POSITIONAL CLONING OF THE MEN1 GENE

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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. The MEN1 encoded nuclear protein, Menin, binds the transcription factors JunD and NFkB, and can repress JunD and NFkB-induced transcription. By expressing WT or mutant JunD in mouse fibroblast cell lines that are null for menin and JunD, we find that interaction with menin is required for the growth suppressor function(s) of JunD. We have developed both conventional and conditional mouse knockout models, which yield phenotypes that are remarkably similar to the human MEN1 disease, and have allowed us to delineate the stages in tumor development. In addition, we have developed tissue specific menin-inducible transgenic mouse models. Expression changes associated with presence or absence of menin in cell lines and during tumorigenesis, and specifically identification of the promoters of the genes with which menin is associated, are being studied to understand the biology of menin. The role of menin in differentiation of ES cells to pancreatic islet and hematopoietic lineages is being explored. In addition, tissue specific transgenic expression and knockout models for MEN1 are being developed in Drosophila. These models should help to understand the functional role(s) of menin and suggest possible therapeutic directions.