This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Knowles, H. J. Articles by Harris, A. L. Search for Related Content PubMed PubMed Citation Articles by Knowles, H. J. Articles by Harris, A. L.

Normoxic Stabilization of Hypoxia-Inducible Factor-1 by Modulation of the Labile Iron Pool in Differentiating U937 Macrophages: Effect of Natural Resistance–Associated Macrophage Protein 1

¹ Cancer Research UK Molecular Oncology Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital and ² Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, United Kingdom

Requests for reprints: Adrian L. Harris, Cancer Research UK Molecular Oncology Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom. Phone: 44-1865-222457; Fax: 44-1865-222431; E-mail: harrisa{at}cancer.org.uk.

Hypoxia-inducible factor (HIF) is a transcription factor with major roles in many cellular and systemic responses to hypoxia. Activation of HIF pathways under hypoxia is mediated by suppression of the Fe²⁺- and O₂-dependent HIF hydroxylase enzymes that normally inactivate HIF subunits. Mechanisms underlying induction of HIF in normoxic conditions are less clearly understood. In human cancers, infiltrating macrophages show up-regulation of HIF and it has recently been shown that normoxic expression of HIF-1 is essential for macrophage function. Here, we report studies of HIF-1 induction following phorbol-12-myristate 13-acetate (PMA)–induced differentiation of monocytic U937 and THP1 cells. HIF-1 was markedly up-regulated under normoxia in this setting and this involved failure of HIF-1 prolyl hydroxylation despite the presence of O₂. Fluorescence measurements showed that differentiation was associated with marked reduction of the labile iron pool. Both the reduction in labile iron pool and the up-regulation of HIF-1 were suppressed by RNA interference–mediated down-regulation of the iron transporter natural resistance–associated macrophage protein 1. Up-regulation of HIF-1 following PMA-induced differentiation was also abolished by addition of Fe²⁺ or ascorbate. These results indicate that physiologic changes in macrophage iron metabolism have an important effect on HIF hydroxylase pathways and suggest means by which the system could be manipulated for therapeutic benefit. (Cancer Res 2006; 66(5): 2600-7)

This article has been cited by other articles:

				E. L. Page, D. A. Chan, A. J. Giaccia, M. Levine, and D. E. Richard Hypoxia-inducible Factor-1{alpha} Stabilization in Nonhypoxic Conditions: Role of Oxidation and Intracellular Ascorbate Depletion Mol. Biol. Cell, January 1, 2008; 19(1): 86 - 94. [Abstract] [Full Text] [PDF]

				H. K. Bayele, C. Peyssonnaux, A. Giatromanolaki, W. W. Arrais-Silva, H. S. Mohamed, H. Collins, S. Giorgio, M. Koukourakis, R. S. Johnson, J. M. Blackwell, et al. HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA forming microsatellite Blood, October 15, 2007; 110(8): 3039 - 3048. [Abstract] [Full Text] [PDF]

				C. De Ponti, R. Carini, E. Alchera, M. P. Nitti, M. Locati, E. Albano, G. Cairo, and L. Tacchini Adenosine A2a receptor-mediated, normoxic induction of HIF-1 through PKC and PI-3K-dependent pathways in macrophages J. Leukoc. Biol., August 1, 2007; 82(2): 392 - 402. [Abstract] [Full Text] [PDF]

				B. Brune and J. Zhou Nitric oxide and superoxide: Interference with hypoxic signaling Cardiovasc Res, July 15, 2007; 75(2): 275 - 282. [Abstract] [Full Text] [PDF]

				D. C. Birle and D. W. Hedley Suppression of the Hypoxia-Inducible Factor-1 Response in Cervical Carcinoma Xenografts by Proteasome Inhibitors Cancer Res., February 15, 2007; 67(4): 1735 - 1743. [Abstract] [Full Text] [PDF]

				Y. Pan, K. D. Mansfield, C. C. Bertozzi, V. Rudenko, D. A. Chan, A. J. Giaccia, and M. C. Simon Multiple Factors Affecting Cellular Redox Status and Energy Metabolism Modulate Hypoxia-Inducible Factor Prolyl Hydroxylase Activity In Vivo and In Vitro Mol. Cell. Biol., February 1, 2007; 27(3): 912 - 925. [Abstract] [Full Text] [PDF]

				A. A. Qutub and A. S. Popel A computational model of intracellular oxygen sensing by hypoxia-inducible factor HIF1{alpha}. J. Cell Sci., August 15, 2006; 119(Pt 16): 3467 - 3480. [Abstract] [Full Text] [PDF]