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The Multiple Endocrine Neoplasia Type 1 Gene Product, Menin, Inhibits Insulin Production in Rat Insulinoma Cells

First Department of Internal Medicine (Y.S., K.M., H.I., W.M.C., M.S., H.D., T.I.), Kagawa Medical University, Kagawa, 761-0793, Japan; and Departments of Medicine and Biochemistry & Molecular Biology, (N.C.W.W.), Faculty of Medicine, University of Calgary, Health Sciences Center, Calgary, Alberta, Canada T2N 4N1

A mutant gene isolated from a patient with multiple endocrine neoplasia type 1, MEN1 encodes a protein, menin. Features of MEN1 include multiple endocrine tumors of the parathyroid glands, anterior pituitary and pancreatic islets. Insulinoma, arising from the pancreas is the most common MEN1-related tumor. Menin is a nuclear protein and interacts with the transcription factor, Jun D, but whether menin has a role in the pathogenesis of MEN1-related endocrine tumors including insulinoma remains unknown. In this study, we examined the effects of menin on production of human insulin. Insulinoma cells, INS-1 were co-transfected with a vector that expressed menin and a reporter template containing 235 bp of the rat insulin gene 5'-flanking region fused to the luciferase gene to yield pINS-LUC. Promoter activity of the insulin gene was significantly decreased in co-transfected cells as compared to mock-transfected controls. INS-1 cells stably transfected with a vector that expressed menin were used to examine the insulin secretion. In cells with a high level of menin expression, both insulin secretion and thymidine incorporation into DNA were inhibited when compared to mock-transfected cells. Additionally, the rate of apoptosis of menin-transfected cells was increased compared to mock-transfected cells. These observations suggest that menin inhibits insulin promoter activity and secretion, and also cell proliferation, raising the possibility that menin may play an important role in the pathogenesis of insulinoma.

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