title: Regulation of growth differentiation factor 15 expression by intracellular iron.
abstract: Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor-beta 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.
authors.affiliation: Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, UK.
authors.forename: Samira
authors.initials: S
authors.lastname: Lakhal
authors.forename: Nick P
authors.initials: NP
authors.lastname: Talbot
authors.forename: Alexi
authors.initials: A
authors.lastname: Crosby
authors.forename: Chantal
authors.initials: C
authors.lastname: Stoepker
authors.forename: Alain R M
authors.initials: AR
authors.lastname: Townsend
authors.forename: Peter A
authors.initials: PA
authors.lastname: Robbins
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Pugh
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
authors.forename: David R
authors.initials: DR
authors.lastname: Mole
mesh_terms: D000230:Adenocarcinoma; D018798:Anemia, Iron-Deficiency / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms; D006528:Carcinoma, Hepatocellular; D027682:Cation Transport Proteins / Q000235:genetics; D015687:Cell Hypoxia / Q000502:physiology; D003676:Deferoxamine / Q000008:administration & dosage*; D055436:Growth Differentiation Factor 15 / Q000097:blood* / Q000235:genetics*; D006367:HeLa Cells; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007668:Kidney / Q000166:cytology; D007680:Kidney Neoplasms; D008565:Membrane Proteins / Q000235:genetics; D010100:Oxygen / Q000378:metabolism; D017262:Siderophores / Q000008:administration & dosage; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D051154:Wnt2 Protein / Q000378:metabolism; D000098742:Ferroportin; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D027682:Cation Transport Proteins; D003676:Deferoxamine; D055436:Growth Differentiation Factor 15; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron; D008565:Membrane Proteins; D010100:Oxygen; D017262:Siderophores; D051154:Wnt2 Protein; D000098742:Ferroportin; D000099162:Endothelial PAS Domain-Containing Protein 1; C526140:GDF15 protein, human; C103673:HFE protein, human; C497442:HIF1A protein, human; C495244:WNT2 protein, human