POSITIONAL CLONING OF MEN1 GENE

多发性内分泌肿瘤1型（MEN1）是一种以甲状旁腺、胰腺内分泌和垂体前叶组织多发肿瘤为特征的癌症综合征。早些时候，我们已经证明MEN1基因的遗传突变是导致这种综合征的原因。我们还发现MEN1编码的蛋白Menin存在于细胞核中，与转录因子JunD和NFkB结合，可以抑制JunD和NFkB诱导的转录。MEN1同源基因已从包括小鼠和果蝇在内的几个物种中被鉴定出来。我们已经开发了一种小鼠敲除模型，其肿瘤表型与人类MEN1疾病非常相似。此外，组织特异性转基因表达和敲除模型正在果蝇中开发。这些模型有望帮助理解menin的功能作用。我们现在已经建立了缺乏menin表达的小鼠胚胎干细胞和成纤维细胞系，以及一些过度表达menin的人和小鼠细胞系。缺乏menin（如果有的话）对诱导分化为胰岛细胞的ES细胞的影响正在探索中。我们对全球基因表达变化的研究已经在缺乏menin的细胞中鉴定了近50个转录本。现在可以探索这些转录本在绘制menin生物学途径中的重要性。

Multiple endocrine neoplasia type 1 (MEN1) is a cancer syndrome characterized by multiple tumors of the parathyroid, pancreatic endocrine, and anterior pituitary tissues. Earlier, we have shown that inherited mutations in the MEN1 gene are responsible for this syndrome. We have also shown that the MEN1 encoded protein, Menin, resides in the nucleus, binds the transcription factors JunD and NFkB, and can repress JunD and NFkB-induced transcription. MEN1 orthologs from several species have been identified including from mouse and Drosophila. We have developed a mouse knockout model, which has a tumor phenotype remarkably similar to the human MEN1 disease. In addition, tissue specific transgenic expression and knockout models are 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 several human and mouse cell lines that over express menin. The effect of lack of menin, if any, in ES cells that are induced to differentiate into pancreatic islet cells is being explored. Our efforts to study changes in global gene expression has led to the identification of nearly 50 transcripts in cells lacking menin. The importance of these transcripts in mapping out the pathway of menin biology can now be explored.