Transcription regulation of the multiple endocrine neoplasia type 1 gene in human and mouse.
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.
Zablewska
Barbara
B
Department of Molecular Medicine, Karolinska Institutet, S-17176 Stockholm, Sweden.
Bylund
Lovisa
L
Mandic
Slavena A
SA
Fromaget
Maud
M
Gaudray
Patrick
P
Weber
Günther
G
D016475:3T3 Cells; D024506:5' Flanking Region / Q000235:genetics; D000818:Animals; D002460:Cell Line; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D051379:Mice; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D023282:Nuclease Protection Assays; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins; D034622:RNA Interference / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics*; D014162:Transfection
D018076:DNA, Complementary; C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins