The role and mechanism of high expression of cyclin B2 in MEN1 insulinoma.
- Author:
Ting WU
1
;
Xiao-Hua HUANG
Author Information
1. Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen 361005, China. wuting78@yahoo.com.cn
- Publication Type:Journal Article
- MeSH:
Animals;
Cell Proliferation;
Cyclin B2;
genetics;
metabolism;
Histones;
metabolism;
Insulinoma;
metabolism;
pathology;
Mice;
Mice, Knockout;
Multiple Endocrine Neoplasia Type 1;
genetics;
Mutation;
Pancreatic Neoplasms;
metabolism;
pathology;
Proto-Oncogene Proteins;
genetics
- From:
Acta Physiologica Sinica
2011;63(6):555-564
- CountryChina
- Language:Chinese
-
Abstract:
Multiple endocrine neoplasia type 1 (MEN1) is a dominantly inherited tumor syndrome characterized by development of various combinations of tumors in multiple endocrine glands, including the pituitary, parathyroid or pancreas. MEN1 results from mutations in tumor suppressor gene Men1, which encodes nuclear protein menin. Menin has been shown to preferentially repress cell proliferation in endocrine tissues including pancreatic beta cells. Herein, the present study was to explore the potential mechanisms underlying menin in repressing cell proliferation in mice MEN1 insulinoma. In the Gene Set Enrichment Analysis (GSEA), Ccnb2 (encoding cyclin B2) was up-regulated in pancreatic islets of Men1-excised mice after 14-day tamoxifen-feeding. Immunofluorescence with antibody against cyclin B2 revealed that the expression of cyclin B2 was greatly increased in MEN1 insulinoma. In Men1(-/-) cells, Men1 ablation leaded to an increase in cyclin B2 expression. Immunofluorescent staining by phospho-H3S10 antibody revealed the increasing number of Men1(-/-) cells in mitosis. Cells were seeded at a density of 5 × 10(4), then counted on day 2, 4 and 6, and the cell growth curve revealed Men1 ablation increased the cell proliferation. In contrast, knockdown of cyclin B2 by shRNA diminished the number of cells in mitosis and reduced cell proliferation. Further, chromatin immunoprecipitation (ChIP) assay indicated that menin affected the histone modification of the promoter of Ccnb2 by reducing the level of histone H3 lysine 4 tri-methylation (H3K4me3) and histone H3 acetylation but not affecting the level of histone H3 lysine 9 tri-methylation (H3K9me3) or histone H3 lysine 27 tri-methylation (H3K27me3). Our results suggest that menin may inhibit MEN1 insulinoma by suppressing cyclin B2 expression via histone modification.
