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J Biol Chem, Vol. 274, Issue 17, 12115-12123, April 23, 1999
From the The aryl hydrocarbon receptor (AHR) and the
Cross-talk between the Aryl Hydrocarbon Receptor and Hypoxia
Inducible Factor Signaling Pathways
DEMONSTRATION OF COMPETITION AND COMPENSATION
, Department of Pharmaceutics and Medicinal
Chemistry, School of Pharmacy and Health Sciences, University of the
Pacific, Stockton, California 95211 and the § McArdle
Laboratory for Cancer Research, University of Wisconsin School of
Medicine, Madison, Wisconsin 53706
-class hypoxia inducible factors (HIF1, HIF2, and HIF3) are
basic helix-loop-helix PAS (bHLH-PAS) proteins that heterodimerize with
ARNT. In response to 2,3,7,8-tetrachlorodibenzo-p-dioxin,
the AHR·ARNT complex binds to "dioxin responsive enhancers"
(DREs) and activates genes involved in the metabolism of xenobiotics,
e.g. cytochrome P4501A1 (Cyp1a1). The
HIF1·ARNT complex binds to "hypoxia responsive enhancers" and
activates the transcription of genes that regulate adaptation to low
oxygen, e.g. erythropoietin (Epo). We
postulated that activation of one pathway would inhibit the other due
to competition for ARNT or other limiting cellular factors. Using
pathway specific reporters in transient transfection assays, we
observed that DRE driven transcription was markedly inhibited by
hypoxia and that hypoxia responsive enhancer driven transcription was
inhibited by AHR agonists. When we attempted to support this cross-talk model using endogenous loci, we observed that activation of the hypoxia
pathway inhibited Cyp1a1 up-regulation, but that activation of the AHR actually enhanced the induction of Epo by
hypoxia. To explain this unexpected additivity, we examined the
Epo gene and found that its promoter harbors DREs
immediately upstream of its transcriptional start site. These
experiments outline conditions where inhibitory and additive cross-talk
occur between the hypoxia and dioxin signal transduction pathways and
identify Epo as an AHR-regulated gene.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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