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https://hdl.handle.net/2440/24048
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Type: | Journal article |
Title: | Cell-specific regulation of hypoxia-inducible factor (HIF)-1α and HIF-2α stabilization and transactivation in a graded oxygen environment |
Other Titles: | Cell-specific regulation of hypoxia-inducible factor (HIF)-1 alpha and HIF-2 alpha stabilization and transactivation in a graded oxygen environment |
Author: | Bracken, C. Fedele, A. Karttunen, S. Balrak, W. Lisy, K. Whitelaw, M. Peet, D. |
Citation: | Journal of Biological Chemistry, 2006; 281(32):22575-22585 |
Publisher: | Amer Soc Biochemistry Molecular Biology Inc |
Issue Date: | 2006 |
ISSN: | 0021-9258 1083-351X |
Organisation: | Centre for the Molecular Genetics of Development |
Statement of Responsibility: | Cameron P. Bracken, Anthony O. Fedele, Sarah Linke, Wiltiana Balrak, Karolina Lisy, Murray L. Whitelaw, and Daniel J. Peet |
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. |
Keywords: | COS Cells Caco-2 Cells Hela Cells PC12 Cells Animals Humans Rats Oxygen Transcription Factors Gene Expression Regulation Amino Acid Sequence Sequence Homology, Amino Acid Molecular Sequence Data Basic Helix-Loop-Helix Transcription Factors Hypoxia-Inducible Factor 1, alpha Subunit Transcriptional Activation Hypoxia Chlorocebus aethiops |
Rights: | Copyright © 2006 by the American Society for Biochemistry and Molecular Biology. |
DOI: | 10.1074/jbc.M600288200 |
Published version: | http://dx.doi.org/10.1074/jbc.m600288200 |
Appears in Collections: | Aurora harvest 2 Centre for the Molecular Genetics of Development publications Molecular and Biomedical Science publications |
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