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

Brain Res. 2012 Jan 9;1430:18-24. doi: 10.1016/j.brainres.2011.10.046. Epub 2011 Nov 4.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Glucose Transporter Type 3 / biosynthesis*
  • Glucose Transporter Type 3 / genetics
  • Glucose Transporter Type 3 / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
  • Insulin-Like Growth Factor I / pharmacology
  • Insulin-Like Growth Factor I / physiology*
  • Neurons / enzymology
  • Neurons / metabolism
  • PC12 Cells
  • Phosphatidylinositol 3-Kinases / physiology*
  • Proto-Oncogene Proteins c-akt / physiology*
  • Rats
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases / physiology*

Substances

  • Glucose Transporter Type 3
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Proto-Oncogene Proteins c-akt