IGF-1 induces hypoxia-inducible factor 1α-mediated GLUT3 expression through PI3K/Akt/mTOR dependent pathways in PC12 cells

• Published in: Brain research Vol. 1430; no. 9; pp. 18 - 24
• Main Authors: Yu, Jian, Li, Junliang, Zhang, Shanyi, Xu, Xinke, Zheng, Meiguang, Jiang, Guangyi, Li, Fangcheng
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 09.01.2012; Elsevier
• Subjects: (PI3K)/Akt/mTOR pathways; Animals; Biological and medical sciences; brain; cell membranes; Cell physiology; cytokines; Fundamental and applied biological sciences. Psychology; genes; glucose; Glucose Transporter Type 3 - biosynthesis; Glucose Transporter Type 3 - genetics; Glucose Transporter Type 3 - metabolism; glucose transporters; GLUT3; growth factors; HIF-1α; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; IGF-1; Insulin-Like Growth Factor I - pharmacology; Insulin-Like Growth Factor I - physiology; ischemia; mammals; Molecular and cellular biology; Neurology; neurons; Neurons - enzymology; Neurons - metabolism; PC12 Cells; phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - physiology; protein synthesis; Proto-Oncogene Proteins c-akt - physiology; Rats; Responses to growth factors, tumor promotors, other factors; secretion; Signal Transduction - physiology; TOR Serine-Threonine Kinases - physiology; transcription factors; IGF-1; HIF-1α; (PI3K)/Akt/mTOR pathways; GLUT3; PC12 cells; Oxygen; Rat; Rodentia; Environmental factor; Glucose; Insulin like growth factor 1; In vitro; Vertebrata; Mammalia; Cell line; Neuron; Animal; Hypoxia; Carrier protein
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2011.10.046

Abstract 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 CoCl2 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.