POSITIONAL CLONING OF MEN1 GENE

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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.