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Type: Journal article
Title: Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor
Author: Gradin, K.
McGuire, J.
Wenger, R.
Kvietikova, I.
Whitelaw, M.
Toftgard, R.
Tora, L.
Gassman, M.
Poellinger, L.
Citation: Molecular and Cellular Biology, 1996; 16(10):5221-5231
Publisher: Informa UK Limited
Issue Date: 1996
ISSN: 0270-7306
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.
Keywords: Hela Cells
Tumor Cells, Cultured
Carcinoma, Hepatocellular
Liver Neoplasms
Cytochrome P-450 CYP1A1
DNA-Binding Proteins
Nuclear Proteins
Receptors, Aryl Hydrocarbon
Recombinant Fusion Proteins
Transcription Factors
RNA, Messenger
Signal Transduction
Cell Hypoxia
Organ Specificity
Sequence Deletion
Helix-Loop-Helix Motifs
Genes, Reporter
HSP90 Heat-Shock Proteins
Aryl Hydrocarbon Receptor Nuclear Translocator
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit
DOI: 10.1128/MCB.16.10.5221
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Appears in Collections:Aurora harvest 2
Biochemistry publications

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