Hypoxia and Iron Metabolism-associated Proteins

ISSN 1007-7626 CN 11-3870 / Q http / / cjbmb bjmu edu cn Chinese Journal of Biochemistry and Molecular Biology 2012 10 28 10 897 ~ 905 * 226001 hypoxia-inducible factors HIFs DNA Haber-Weiss Fenton HIFs 1 HIFs R364 4 Hypoxia and Iron Metabolism-associated Proteins YU Min-Yan ZHU Li * Institute of Nautical Medicine Nantong University Nantong 226001 Jiangsu China Abstract Iron and oxygen are essential substances for cellular activities in body tissues Hypoxiainducible factors HIFs one kind of transcription factors that respond to available oxygen changes in the cellular environment specifically at hypoxia conditions regulate the transcription of a series of target genes Iron participates in a wide variety of metabolic processes including DNA synthesis oxygen transport and electron transport Excess amount of free iron may result in the formation of free radicals via Haber-Weiss or Fenton reactions then induce cell injury and cell death The coordinated regulation of iron metabolism-associated proteins for iron absorption storage and utilization is critical for the maintenance of cellular iron homeostasis The genes involved in iron homeostasis including transferrin TF transferrin receptor TFR divalent metal transporter 1 DMT1 hepcidin HAMP ferroportin 1 FPN1 ceruloplasmin CP ferritin FT are the target genes of HIFs although some of which are regulated indirectly under hypoxia The changes of intracellular iron concentration also modulate the expression of HIFs This review discusses the relationship between hypoxia and iron metabolism-associated proteins special focuses on the regulation of iron metabolism-associated proteins Key words hypoxia hypoxia-inducible factors iron homeostasis iron metabolism hypoxia 2012-07-06 2012-07-31 ATP No 30971197 No 31171143 * Tel 0513-85051796 E-mail zhulizhou@ ntu edu cn Received July 6 2012 Accepted July 31 2012 Supported by National Natural Science Foundation of China No 30971197 No 31171143 * Corresponding auther Tel 0513-85051796 E-mail zhulizhou@ ntu edu cn 1

898 28 2 3 vhl - vhl 1 hypoxia-inducible E3 16 HIFα factor-1 HIF-1 HIFα RNA 1 min 17 PHD iron regulatory proteins IRPs IRP1 IRP2 mrna 4 iron responsive element IRE 5 element HRE HIFα-HIFβ CREB camp response elementbinding protein CBP p300 DNA 6 7 HIF-1α HIF-1 100 Haber-Weiss Fenton 12 DNA 8 HIF / HRE HIF / HRE IRPs 9-2 11 Fe 3 + labile iron pool transferrin TF LIP 2 transferrin receptor TFR Fe 2 + Fe 3 + IRP1 IRP2 ceruloplasmin CP Fe 2 + 18 IRP1 IRP2 RNA 1 divalent metal transporter 1 DMT1 ferritin FT responsive element IRE mrnas ferroportin 1 FPN1 hepcidin HAMP 4Fe-4S 1 / IRE HIF-1 IRP1 HIF IRE 18 12 HIF 1 1 IRP1 IREs α 1 β α 3 HIF-1α HIF-2α HIF-3α β 3 HIF-1β HIF-2β HIF-3β 3 IRP1 13 1 14 HIFβ RNA IRP1 IRP2 19 aryl hydrocarbon receptor nuclear IRP2 20 translocator ARNT IRP2 mrna IRE 15 21 IRP2 22 IRP2-IRE α IRP1-IRE HIFα prolyl IRP2 23 hydroxylase PHD HIFα HIFα HIFβ hypoxia responsive RNA iron IRP1 m-aco IRP2 IRP1 4Fe-4S 2 E3 IRP2 HIFα 2 F HIFα - von-hippel-lindau 5 F-box and leucine-rich repeat protein 5

10 899 FBXL5 S 1 S-phase kinase- associated protein 1 SKP1 2 TF 2 1 1 cullin1 CUL1 1 ring-box 1 TFR1 RBX1 E3 IRP2 TF mrna HIF FBXL5 28 TF 2 HREs IRP2 IRP1 HIF 3'HRE 5'HRE HIF FBXL5 IRP2 28 HIF TF 24 25 IRPs mrnas 3 2 3' 5'- untranslated regions UTR IRE IRPs 5'-UTR IREs ferritin M28 TFR TF heavy chain FTH ferritin light chain FTL 5- FPN1 9 26 27 TFR2 TF TFR2 TF IRPs TFR mrna 3'-UTR IREs 31 TFR1 1 HRE TFR1 IRPs IRE TFR1 mrna 3' UTR 5 IREs 33 IRP1 3 TFR1 IREs IRP2 TFR1 IREs TFR1 mrna TFR1 TFR1 31 10 Table 1 HIF hemoglobin Hb 3 3 1 Fig 1 DMT1 568 Table 1 Summary of iron metabolism-associated proteins regulated by hypoxia through HIF DMT1 Protein Function HRE position TF Iron transport Enhancer region 2 DMT1 TFR1 Binds TF-2Fe 3 + 3' UTR DMT1 Iron import DMT1 promoter region 36 DMT1 4 Hepcidin Induces FPN degradation HAMP promoter region FPN1 Iron export Transcriptional HIF Lee 37 DMT1 5' 2 CP Ferroxidase Enhancer region DCYTB Ferric reductase DCYTB promoter region IRP1 Control of mrna stability 5'regulatory region IRP2 Control of mrna stability 5'regulatory region 3 1 TF mrna TFR1 TFR2 760 801 29 30 TFR1 TFR1 TFR 1 HIF HREs DMT1 2 HREs 38 Wang 39 DMT1 1B HRE HIF-1 DMT1 DMT1 TF 698 HIF-1α 2 40 3'- UTR 1 IRE Fe 3 + TF IRE HIF-1α TF HIF-2α DMT1 1 1 41 HIF-2α 5'-UTR

900 28 Fig 1 The current view of hypoxic regulation of iron transport and storage 1 The general scheme of known iron transport storage and metabolic pathways is summarized Not all pathways will be present in all cell types Iron is transported into the cell by a binding to TF which in turn through the assistance of HFE binds to TFR and is internalized into clathrin-coated vesicles b DMT1 or c HCP1 or a yet-undiscovered membrane-bound heme transport protein Clathrin-coated vesicles fuse with early endosome with the assistance of HTT and are thought to fuse with mitochondria to release iron directly into this organelle Fe 3 + is converted to Fe 2 + through the actions of a STEAP coupled to DMT1 in early endosomes b DCYTB coupled to DMT1 at the cell membrane or c HO-1 to remove iron from heme Iron present in the labile iron pool LIP is then available for 1 transport into the mitochondria through MF 2 storage by ferritin 3 interaction with iron-binding proteins 4 participation in the Fenton reaction or 5 export through FPN1 controlled by HAMP and HEPH Proteins up-regulated or down-regulated by hypoxia are marked with either an up- or a down-oriented red arrow Abbreviations used in the figure ALAS2 erythroid-specific aminolevulinate synthase CP ceruloplasmin DCYTB duodenal cytochrome b DMT1 divalent metal transporter 1 FECH ferrochelatase HCP1 heme carrier protein 1 HO-1 heme oxygenase-1 HTT Huntingtin MF mitoferrin STEAP six transmembrane epithelial antigen of the prostate TF transferrin TFR transferrin receptor 1 IRE 38 DMT1 Hepcidin HIF-2α hepcidin 42 HIF-1α 41 DMT1 HAMP HIF-1 3 4 41 Hb HIF-2 43-45 HAMP Hepcidin 45 HIF-1α HIF-2α HAMP Hepcidin HIF CO FPN1 HAMP HREs hepcidin 46 HAMP

10 901 HRE hepcidin CP mrna 25 CP Choi 47 hepcidin 53 HIF-1α hepcidin CP HIF 54 HIF-2α CP 3 HREs reactive oxygen species ROS CCAAT / α CCAAT enhancer binding protein a C / EBP α 3 signal CP transducer and activator of transcription 3 STAT-3 22% 13 HAMP HAMP CP 37% 57 CP hemochromatosis HFE TFR2 Hemojuvelin HJV 6 CP transmembrane protease serine 6 TMPRSS6 3 7 6 interleukin 6 receptor IL-6R hepcidin 48 3 5 FTL 24 FPN1 1 4 500 FPN1 FTH FTL N- FT ROS 34 FPN1 571 ROS FT 59 DMT1 12 FT 60 ROS FPN1 ph FT hephaestin HEPH CP FT TF 61 Fe 2 + Fe 3 + Hepcidin FPN1 IRP1 IRP2 49 Janus 2 Janus kinase HEK293 2 Jak2 FPN1 Jak2 FPN1 FPN1 HIF 2% O 2 FTH FTL IRP PHD 63 64 FTH FTL mrna 5'-UTRs IREs FPN1 mrna IRP1 RNA 65 HIFα 50 FPN1 hepcidin HIF-2α 41 HIF-1α - / - FPN1 IRP1 hepcidin 51 HIF FPN1 5' UTR 1 HRE CP 55 56 3 FT 58 FT FTH FTH FTL 5'-UTRs IREs FTH FTL FTL 62 20% O 2 FT FT FT FT 1 IRE IRP2 66 3 8 3 6 lactotransferrin LTF CP Fe 2 + LTF Fe 3 + TF Cianetti 52 CP LTF 4 2 mrna 1% Fe 3 + Fe 3 + 2 67

902 28 LTF 1 HRE HIF / Fe 3 + LTF HRE IRP1 mrna IRP1 LTF mrna 68 LTF 4 HIF 69 HEPH 1 6 70 FPN1 71 HEPH 1 HEPH HFE 348 Ⅰ desferrioxamine DFO HIF-1α HIF α HEPH 3 HIFα Ⅰ 72 HFE HFE TF furin HJV shjv bone morphogenic protein BMP hepcidin hepcidin HJV hepcidin TF TFR DMT1 CP B duodenal cytochrome B DCYTB b 1 b 561 HIF Fe 3 + Fe 2 + DMT1 DCYTB mrna 76 DCYTB HIF-2α 38 DMT1 DCYTB References 2 HREs 38 HIF-2α DCYTB 1 Chepelev N L Willmore W G Regulation of iron pathways in HREs 77 HepG2 SH-SY5Y IRP1 mrna MatInspector IRP1 5' 3 IRP2 5' PHD PHD DFO HIF-1α 78 IRPs 2α 5'UTR 1 IRE HIF / HRE HIFα HIF HIF response to hypoxia J Free Radical Biol Med 2011 50 6 645-666 2 Thomas J D Johannews G J Identification of mrnas that continue to associate with polysomes during hypoxia J RNA 2007 13 7 1116-1131 3 Martens L K Kirschner K M Warnecke C et al β2- Ⅰ 10 mrna IRE 79 HIF- TFR HFE 1 IRPs IRPs HIF- HFE 2α HIF 73 HFE 5 HJV 426 HJV furin HJV shjv furin 74 HIF 75 Hypoxia-

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