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J. Biol. Chem., Vol. 281, Issue 32, 22575-22585, August 11, 2006

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Cell-specific Regulation of Hypoxia-inducible Factor (HIF)-1 and HIF-2 Stabilization and Transactivation in a Graded Oxygen Environment^*

From the School of Molecular and Biomedical Science, and the Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, South Australia 5005, Australia

The hypoxia-inducible factor (HIF)-1 and HIF-2 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-1 and HIF-2 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- proteins were observed within certain cell lines, such as rat adrenal PC12s, emphasizing the cell-specific nature of HIF- regulation. We characterize a conserved amino acid substitution between HIF-1 and HIF-2 that contributes to the intrinsically higher FIH-1-mediated asparaginyl hydroxylation of HIF-1 and, hence, lower HIF-1 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- is stabilized prior to transactivation (PC12, HepG2, and CACO2). Interestingly, the initial stabilization of HIF- prior to transactivation up-regulation predicted from in vitro derived hydroxylation data is only true for a subset of cells.

Received for publication, January 11, 2006 , and in revised form, June 5, 2006.

^* This work was supported by the National Health and Medical Research Council of Australia. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Australian Research Council through the Special Research Centre for the Molecular Genetics of Development. Present address: Division of Gene Regulation and Expression, School of Life Sciences, University of Dundee, MSI/WTB Complex, Dow St., Dundee DD1 5EH, United Kingdom.

² Present address: Telethon Institute of Genetics and Medicine (TIGEM), Via Pietro Castellino 111, 80131 Naples, Italy.

³ To whom correspondence should be addressed: School of Molecular and Biomedical Science, University of Adelaide, South Australia 5005, Australia. Tel.: 61-8-8303-5367; Fax: 61-8-8303-4362; E-mail: daniel.peet{at}adelaide.edu.au.

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