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Transcription Regulation of the Multiple Endocrine Neoplasia Type 1 Gene in Human and Mouse

Department of Molecular Medicine (B.Z., L.B., S.A.M., G.W.), Karolinska Institutet, S-17176 Stockholm, Sweden; Instabilité et Alterations des Génomes (B.Z., M.F., P.G.), 06107 Nice, France; and Institut National de la Santé et de la Recherche Médicale U45, Hôpital E. Herriot (M.F.), 69437 Lyon, France

Address all correspondence and requests for reprints to: Günther Weber, Ph.D., Department of Molecular Medicine, Tumor Biochemistry Unit, CMM, L8:02, Karolinska Hospital, S-17176 Stockholm, Sweden. E-mail: gunther.weber{at}cmm.ki.se.

Multiple endocrine neoplasia type I (MEN1) is an autosomal dominant tumor syndrome, with the presence of tumors in parathyroid, pancreatic, and anterior pituitary. The tumor suppressor gene MEN1, located on chromosome 11q13, encodes a 610 amino acid, 68-kDa protein, menin. Menin is conserved among species but has no similarity with any known protein. To investigate how the expression is regulated in both man and mouse, we assayed a greater than 1-kb region upstream of the second exon for promoter activity in luciferase reporter vectors. The basic promoter was located closely upstream the most commonly expressed first exon. The region further upstream modified the activity. Repetitive elements of the short interspersed/Alu type covered the entire human upstream regulatory region and were the only apparent motif in common with its murine ortholog. Previous studies have indicated a compensatory induction of the second allele because of inactivation of the first allele. We found that overexpression of menin in an inducible cell culture system down-regulated the proximal promoter. In response to down-regulation of MEN1 expression by RNA interference, the regulatory region activated the promoter in a compensatory manner. Our data confirm that the expression of the MEN1 gene is regulated by a feedback from its product menin.

This work was supported in part by the Association pour la Recherche sur le Cancer (ARC Grant 4438) (to P.G.), King Gustaf V:s Jubilee Foundation (to G.W.), and the Swedish Cancer Society. B.Z. was supported by a grant from the Wenner-Gren Foundation and a stipend from CNRS.

Abbreviations: HDAC, Histone deacetylase; HEK, human embryo kidney; MEN1, multiple endocrine neoplasia type I; NFB, nuclear factor B; RACE, rapid amplification of cDNA ends; RNAi, RNA interference; SINE, short interspersed repetitive element; siRNA, small interfering RNA oligonucleotide duplex.

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