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https://hdl.handle.net/2440/11349
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dc.contributor.author | Gradin, K. | - |
dc.contributor.author | McGuire, J. | - |
dc.contributor.author | Wenger, R. | - |
dc.contributor.author | Kvietikova, I. | - |
dc.contributor.author | Whitelaw, M. | - |
dc.contributor.author | Toftgard, R. | - |
dc.contributor.author | Tora, L. | - |
dc.contributor.author | Gassman, M. | - |
dc.contributor.author | Poellinger, L. | - |
dc.date.issued | 1996 | - |
dc.identifier.citation | Molecular and Cellular Biology, 1996; 16(10):5221-5231 | - |
dc.identifier.issn | 0270-7306 | - |
dc.identifier.issn | 1098-5549 | - |
dc.identifier.uri | http://hdl.handle.net/2440/11349 | - |
dc.description.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. | - |
dc.language.iso | en | - |
dc.publisher | Informa UK Limited | - |
dc.source.uri | http://dx.doi.org/10.1128/mcb.16.10.5221 | - |
dc.subject | Hela Cells | - |
dc.subject | Tumor Cells, Cultured | - |
dc.subject | Humans | - |
dc.subject | Carcinoma, Hepatocellular | - |
dc.subject | Liver Neoplasms | - |
dc.subject | Cobalt | - |
dc.subject | Dioxins | - |
dc.subject | Cytochrome P-450 CYP1A1 | - |
dc.subject | Luciferases | - |
dc.subject | DNA-Binding Proteins | - |
dc.subject | Nuclear Proteins | - |
dc.subject | Receptors, Aryl Hydrocarbon | - |
dc.subject | Recombinant Fusion Proteins | - |
dc.subject | Transcription Factors | - |
dc.subject | RNA, Messenger | - |
dc.subject | Transfection | - |
dc.subject | Signal Transduction | - |
dc.subject | Cell Hypoxia | - |
dc.subject | Organ Specificity | - |
dc.subject | Mutagenesis | - |
dc.subject | Sequence Deletion | - |
dc.subject | Helix-Loop-Helix Motifs | - |
dc.subject | Genes, Reporter | - |
dc.subject | Female | - |
dc.subject | Male | - |
dc.subject | HSP90 Heat-Shock Proteins | - |
dc.subject | Aryl Hydrocarbon Receptor Nuclear Translocator | - |
dc.subject | Hypoxia-Inducible Factor 1 | - |
dc.subject | Hypoxia-Inducible Factor 1, alpha Subunit | - |
dc.title | Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1128/MCB.16.10.5221 | - |
pubs.publication-status | Published | - |
Appears in Collections: | Aurora harvest 2 Biochemistry publications |
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