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https://hdl.handle.net/2440/11349
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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 1098-5549 |
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 Humans Carcinoma, Hepatocellular Liver Neoplasms Cobalt Dioxins Cytochrome P-450 CYP1A1 Luciferases DNA-Binding Proteins Nuclear Proteins Receptors, Aryl Hydrocarbon Recombinant Fusion Proteins Transcription Factors RNA, Messenger Transfection Signal Transduction Cell Hypoxia Organ Specificity Mutagenesis Sequence Deletion Helix-Loop-Helix Motifs Genes, Reporter Female Male 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 |
Published version: | http://dx.doi.org/10.1128/mcb.16.10.5221 |
Appears in Collections: | Aurora harvest 2 Biochemistry publications |
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