POSITIONAL CLONING OF MEN1 GENE

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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.