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Transfection of the Multiple Endocrine Neoplasia Type 1 Gene to a Human Endocrine Pancreatic Tumor Cell Line Inhibits Cell Growth and Affects Expression of JunD, -Like Protein 1/Preadipocyte Factor-1, Proliferating Cell Nuclear Antigen, and QM/Jif-1

Departments of Surgical Sciences (P.S., D.L., G.W., J.R.) and Medical Sciences (P.G., M.S., Y.Z., A.G., K.Ö., S.W., B.S.), University Hospital, 751 85 Uppsala, Sweden

Address all correspondence and requests for reprints to: Britt Skogseid, Department of Medical Sciences, University Hospital, 751 85 Uppsala, Sweden. E-mail: britt.skogseid{at}medsci.uu.se.

In the absence of metastases or overgrowth to adjacent organs, the lack of reliable markers for malignancy is a well-recognized problem for clinicians managing patients with endocrine tumors. Apart from inactivation of the multiple endocrine neoplasia type 1 (MEN1) gene, the molecular mechanisms involved in tumorigenesis of the endocrine organs and MEN1-associated nonendocrine lesions are vastly unknown. To try to learn more about down-stream effects on MEN1 gene inactivation, we used the BON1 cells, showing low levels of endogenous menin, and transfected them with a MEN1 gene construct. On restoring the menin expression, we recorded inhibition of cell growth. We also performed macroarray and present data on differentially expressed genes in the transfected cells, after corroboration by Northern blots and quantitative PCR. JunD was up-regulated in menin-expressing clones, whereas -like protein 1/preadipocyte factor-1 (involved in differentiation and growth of the pancreatic endocrine cells), proliferating cell nuclear antigen, and QM/Jif-1 (a negative regulator of c-Jun) became down-regulated. These findings might contribute to the understanding of the tissue-specific features of MEN1. We also show that homozygous inactivation of the MEN1 gene statistically correlates to higher expression of -like protein 1/preadipocyte factor-1, proliferating cell nuclear antigen, and QM/Jif-1, as well as lower MEN1 expression, in a limited sample of malignant endocrine pancreatic tumors.

This work was supported by grants from The Swedish Medical Research Council, The Swedish Cancer Society, Lions Cancer Research Fund, and The Swedish Society of Medicine.

Abbreviations: AI, Apoptotic index; AP-1, activator protein-1; BON/v, BON1 transfected with vector without insert; BON/wt, BON1 wild type; dlk1, -like protein 1; FA1, fetal antigen 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LOH, loss of heterozygosity; MEN1, multiple endocrine neoplasia type 1; PCNA, proliferating cell nuclear antigen; PLCB3, phospholipase Cß3; Pref-1, preadipocyte factor-1; PRL, prolactin; QPCR, quantitative RT-PCR; RT, room temperature.

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