POSITIONAL CLONING OF 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, and 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, and has allowed us to delineate the stages in tumor development. In addition, we have developed tissue specific menin-inducible transgenic mouse models. Gene expression changes associated with the presence or absence of menin in mouse fibroblast cell lines and in islet cells at various stages of tumor formation are being studied. A model to re- express menin in knockout mice and to monitor the tumor growth/regression by a combination of histological analysis and non-invasive imaging methods is being developed. 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. In addition, tissue specific transgenic expression and knockout models for MEN1 are also being developed in Drosophila. These models should help to understand the functional role(s) of menin.