Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine ; Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine.
Acta Histochem Cytochem. 2013 Apr 30;46(2):51-8. doi: 10.1267/ahc.12035. Epub 2013 Mar 5.
Proliferation of pancreatic β-cells is an important mechanism underlying β-cell mass adaptation to metabolic demands. Increasing β-cell mass by regeneration may ameliorate or correct both type 1 and type 2 diabetes, which both result from inadequate production of insulin by β-cells of the pancreatic islet. Transforming growth factor β (TGF-β) signaling is essential for fetal development and growth of pancreatic islets. In this study, we exposed HIT-T15, a clonal pancreatic β-cell line, to TGF-β signaling. We found that inhibition of TGF-β signaling promotes proliferation of the cells significantly, while TGF-β signaling stimulation inhibits proliferation of the cells remarkably. We confirmed that this proliferative regulation by TGF-β signaling is due to the changed expression of the cell cycle regulator p27. Furthermore, we demonstrated that there is no observed effect on transcriptional activity of p27 by TGF-β signaling. Our data show that TGF-β signaling mediates the cell-cycle progression of pancreatic β-cells by regulating the nuclear localization of CDK inhibitor, p27. Inhibition of TGF-β signaling reduces the nuclear accumulation of p27, and as a result this inhibition promotes proliferation of β-cells.
胰岛 β 细胞的增殖是 β 细胞质量适应代谢需求的重要机制。通过再生增加 β 细胞质量可能改善或纠正 1 型和 2 型糖尿病，这两种糖尿病均由胰岛的 β 细胞胰岛素产生不足引起。转化生长因子 β（TGF-β）信号对于胎儿发育和胰岛生长至关重要。在这项研究中，我们使 HIT-T15（一种克隆的胰岛 β 细胞系）暴露于 TGF-β 信号中。我们发现抑制 TGF-β 信号可显著促进细胞增殖，而 TGF-β 信号刺激可显著抑制细胞增殖。我们证实，TGF-β 信号对细胞周期调节剂 p27 的表达变化导致了这种增殖调节。此外，我们证明 TGF-β 信号对 p27 的转录活性没有观察到影响。我们的数据表明，TGF-β 信号通过调节 CDK 抑制剂 p27 的核定位来介导胰岛 β 细胞的细胞周期进程。抑制 TGF-β 信号会减少 p27 的核积累，因此这种抑制会促进 β 细胞的增殖。
