Core Facility of Genetically Engineered Mice, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, PR China.
Biochemistry. 2010 Jan 12;49(1):218-25. doi: 10.1021/bi901414g.
Multiple lines of evidence have shown that the functional defect of pancreatic beta cells is the root cause of type 2 diabetes. FoxO1, a key transcription factor of fundamental cellular physiology and functions, has been implicated in this process. However, the underlying molecular mechanism is still largely unknown. Here, we show that the overexpression of FoxO1 promotes the proliferation of cultured pancreatic beta cells exposed to low nutrition, while no change in apoptosis was observed compared with the control group. Moreover, by using two specific inhibitors for PI3K and MAPK signaling, we found that FoxO1 might be the downstream transcription factor of these two pathways. Furthermore, a luciferase assay demonstrated that FoxO1 could regulate the expression of Ccnd1 at the transcription level. Collectively, our findings indicated that FoxO1 modulated by both MAPK and PI3K signaling pathways was prone to cause the proliferation, but not the apoptosis, of pancreatic beta cells exposed to low nutrition, at least partially, by regulating the expression of Ccnd1 at the transcription level.
多项证据表明，2 型糖尿病的根本病因是胰岛β细胞的功能缺陷。FoxO1 作为基础细胞生理学和功能的关键转录因子，与该过程相关。然而，其潜在的分子机制在很大程度上仍是未知的。本研究表明，FoxO1 的过表达促进了暴露于低营养环境中的培养胰岛β细胞的增殖，而与对照组相比，凋亡没有变化。此外，通过使用两种特定的 PI3K 和 MAPK 信号通路抑制剂，我们发现 FoxO1 可能是这两条通路的下游转录因子。此外，荧光素酶检测表明 FoxO1 可以在转录水平上调节 Ccnd1 的表达。综上，我们的研究结果表明，FoxO1 受 MAPK 和 PI3K 信号通路的调节，至少部分通过调节 Ccnd1 的转录水平，容易导致暴露于低营养环境中的胰岛β细胞增殖，而不是凋亡。
