Sayo Yoshitaka, Murao Koji, Imachi Hitomi, Cao Wen Ming, Sato Makoto, Dobashi Hiroaki, Wong Norman C W, Ishida Toshihiko
First Department of Internal Medicine, Kagawa Medical University, Kagawa, 761-0793, Japan.
Endocrinology. 2002 Jun;143(6):2437-40. doi: 10.1210/endo.143.6.8950.
A mutant gene isolated from a patient with multiple endocrine neoplasia type 1, MEN1 encodes a protein, menin. Features of MEN1 include multiple endocrine tumors of the parathyroid glands, anterior pituitary and pancreatic islets. Insulinoma, arising from the pancreas is the most common MEN1-related tumor. Menin is a nuclear protein and interacts with the transcription factor, Jun D, but whether menin has a role in the pathogenesis of MEN1-related endocrine tumors including insulinoma remains unknown. In this study, we examined the effects of menin on production of human insulin. Insulinoma cells, INS-1 were co-transfected with a vector that expressed menin and a reporter template containing 235 bp of the rat insulin gene 5'-flanking region fused to the luciferase gene to yield pINS-LUC. Promoter activity of the insulin gene was significantly decreased in co-transfected cells as compared to mock-transfected controls. INS-1 cells stably transfected with a vector that expressed menin were used to examine the insulin secretion. In cells with a high level of menin expression, both insulin secretion and thymidine incorporation into DNA were inhibited when compared to mock-transfected cells. Additionally, the rate of apoptosis of menin-transfected cells was increased compared to mock-transfected cells. These observations suggest that menin inhibits insulin promoter activity and secretion, and also cell proliferation, raising the possibility that menin may play an important role in the pathogenesis of insulinoma.
从1型多发性内分泌腺瘤病（MEN1）患者中分离出的一个突变基因，MEN1编码一种蛋白质，即Menin。MEN1的特征包括甲状旁腺、垂体前叶和胰岛的多发性内分泌肿瘤。起源于胰腺的胰岛素瘤是最常见的与MEN1相关的肿瘤。Menin是一种核蛋白，与转录因子Jun D相互作用，但Menin在包括胰岛素瘤在内的MEN1相关内分泌肿瘤的发病机制中是否起作用尚不清楚。在本研究中，我们检测了Menin对人胰岛素产生的影响。将胰岛素瘤细胞INS-1与表达Menin的载体和一个报告模板共转染，该报告模板包含与荧光素酶基因融合的大鼠胰岛素基因5'侧翼区的235 bp，以产生pINS-LUC。与模拟转染对照相比，共转染细胞中胰岛素基因的启动子活性显著降低。用表达Menin的载体稳定转染的INS-1细胞用于检测胰岛素分泌。与模拟转染细胞相比，在Menin表达水平高的细胞中，胰岛素分泌和胸苷掺入DNA均受到抑制。此外，与模拟转染细胞相比，转染Menin的细胞凋亡率增加。这些观察结果表明，Menin抑制胰岛素启动子活性和分泌，以及细胞增殖，这增加了Menin可能在胰岛素瘤发病机制中起重要作用的可能性。
