Regulation of glut1 mRNA by Hypoxia-inducible Factor-1

By Changhu Chen, N. Pore, A. Behrooz, F. Ismail-Beigi, A. Maity. Journal of Biological Chemistry, 2001

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Oncogenic transformation and hypoxia both induceglut1 mRNA. We studied the interaction between theras oncogene and hypoxia in up-regulating glut1mRNA levels using Rat1 fibroblasts transformed with H-ras (Rat1-ras). Transformation with H-ras led to a substantial increase in glut1mRNA levels under normoxic conditions and additively increasedglut1 mRNA levels in concert with hypoxia. Using a luciferase reporter construct containing 6 kilobase pairs of theglut1 promoter, we showed that this effect was mediated at the transcriptional level. Promoter activity was much higher in Rat1-ras cells than in Rat1 cells and could be down-regulated by cotransfection with a dominant negative Ras construct (RasN17). A 480-base pair (bp) cobalt/hypoxia-responsive fragment of the promoter containing a HIF-1 binding site showed significantly higher activity in Rat1-ras cells than in Rat1 cells, suggesting that Ras might mediate its effect through HIF-1 even under normoxic conditions. Consistent with this, Rat1-ras cells displayed higher levels of HIF1-α protein under normoxic conditions. In addition, a promoter construct containing a 4-bp mutation in the HIF1 binding site showed lower activity in Rat1-ras cells than a construct with an intact HIF1 binding site. The activity of the latter construct but not the former could be down-regulated by RasN17, supporting the importance of the HIF1 binding site in regulation by Ras. The phosphatidylinositol 3-kinase inhibitor LY29004 down-regulated glut1 promoter activity and mRNA levels under normoxia and also decreased HIF1α protein levels in these cells. Collectively these results indicate that H-Ras up-regulates theglut1 promoter, at least in part, by increasing HIF-1α protein levels leading to transactivation of promoter through the HIF-1 binding site.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/93665482cee5308a4dbb59f2ed9f2d5bb6699322

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Citations in the corpus

KRAS: feeding pancreatic cancer proliferation (2014, neutral): “Although HIF-1α has been shown to mediate GLUT1 expression in HRAS-transformed fibroblasts [39] and Ras-dependent glycolytic upregulation in glioblastoma [40], recent studies contend that KRAS-mediated glucose metabolic reprogramming is not dependent on HIF-1α [11,31].”
Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer (2005, background): “In a transformed rat fibroblast cell line hypoxia induced increased transcription of a GLUT1 reporter gene (Chen et al., 2001).”
Cancer's molecular sweet tooth and the Warburg effect. (2006, background): “Oncogenic HRas has been reported to increase the level of HIF-1 (10), and phosphatidylinositol 3-kinase signaling may stabilize HIF-1 (9).”
Glucose Metabolism Regulates T Cell Activation, Differentiation, and Functions (2014, background): “HIF-1α transcriptionally activates genes encoding glucose transporters, and rate limiting enzymes involved in glycolysis, and therefore plays a significant role in T cell differentiation and functions (39, 51).”
Why do cancers have high aerobic glycolysis? (2004, background): “RAS activation of GLUT1 transcription seems to be mediated through HIF1α transactivatio”