title: Tumor suppressor menin regulates expression of insulin-like growth factor binding protein 2.
abstract: Multiple endocrine neoplasia type I (MEN1) is an inherited tumor syndrome characterized by development of tumors in multiple endocrine organs. The gene mutated in MEN1 patients, Men1, encodes a nuclear protein, menin. Menin interacts with several transcription factors and inhibits their activities. However, it is unclear whether menin is essential for the repression of the expression of endogenous genes. Here, using menin-null cells, we show that menin is essential for repression of the endogenous IGFBP-2, a gene that can regulate cell proliferation. Additionally, complementation of menin-null cells with wild-type menin, but not with a MEN1 disease-related point mutant, restores the function of menin in repressing IGFBP-2. Consistent with this, the promoter of IGFBP-2 is repressed by wild-type menin, but not by a MEN1-related point mutant. Menin also alters the structure of the chromatin surrounding the promoter of the IGFBP-2 gene, as demonstrated by the deoxyribonuclease I hypersensitivity assay. Furthermore, nuclear localization signals in menin are crucial for repressing the expression of IGFBP-2. Together, these results suggest that menin regulates the expression of the endogenous IGFBP-2 gene at least in part through the promoter of IGFBP-2.
authors.affiliation: Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: La
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schnepp
authors.forename: Clark
authors.initials: C
authors.lastname: D  Petersen
authors.forename: Albert
authors.initials: A
authors.lastname: C  Silva
authors.forename: Xianxin
authors.initials: X
authors.lastname: Hua
mesh_terms: D000818:Animals; D002455:Cell Division; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D005816:Genetic Complementation Test; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D018761:Multiple Endocrine Neoplasia Type 1 / Q000503:physiopathology*; D016296:Mutagenesis; D011401:Promoter Regions, Genetic / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018971:Insulin-Like Growth Factor Binding Protein 2; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins