Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
Endocrinology. 2011 Jul;152(7):2589-98. doi: 10.1210/en.2010-1372. Epub 2011 Apr 26.
Understanding the molecular triggers of pancreatic β-cell proliferation may facilitate the development of regenerative therapies for diabetes. Genetic studies have demonstrated an important role for cyclin D2 in β-cell proliferation and mass homeostasis, but its specific function in β-cell division and mechanism of regulation remain unclear. Here, we report that cyclin D2 is present at high levels in the nucleus of quiescent β-cells in vivo. The major regulator of cyclin D2 expression is glucose, acting via glycolysis and calcium channels in the β-cell to control cyclin D2 mRNA levels. Furthermore, cyclin D2 mRNA is down-regulated during S-G(2)-M phases of each β-cell division, via a mechanism that is also affected by glucose metabolism. Thus, glucose metabolism maintains high levels of nuclear cyclin D2 in quiescent β-cells and modulates the down-regulation of cyclin D2 in replicating β-cells. These data challenge the standard model for regulation of cyclin D2 during the cell division cycle and suggest cyclin D2 as a molecular link between glucose levels and β-cell replication.
了解胰腺β细胞增殖的分子触发因素可能有助于开发糖尿病的再生治疗方法。遗传研究表明细胞周期蛋白 D2 在β细胞增殖和质量平衡中起重要作用，但它在β细胞分裂中的具体功能和调节机制仍不清楚。在这里，我们报告细胞周期蛋白 D2 在体内静止的β细胞的核内存在高水平。细胞周期蛋白 D2 表达的主要调节剂是葡萄糖，它通过β细胞中的糖酵解和钙通道作用来控制细胞周期蛋白 D2 mRNA 水平。此外，细胞周期蛋白 D2 mRNA 在每个β细胞分裂的 S-G2-M 期下调，其机制也受葡萄糖代谢的影响。因此，葡萄糖代谢在静止的β细胞中维持高水平的核细胞周期蛋白 D2，并调节复制的β细胞中细胞周期蛋白 D2 的下调。这些数据挑战了细胞分裂周期中细胞周期蛋白 D2 调节的标准模型，并表明细胞周期蛋白 D2 是葡萄糖水平与β细胞复制之间的分子联系。
