POSITIONAL CLONING OF MEN1 GENE

多发性内分泌肿瘤1型(MEN1)以甲状旁腺、胰腺内分泌和垂体前叶组织的多发性肿瘤为特征。我们早些时候已经证明，MEN1基因的遗传突变是导致MEN1综合征的原因。我们还发现MEN1编码的核蛋白Menin与转录因子Jund和NFkB结合，并能抑制Jund和NFkB诱导的转录。我们已经开发了常规和有条件的小鼠基因敲除模型，这些模型产生的表型与人类MEN1疾病非常相似。此外，我们还利用基于四环素的方法开发了组织特异性薄荷素诱导的转基因小鼠模型。在果蝇中，MEN1的组织特异性转基因表达和敲除模型也正在开发中。这些模型有望帮助理解薄荷素的功能作用(S)。我们现在已经建立了缺乏脑膜素表达的小鼠ES和成纤维细胞系，并在缺失的成纤维细胞中表达脑膜素，以探索与存在或不存在脑膜素相关的基因表达变化。我们还在使用siRNA双链来抑制HeLa细胞中MEN1的表达。正在努力探索脑膜素在分化中的作用，如果有的话，通过诱导脑膜素缺失的ES细胞分化为胰岛细胞。

Multiple endocrine neoplasia type 1 (MEN1) is characterized by multiple tumors of the parathyroid, pancreatic endocrine, and anterior pituitary tissues. We have shown earlier that inherited mutations in the MEN1 gene are responsible for the MEN1 syndrome. We have also shown that 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. In addition, we have developed tissue specific menin-inducible transgenic mouse models using tetracycline based approaches. A tissue specific transgenic expression, and knockout models for MEN1 are also being developed in Drosophila. These models are expected to help understand the functional role(s) of menin. We have now established mouse ES and fibroblast cell lines that lack menin expression, and menin is being expressed in null fibroblasts to explore the gene expression changes associated with the presence or absence of menin. We are also using siRNA duplexes to suppress the expression of MEN1 in HeLa cells. 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.