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Blood, 12 February 2009, Vol. 113, No. 7, pp. 1555-1563. Prepublished online as a Blood First Edition Paper on December 1, 2008; DOI 10.1182/blood-2008-07-170431. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-07-170431v1 113/7/1555    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lakhal, S. Articles by Mole, D. R. Search for Related Content PubMed PubMed Citation Articles by Lakhal, S. Articles by Mole, D. R. Related Collections Red Cells, Iron, and Erythropoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS, IRON, AND ERYTHROPOIESIS Regulation of growth differentiation factor 15 expression by intracellular iron Samira Lakhal1, Nick P. Talbot2, Alexi Crosby2, Chantal Stoepker1, Alain R. M. Townsend3, Peter A. Robbins2, Christopher W. Pugh1, Peter J. Ratcliffe1, and David R. Mole1 1 Henry Wellcome Building for Molecular Physiology and 2 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford; and 3 Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor–β superfamily and has been identified in different contexts as a hypoxia-inducible gene product and as a molecule involved in hepcidin regulation. The biology of iron and oxygen is closely related, and known regulatory pathways involving hypoxia-inducible factor (HIF) and iron-regulatory proteins (IRPs) are responsive to both these stimuli. We therefore sought to characterize the regulation of GDF15 by iron and oxygen and to define the involvement or otherwise of HIF and IRP pathways. Here we show that GDF15 is strongly up-regulated by stimuli that deplete cells of iron and that this response is specifically antagonized by the reprovision of iron. GDF15 exhibits greater sensitivity to iron depletion than hypoxia, and responses to hypoxia and iron depletion are independent of HIF and IRP activation, suggesting a novel mechanism of regulation. We also report significant induction of serum GDF15 in iron-deficient subjects and after administration of an iron chelator to normal subjects. These findings indicate that GDF15 can be induced by pathophysiologic changes in iron availability, raising important questions about the mechanism of regulation and its role in iron homeostasis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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