title: Ferristatin II promotes degradation of transferrin receptor-1 in vitro and in vivo.
abstract: Previous studies have shown that the small molecule iron transport inhibitor ferristatin (NSC30611) acts by down-regulating transferrin receptor-1 (TfR1) via receptor degradation. In this investigation, we show that another small molecule, ferristatin II (NSC8679), acts in a similar manner to degrade the receptor through a nystatin-sensitive lipid raft pathway. Structural domains of the receptor necessary for interactions with the clathrin pathway do not appear to be necessary for ferristatin II induced degradation of TfR1. While TfR1 constitutively traffics through clathrin-mediated endocytosis, with or without ligand, the presence of Tf blocked ferristatin II induced degradation of TfR1. This effect of Tf was lost in a ligand binding receptor mutant G647A TfR1, suggesting that Tf binding to its receptor interferes with the drug's activity. Rats treated with ferristatin II have lower TfR1 in liver. These effects are associated with reduced intestinal (59)Fe uptake, lower serum iron and transferrin saturation, but no change in liver non-heme iron stores. The observed hypoferremia promoted by degradation of TfR1 by ferristatin II appears to be due to induced hepcidin gene expression.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Shaina L
authors.initials: SL
authors.lastname: Byrne
authors.forename: Peter D
authors.initials: PD
authors.lastname: Buckett
authors.forename: Jonghan
authors.initials: J
authors.lastname: Kim
authors.forename: Flora
authors.initials: F
authors.lastname: Luo
authors.forename: Jack
authors.initials: J
authors.lastname: Sanford
authors.forename: Juxing
authors.initials: J
authors.lastname: Chen
authors.forename: Caroline
authors.initials: C
authors.lastname: Enns
authors.forename: Marianne
authors.initials: M
authors.lastname: Wessling-Resnick
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002966:Clathrin / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D006367:HeLa Cells; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007501:Iron; D008099:Liver; D008297:Male; D021962:Membrane Microdomains; D008565:Membrane Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; D001713:Biphenyl Compounds; C068126:CD71 antigen; D002966:Clathrin; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin; D013450:Sulfones; C545564:Tfrc protein, rat; C531943:ferristatin; C588093:ferristatin II; D007501:Iron
references.citation: Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1472-7
references.pmid: 9465039
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 May;288(5):L887-93
references.pmid: 15618452
references.citation: Haematologica. 2010 Aug;95(8):1269-77
references.pmid: 20220061
references.citation: Proc Natl Acad Sci U S A. 1983 Apr;80(8):2258-62
references.pmid: 6300903
references.citation: Am J Physiol Cell Physiol. 2009 Dec;297(6):C1567-75
references.pmid: 19828835
references.citation: Nature. 1995 Mar 9;374(6518):190-2
references.pmid: 7877694
references.citation: Chem Biol. 2008 Jul 21;15(7):647-53
references.pmid: 18635001
references.citation: Biochim Biophys Acta. 1997 Mar 14;1331(1):1-40
references.pmid: 9325434
references.citation: J Biol Chem. 2006 Sep 29;281(39):28494-8
references.pmid: 16893896
references.citation: J Biol Chem. 2000 Sep 1;275(35):26754-64
references.pmid: 10837464
references.citation: Nat Genet. 1996 Aug;13(4):399-408
references.pmid: 8696333
references.citation: Nat Genet. 2005 Nov;37(11):1264-9
references.pmid: 16227996
references.citation: J Clin Invest. 2011 Dec;121(12):4880-8
references.pmid: 22045566
references.citation: Nat Rev Mol Cell Biol. 2011 Jul 22;12(8):517-33
references.pmid: 21779028
references.citation: Nat Genet. 2003 Jan;33(1):21-2
references.pmid: 12469120
references.citation: Blood. 2010 Apr 22;115(16):3374-81
references.pmid: 20177050
references.citation: Nat Genet. 1997 Aug;16(4):383-6
references.pmid: 9241278
references.citation: J Cell Sci. 1987 May;87 ( Pt 4):495-506
references.pmid: 2888775
references.citation: Toxicology. 1984 Jun;31(3-4):271-82
references.pmid: 6740702
references.citation: Nat Cell Biol. 2003 May;5(5):410-21
references.pmid: 12717440
references.citation: J Biol Chem. 2001 Mar 16;276(11):7811-9
references.pmid: 11113132
references.citation: Nat Genet. 2008 May;40(5):569-71
references.pmid: 18408718
references.citation: J Cell Biol. 1987 Jul;105(1):207-14
references.pmid: 3611186
references.citation: Lancet. 2003 Feb 22;361(9358):669-73
references.pmid: 12606179
references.citation: Nat Genet. 2006 May;38(5):531-9
references.pmid: 16604073
references.citation: Blood. 2005 Feb 15;105(4):1803-6
references.pmid: 15486069
references.citation: EMBO J. 2006 Dec 13;25(24):5648-58
references.pmid: 17139247
references.citation: Chem Biol. 2004 Mar;11(3):407-16
references.pmid: 15123270
references.citation: Biochem J. 1999 Jul 1;341 ( Pt 1):11-4
references.pmid: 10377239
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2760-5
references.pmid: 15701692
references.citation: Blood. 2010 Dec 16;116(25):5679-87
references.pmid: 20837779
references.citation: Cell Regul. 1990 Mar;1(4):369-77
references.pmid: 2100204
references.citation: Nat Genet. 2004 Jan;36(1):77-82
references.pmid: 14647275
references.citation: J Biol Chem. 1983 Apr 25;258(8):4715-24
references.pmid: 6300098
references.citation: Gastroenterology. 2011 Apr;140(4):1261-1271.e1
references.pmid: 21199652
references.citation: J Clin Invest. 2001 Aug;108(4):619-23
references.pmid: 11518736
references.citation: Am J Hematol. 2012 Apr;87(4):392-400
references.pmid: 22290531
references.citation: Traffic. 2003 Nov;4(11):724-38
references.pmid: 14617356
references.citation: Am J Hematol. 2009 Mar;84(3):170-6
references.pmid: 19140186
references.citation: J Biol Chem. 1997 Jan 24;272(4):2116-21
references.pmid: 8999911
references.citation: Biochem J. 1989 Nov 15;264(1):35-46
references.pmid: 2604716
references.citation: Annu Rev Pharmacol Toxicol. 2013;53:17-36
references.pmid: 23020294
references.citation: Cell Metab. 2009 Mar;9(3):217-27
references.pmid: 19254567
references.citation: Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1148-53
references.pmid: 9448300
references.citation: Physiology (Bethesda). 2006 Dec;21:430-9
references.pmid: 17119156
references.citation: Cell Metab. 2008 Mar;7(3):205-14
references.pmid: 18316026
references.citation: Cell. 1983 Jan;32(1):267-75
references.pmid: 6297785
references.citation: J Clin Invest. 2007 Jul;117(7):1933-9
references.pmid: 17607365
references.citation: Blood. 2012 Nov 1;120(18):3829-36
references.pmid: 22990014
references.citation: Science. 1995 Sep 29;269(5232):1872-5
references.pmid: 7569928
references.citation: Am J Physiol Lung Cell Mol Physiol. 2011 Apr;300(4):L659-65
references.pmid: 21278260
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6775-80
references.pmid: 10359788
references.citation: Blood. 1993 Sep 1;82(5):1608-17
references.pmid: 8364209
references.citation: PLoS One. 2012;7(8):e42703
references.pmid: 22900042
references.citation: J Mol Biol. 2001 Oct 19;313(2):385-97
references.pmid: 11800564
references.citation: PLoS One. 2011;6(9):e25515
references.pmid: 21966538
references.citation: J Biol Chem. 2007 Dec 21;282(51):36862-70
references.pmid: 17956864
references.citation: J Biol Chem. 1998 Aug 21;273(34):22068-74
references.pmid: 9705350
references.citation: Nat Genet. 2000 May;25(1):14-5
references.pmid: 10802645
references.citation: J Cell Biol. 1985 Feb;100(2):633-7
references.pmid: 2857182
references.citation: Nature. 2008 Oct 16;455(7215):992-6
references.pmid: 18794901
references.citation: Blood. 2011 Nov 3;118(18):4977-84
references.pmid: 21730356
references.citation: J Biol Chem. 1995 Apr 21;270(16):9067-73
references.pmid: 7721820
references.citation: J Biol Chem. 2010 Oct 15;285(42):32141-50
references.pmid: 20682781
references.citation: J Am Soc Nephrol. 2007 Feb;18(2):394-400
references.pmid: 17229910
references.citation: Nature. 1997 Jul 31;388(6641):482-8
references.pmid: 9242408
references.citation: J Mol Med (Berl). 2010 May;88(5):477-86
references.pmid: 20169331
references.citation: Science. 2004 Dec 17;306(5704):2090-3
references.pmid: 15514116
references.citation: J Biol Chem. 1983 Aug 25;258(16):9681-9
references.pmid: 6309781
references.citation: Proc Natl Acad Sci U S A. 1982 Oct;79(20):6186-90
references.pmid: 6292894
references.citation: Am J Physiol Gastrointest Liver Physiol. 2009 Apr;296(4):G798-804
references.pmid: 19179627
references.citation: Science. 2008 May 23;320(5879):1088-92
references.pmid: 18451267
references.citation: Cell Metab. 2005 Mar;1(3):191-200
references.pmid: 16054062
references.citation: Cell. 1998 Jun 12;93(6):1021-9
references.pmid: 9635431
references.citation: Blood. 2002 Nov 15;100(10):3776-81
references.pmid: 12393428
references.citation: Blood. 1984 Sep;64(3):748-53
references.pmid: 6380622
references.citation: J Biol Chem. 1986 Aug 5;261(22):10319-31
references.pmid: 3015925
references.citation: Cell Metab. 2008 Feb;7(2):173-8
references.pmid: 18249176
references.citation: Blood. 2010 Nov 4;116(18):3627-34
references.pmid: 20644113
references.citation: Annu Rev Biochem. 1980;49:357-93
references.pmid: 6996567
references.citation: Blood. 2009 Feb 19;113(8):1805-8
references.pmid: 18955558
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 Jan;290(1):G156-63
references.pmid: 16081760