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https://hdl.handle.net/2440/24048
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dc.contributor.author | Bracken, C. | - |
dc.contributor.author | Fedele, A. | - |
dc.contributor.author | Karttunen, S. | - |
dc.contributor.author | Balrak, W. | - |
dc.contributor.author | Lisy, K. | - |
dc.contributor.author | Whitelaw, M. | - |
dc.contributor.author | Peet, D. | - |
dc.date.issued | 2006 | - |
dc.identifier.citation | Journal of Biological Chemistry, 2006; 281(32):22575-22585 | - |
dc.identifier.issn | 0021-9258 | - |
dc.identifier.issn | 1083-351X | - |
dc.identifier.uri | http://hdl.handle.net/2440/24048 | - |
dc.description.abstract | The hypoxia-inducible factor (HIF)-1α and HIF-2α are closely related, key transcriptional regulators of the hypoxic response, countering a low oxygen situation with the up-regulation of target genes associated with numerous processes, including vascularization and glycolysis. This involves a dual mechanism of control through both stabilization and transactivation, regulated via prolyl and asparaginyl hydroxylation. Despite high similarity with respect to protein sequence and activation pathway, a growing number of physiological and mechanistic differences between HIF-1α and HIF-2α are being reported. To further characterize this nonredundancy, the stabilization of endogenous proteins and regulation of the transactivation domains were compared in a graded oxygen environment across a series of cell lines. Although generally similar results were found, interesting and specific differences between the HIF-α proteins were observed within certain cell lines, such as rat adrenal PC12s, emphasizing the cell-specific nature of HIF-α regulation. We characterize a conserved amino acid substitution between HIF-1α and HIF-2α that contributes to the intrinsically higher FIH-1-mediated asparaginyl hydroxylation of HIF-1α and, hence, lower HIF-1α activity. In addition, our data demonstrate that the different cell lines can be classified into two distinct groups: those in which stabilization and transactivation proceed in conjunction (HeLa, 293T, and COS-1) and those cells in which HIF-α is stabilized prior to transactivation (PC12, HepG2, and CACO2). Interestingly, the initial stabilization of HIF-α prior to transactivation up-regulation predicted from in vitro derived hydroxylation data is only true for a subset of cells. | - |
dc.description.statementofresponsibility | Cameron P. Bracken, Anthony O. Fedele, Sarah Linke, Wiltiana Balrak, Karolina Lisy, Murray L. Whitelaw, and Daniel J. Peet | - |
dc.language.iso | en | - |
dc.publisher | Amer Soc Biochemistry Molecular Biology Inc | - |
dc.rights | Copyright © 2006 by the American Society for Biochemistry and Molecular Biology. | - |
dc.source.uri | http://dx.doi.org/10.1074/jbc.m600288200 | - |
dc.subject | COS Cells | - |
dc.subject | Caco-2 Cells | - |
dc.subject | Hela Cells | - |
dc.subject | PC12 Cells | - |
dc.subject | Animals | - |
dc.subject | Humans | - |
dc.subject | Rats | - |
dc.subject | Oxygen | - |
dc.subject | Transcription Factors | - |
dc.subject | Gene Expression Regulation | - |
dc.subject | Amino Acid Sequence | - |
dc.subject | Sequence Homology, Amino Acid | - |
dc.subject | Molecular Sequence Data | - |
dc.subject | Basic Helix-Loop-Helix Transcription Factors | - |
dc.subject | Hypoxia-Inducible Factor 1, alpha Subunit | - |
dc.subject | Transcriptional Activation | - |
dc.subject | Hypoxia | - |
dc.subject | Chlorocebus aethiops | - |
dc.title | Cell-specific regulation of hypoxia-inducible factor (HIF)-1α and HIF-2α stabilization and transactivation in a graded oxygen environment | - |
dc.title.alternative | Cell-specific regulation of hypoxia-inducible factor (HIF)-1 alpha and HIF-2 alpha stabilization and transactivation in a graded oxygen environment | - |
dc.type | Journal article | - |
dc.contributor.organisation | Centre for the Molecular Genetics of Development | - |
dc.identifier.doi | 10.1074/jbc.M600288200 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Lisy, K. [0000-0003-2604-4290] | - |
dc.identifier.orcid | Peet, D. [0000-0002-6085-8936] | - |
Appears in Collections: | Aurora harvest 2 Centre for the Molecular Genetics of Development publications Molecular and Biomedical Science publications |
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