Department of Neurosurgery, The Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.
Brain Res. 2012 Jan 9;1430:18-24. doi: 10.1016/j.brainres.2011.10.046. Epub 2011 Nov 4.
Glucose metabolism is essential for most mammalian neurons, and the passage of glucose across cell membranes is mainly facilitated by glucose transporter 3 (GLUT3). In ischemia/reperfusion injured brains, increase of IGF-1 secretion and GLUT3 up-regulation, are regarded as protective processes. Recent works have shown that various growth factors and cytokines including IGF-1 can stimulate HIF-1α expression, thereby triggering transcription of numerous hypoxia-inducible genes by oxygen-independent mechanisms. So, we hypothesized that HIF-1α might play important role in the process of IGF-1 induced GLUT3. Using echinomycin, a HIF-1 inhibitor, and HIF-1α siRNA, we demonstrated IGF-1 induced GLUT3 expression through HIF-1α in neuronal PC12 cells. Moreover, IGF-1 stimulated HIF-1α and GLUT3 protein expression through phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR dependent pathways. Analysis of GLUT3 promoter deletion sequences indicated that a putative hypoxia-response element (HRE) was critical in GLUT3 promoter activity when PC12 cells were treatment with CoCl(2) and IGF-1. In conclusion, we showed that the expression of GLUT3 in response to IGF-1 was dependent on PI-3-kinase and mTOR activity, and required the transcription factor HIF-1α.
葡萄糖代谢对大多数哺乳动物神经元至关重要，而葡萄糖穿过细胞膜的过程主要是由葡萄糖转运蛋白 3（GLUT3）促进的。在缺血/再灌注损伤的大脑中，IGF-1 分泌的增加和 GLUT3 的上调被认为是保护过程。最近的研究表明，包括 IGF-1 在内的各种生长因子和细胞因子可以刺激 HIF-1α 的表达，从而通过非氧依赖机制触发许多缺氧诱导基因的转录。因此，我们假设 HIF-1α 可能在 IGF-1 诱导的 GLUT3 过程中发挥重要作用。使用 HIF-1 抑制剂依西美坦和 HIF-1α siRNA，我们证明了 IGF-1 在神经元 PC12 细胞中通过 HIF-1α 诱导 GLUT3 的表达。此外，IGF-1 通过磷脂酰肌醇 3-激酶（PI3K）/Akt/mTOR 依赖途径刺激 HIF-1α 和 GLUT3 蛋白的表达。对 GLUT3 启动子缺失序列的分析表明，当 PC12 细胞用 CoCl2 和 IGF-1 处理时，一个假定的缺氧反应元件（HRE）在 GLUT3 启动子活性中是关键的。总之，我们表明，IGF-1 对 GLUT3 的表达依赖于 PI-3-激酶和 mTOR 活性，并且需要转录因子 HIF-1α。
