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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
Organisation: Centre for the Molecular Genetics of Development
Statement of
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; Cercopithecus aethiops; 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
Rights: Copyright © 2006 by the American Society for Biochemistry and Molecular Biology.
RMID: 0020061031
DOI: 10.1074/jbc.M600288200
Appears in Collections:Molecular and Biomedical Science publications
Centre for the Molecular Genetics of Development publications

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