编码的核蛋白Menin与转录因子JunD和NF κ B结合，可以抑制JunD和NF κ B诱导的转录。我们已经开发了常规和条件性小鼠基因敲除模型，这些模型产生的表型与人类MEN 1疾病非常相似，并使我们能够描绘肿瘤发展的阶段。此外，我们已经开发了组织特异性脑膜炎诱导的转基因小鼠模型。在小鼠成纤维细胞系和胰岛细胞中与menin存在或不存在相关的基因表达变化， 肿瘤形成正在研究中。正在开发一种在基因敲除小鼠中重新表达menin并通过组织学分析和非侵入性成像方法的组合来监测肿瘤生长/消退的模型。目前正在努力探索menin在 分化，如果有的话，通过诱导无menin的ES细胞分化成胰岛细胞。此外，MEN 1的组织特异性转基因表达和敲除模型也正在研究中。 在果蝇中发展起来的。这些模型应该有助于理解menin的功能作用。

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, and the MEN1 encoded nuclear protein, Menin, binds the transcription factors JunD and NFkB, and can repress JunD and NFkB-induced transcription. We have developed both conventional and conditional mouse knockout models, which yield phenotypes that are remarkably similar to the human MEN1 disease, and has allowed us to delineate the stages in tumor development. In addition, we have developed tissue specific menin-inducible transgenic mouse models. Gene expression changes associated with the presence or absence of menin in mouse fibroblast cell lines and in islet cells at various stages of tumor formation are being studied. A model to re- express menin in knockout mice and to monitor the tumor growth/regression by a combination of histological analysis and non-invasive imaging methods is being developed. Efforts are underway to explore the role of menin on differentiation, if any, by inducing menin-null ES cells to differentiate into pancreatic islet cells. In addition, tissue specific transgenic expression and knockout models for MEN1 are also being developed in Drosophila. These models should help to understand the functional role(s) of menin.