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Papers In Press, published online ahead of print February 1, 2006
Biochemistry, University of Bristol, School of Medical Sciences, Bristol BS8 1TD
Corresponding Author: A.Halestrap{at}Bristol.ac.uk
The monocarboxylate transporter MCT4 mediates lactic acid efflux from most tissues that are dependent on glycolysis for their ATP production. Here we demonstrate that expression of MCT4 mRNA and protein was increased > three-fold by 48 hours exposure to 1% O2 whilst MCT1 expression was not increased. The effect was mimicked by CoCl2 (50
J. Biol. Chem, 10.1074/jbc.M511397200
Submitted on October 20, 2005
Revised on January 10, 2006
Accepted on January 31, 2006
The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1
dependent mechansm
M), suggesting transcriptional regulation by hypoxia inducible factor 1
(HIF-1). The predicted promoters for human MCT1, MCT2 and MCT4 were cloned into the pGL3 vector and shown to be active (luciferase luminescence) under basal conditions. Only the MCT4 promoter was activated (> 2-fold) by hypoxia. No response was found in cells lacking HIF-1. Four potential hypoxia response elements (HRE) were identified but deletion analysis implicated only two in the hypoxia response. These were just upstream from the transcription start site and also found in the mouse MCT4 promoter. Mutation of site 2 totally abolished the hypoxic response whilst mutation of site 1 only reduced the response. Gel-shift analysis demonstrated that nuclear extracts of hypoxic but not normoxic HeLa cells contained two transcription factors that bound to DNA probes containing these HREs. The major shifted band was abolished by mutation of site 2 and supershift analysis confirmed HIF-1a bound to this site. Binding of the second factor was abolished by mutation of site 1. We conclude that MCT4, like other glycolytic enzymes, is up-regulated by hypoxia through a HIF-1-mediated mechanism. This adaptive response allows the increased lactic acid produced during hypoxia to be rapidly lost from the cell.
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