Regulation of the rate of glucose transport across plasma membranes is of fundamental importance to normal cell metabolism, glucose homeostasis, and hyperglycemia of diabetes. Expression of the ubiquitous GLUT1 glucose transporter is augmented by several stimuli including serum, thyroid hormone, rise in cytosolic calcium, hypoxia, and inhibition of oxidative phosphorylation. The investigators have shown that the increase in cell GLUT1 mRNA content in response to inhibition of oxidative phosphorylation by azide is mediated by both enhanced transcription and decreased degradation of GLUT1 mRNA. Recently the investigators have made the novel observation that GLUT1 expression in a number of cell lines is markedly augmented by cobalt(II) chloride [Co(II)], an agent which stimulates the expression of hypoxia-responsive genes; members of this gene family are upregulated by hypoxia but not by inhibitors of oxidative phosphorylation. Hence, GLUT1 appears to be the first example of a gene whose expression is regulated in a dual fashion by hypoxia, namely by a reduction in oxygen concentration per se, and by the attendant inhibition of oxidative phosphorylation. The investigators have also found that different regions of the GLUT1 promoter/5'-flanking region are necessary for the transcriptional response to azide and Co(II). In addition, a 480-bp DNA segment located approximately 3.5 kbp upstream of the GLUT1 transcription start-site functions as an """"""""enhancer"""""""", is essential for the response to Co(II), and contains an hypoxia-inducible-element (HIE). More recently the investigators have identified a 666-bp region located approximately 6 kbp upstream of the transcription start-site which appears to be responsible for the stimulation o GLUT1 gene transcription in response to azide. Based on the above findings, studies are proposed in this continuation grant application to test the following hypotheses: 1) Different elements in the GLUT1 promoter region mediate the transcriptional response to azide and Co(ll); 2) Sequences contained in GLUT1 mRNA and specific RNA binding factors mediate the observed stabilization of GLUT1 mRNA in cells treated with azide, calcium ionophores, and anisomycin. Results of these studies will enhance our understanding of the regulation of the GLUTl glucose transporter expression in a number of physiological and pathophysiological conditions, especially those of the adaptive response to hypoxia and to inhibition of oxidative phosphorylation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK045945-04A1
Application #
2616197
Study Section
Metabolism Study Section (MET)
Program Officer
Haft, Carol R
Project Start
1994-08-01
Project End
2002-04-30
Budget Start
1998-05-28
Budget End
1999-04-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Hwang, Daw-Yang; Ismail-Beigi, Faramarz (2006) Control of Glut1 promoter activity under basal conditions and in response to hyperosmolarity: role of Sp1. Am J Physiol Cell Physiol 290:C337-44
Rubin, Darrell; Ismail-Beigi, Faramarz (2003) Distribution of Glut1 in detergent-resistant membranes (DRMs) and non-DRM domains: effect of treatment with azide. Am J Physiol Cell Physiol 285:C377-83
Hwang, Daw-Yang; Ismail-Beigi, Faramarz (2002) Glucose uptake and lactate production in cells exposed to CoCl(2) and in cells overexpressing the Glut-1 glucose transporter. Arch Biochem Biophys 399:206-11
Zhang, J Z; Abbud, W; Prohaska, R et al. (2001) Overexpression of stomatin depresses GLUT-1 glucose transporter activity. Am J Physiol Cell Physiol 280:C1277-83
Hwang, D Y; Ismail-Beigi, F (2001) Stimulation of GLUT-1 glucose transporter expression in response to hyperosmolarity. Am J Physiol Cell Physiol 281:C1365-72
Badr, G A; Tang, J; Ismail-Beigi, F et al. (2000) Diabetes downregulates GLUT1 expression in the retina and its microvessels but not in the cerebral cortex or its microvessels. Diabetes 49:1016-21
Koseoglu, M H; Beigi, F I (1999) Mechanism of stimulation of glucose transport in response to inhibition of oxidative phosphorylation: analysis with myc-tagged Glut1. Mol Cell Biochem 194:109-16
Prasad, R K; Ismail-Beigi, F (1999) Mechanism of stimulation of glucose transport by H2O2: role of phospholipase C. Arch Biochem Biophys 362:113-22
Badr, G A; Zhang, J Z; Tang, J et al. (1999) Glut1 and glut3 expression, but not capillary density, is increased by cobalt chloride in rat cerebrum and retina. Brain Res Mol Brain Res 64:24-33
Saker, F; Voora, D M; Mahajan, S D et al. (1999) Effect of reduced inspired oxygen on fetal growth and maternal glucose metabolism in rat pregnancy. Metabolism 48:738-44

Showing the most recent 10 out of 24 publications