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Volume 272, Number 9,
Issue of February 28, 1997
pp. 5555-5562
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
Dual Control of glut1 Glucose Transporter Gene
Expression by Hypoxia and by Inhibition of Oxidative
Phosphorylation
(Received for publication, May 17, 1996, and in revised form, December 15, 1996)
Alireza
Behrooz
and
Faramarz
Ismail-Beigi
From the Department of Medicine and the Department of Molecular
Biology and Microbiology, School of Medicine, Case Western Reserve
University, Cleveland, Ohio 44106-4951
glut1 gene expression and glucose
transport are stimulated in a variety of cells and tissues in response
to hypoxia. glut1 is also up-regulated by inhibitors of
oxidative phosphorylation (such as azide) in the presence of oxygen.
Here, we test the hypothesis that hypoxia stimulates glut1
gene expression independent of its inhibitory effect on oxidative
phosphorylation. We examined the effect of cobalt chloride, a known
stimulator of genes responsive to reduced oxygen concentration
per se, on GLUT1 expression under normoxic conditions and
compared the results with the response to azide. Exposure of a rat
liver cell line (Clone 9) to 250 µM cobalt chloride
increases GLUT1 mRNA content, which becomes evident at 2 h,
reaches a maximal value of ~12-fold at 8 h, and remains elevated
at ~8-fold at 24 h. GLUT1 mRNA was the only GLUT isoform expressed in control cells and in cells exposed to cobalt chloride or
azide. The induction of GLUT1 mRNA by cobalt chloride is associated with a ~10-fold stimulation of cytochalasin B-inhibitable
3-O-methyl-D-glucose transport at 24 h. In
contrast to the rapid decrease in cell ATP levels and the stimulation
of glucose transport in response to azide, cell ATP content and glucose
transport remained unaltered during the initial 1-h period of exposure
to cobalt chloride. The effect of cobalt chloride on GLUT1 mRNA
content is mimicked by Ni(II) or Mn(II) but not by Fe(II). Employing
actinomycin D, we found no increase in the ~1.5-h half-life of GLUT1
mRNA in cobalt chloride-treated cells, suggesting that the effect
of cobalt chloride on GLUT1 mRNA content is largely mediated at the
transcriptional level; in contrast, GLUT1 mRNA half-life increased
to >8 h in azide-treated cells. In transient transfections we found
that ~6 kilobase pairs (kbp) of 5 -flanking region of the rat
glut1 promoter confers both cobalt chloride- and
azide-inducibility to a reporter gene. Deletion of ~2,500 base pairs
(bp) from the 5 end of the ~6-kbp DNA fragment results in a
reduction of the response to cobalt chloride and a complete loss of the
response to azide. A 666-bp DNA segment located ~6.0 kbp upstream of
the transcription start site was found to be necessary for the increase in reporter gene expression in response to azide, whereas a 480-bp segment located at approximately 3.5 kbp mediated the response to
cobalt chloride. The 480-bp segment is highly homologous to the
previously reported mouse glut1 enhancer and contains
several potential regulatory elements, including a hypoxia-inducible
element; an additional hypoxia-inducible element is present in
the 666-bp segment. Our results suggest that glut1 gene
expression is regulated in a dual fashion by hypoxia per
se and in response to inhibition of oxidative
phosphorylation.

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Copyright © 1997 by the American Society for Biochemistry and Molecular Biology.
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