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Journal Article | Research Support, Non-U.S. Gov't

Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor.

K Gradin, J McGuire, R H Wenger, I Kvietikova, M L fhitelaw, R Toftgård, L Tora, M Gassmann, L Poellinger
K Gradin
Department of Medical Nutrition, Karolinksa Institute, Huddinge, Sweden.
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J McGuire
Department of Medical Nutrition, Karolinksa Institute, Huddinge, Sweden.
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R H Wenger
Department of Medical Nutrition, Karolinksa Institute, Huddinge, Sweden.
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I Kvietikova
Department of Medical Nutrition, Karolinksa Institute, Huddinge, Sweden.
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M L fhitelaw
Department of Medical Nutrition, Karolinksa Institute, Huddinge, Sweden.
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R Toftgård
Department of Medical Nutrition, Karolinksa Institute, Huddinge, Sweden.
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L Tora
Department of Medical Nutrition, Karolinksa Institute, Huddinge, Sweden.
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M Gassmann
Department of Medical Nutrition, Karolinksa Institute, Huddinge, Sweden.
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L Poellinger
Department of Medical Nutrition, Karolinksa Institute, Huddinge, Sweden.
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DOI: 10.1128/MCB.16.10.5221
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ABSTRACT

Hypoxia-inducible factor 1 alpha (HIF-1 alpha) and the intracellular dioxin receptor mediate hypoxia and dioxin signalling, respectively. Both proteins are conditionally regulated basic helix-loop-helix (bHLH) transcription factors that, in addition to the bHLH motif, share a Per-Arnt-Sim (PAS) region of homology and form heterodimeric complexes with the common bHLH/PAS partner factor Arnt. Here we demonstrate that HIF-1 alpha required Arnt for DNA binding in vitro and functional activity in vivo. Both the bHLH and PAS motifs of Arnt were critical for dimerization with HIF-1 alpha. Strikingly, HIF-1 alpha exhibited very high affinity for Arnt in coimmunoprecipitation assays in vitro, resulting in competition with the ligand-activated dioxin receptor for recruitment of Arnt. Consistent with these observations, activation of HIF-1 alpha function in vivo or overexpression of HIF-1 alpha inhibited ligand-dependent induction of DNA binding activity by the dioxin receptor and dioxin receptor function on minimal reporter gene constructs. However, HIF-1 alpha- and dioxin receptor-mediated signalling pathways were not mutually exclusive, since activation of dioxin receptor function did not impair HIF-1 alpha-dependent induction of target gene expression. Both HIF-1 alpha and Arnt mRNAs were expressed constitutively in a large number of human tissues and cell lines, and these steady-state expression levels were not affected by exposure to hypoxia. Thus, HIF-1 alpha may be conditionally regulated by a mechanism that is distinct from induced expression levels, the prevalent model of activation of HIF-1 alpha function. Interestingly, we observed that HIF-1 alpha was associated with the molecular chaperone hsp90. Given the critical role of hsp90 for ligand binding activity and activation of the dioxin receptor, it is therefore possible that HIF-1 alpha is regulated by a similar mechanism, possibly by binding an as yet unknown class of ligands.

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Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor.
K Gradin, J McGuire, R H Wenger, I Kvietikova, M L fhitelaw, R Toftgård, L Tora, M Gassmann, L Poellinger
Molecular and Cellular Biology Oct 1996, 16 (10) 5221-5231; DOI: 10.1128/MCB.16.10.5221

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Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor.
K Gradin, J McGuire, R H Wenger, I Kvietikova, M L fhitelaw, R Toftgård, L Tora, M Gassmann, L Poellinger
Molecular and Cellular Biology Oct 1996, 16 (10) 5221-5231; DOI: 10.1128/MCB.16.10.5221
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