title: Tumorigenic properties of iron regulatory protein 2 (IRP2) mediated by its specific 73-amino acids insert.
abstract: Iron regulatory proteins, IRP1 and IRP2, bind to mRNAs harboring iron responsive elements and control their expression. IRPs may also perform additional functions. Thus, IRP1 exhibited apparent tumor suppressor properties in a tumor xenograft model. Here we examined the effects of IRP2 in a similar setting. Human H1299 lung cancer cells or clones engineered for tetracycline-inducible expression of wild type IRP2, or the deletion mutant IRP2(Delta73) (lacking a specific insert of 73 amino acids), were injected subcutaneously into nude mice. The induction of IRP2 profoundly stimulated the growth of tumor xenografts, and this response was blunted by addition of tetracycline in the drinking water of the animals, to turnoff the IRP2 transgene. Interestingly, IRP2(Delta73) failed to promote tumor growth above control levels. As expected, xenografts expressing the IRP2 transgene exhibited high levels of transferrin receptor 1 (TfR1); however, the expression of other known IRP targets was not affected. Moreover, these xenografts manifested increased c-MYC levels and ERK1/2 phosphorylation. A microarray analysis identified distinct gene expression patterns between control and tumors containing IRP2 or IRP1 transgenes. By contrast, gene expression profiles of control and IRP2(Delta73)-related tumors were more similar, consistently with their growth phenotype. Collectively, these data demonstrate an apparent pro-oncogenic activity of IRP2 that depends on its specific 73 amino acids insert, and provide further evidence for a link between IRPs and cancer biology.
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, and Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Carmen
authors.initials: C
authors.lastname: Maffettone
authors.forename: Guohua
authors.initials: G
authors.lastname: Chen
authors.forename: Ignat
authors.initials: I
authors.lastname: Drozdov
authors.forename: Christos
authors.initials: C
authors.lastname: Ouzounis
authors.forename: Kostas
authors.initials: K
authors.lastname: Pantopoulos
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035942:Iron Regulatory Protein 2 / Q000235:genetics* / Q000502:physiology; D008175:Lung Neoplasms / Q000209:etiology*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D017384:Sequence Deletion; D014183:Transplantation, Heterologous
chemical_list: D035942:Iron Regulatory Protein 2
references.citation: Mol Cell Biol. 2007 Apr;27(7):2423-30
references.pmid: 17242182
references.citation: PLoS Comput Biol. 2007 Oct;3(10):2032-42
references.pmid: 17967053
references.citation: J Biol Chem. 2003 Oct 10;278(41):40337-42
references.pmid: 12888568
references.citation: Nat Genet. 2001 Feb;27(2):209-14
references.pmid: 11175792
references.citation: Nucleic Acids Res. 2002 Apr 1;30(7):1575-84
references.pmid: 11917018
references.citation: Toxicol Appl Pharmacol. 2005 Jan 15;202(2):199-211
references.pmid: 15629195
references.citation: Mol Cell Biol. 2002 Jul;22(13):4638-51
references.pmid: 12052872
references.citation: Biochim Biophys Acta. 2006 Jul;1763(7):668-89
references.pmid: 16872694
references.citation: Biochem J. 2007 Dec 15;408(3):429-39
references.pmid: 17760563
references.citation: Nat Rev Cancer. 2008 Dec;8(12):976-90
references.pmid: 19029958
references.citation: J Biol Chem. 2006 Aug 11;281(32):22865-74
references.pmid: 16760464
references.citation: Cell Cycle. 2008 Mar 1;7(5):592-6
references.pmid: 18256542
references.citation: Cell Metab. 2009 May;9(5):461-73
references.pmid: 19416716
references.citation: J Biol Chem. 2007 Aug 24;282(34):24650-9
references.pmid: 17604281
references.citation: Annu Rev Nutr. 2008;28:197-213
references.pmid: 18489257
references.citation: Blood. 2005 Oct 1;106(7):2580-9
references.pmid: 15956281
references.citation: Mol Cell Biol. 2004 Feb;24(3):954-65
references.pmid: 14729944
references.citation: Blood Cells Mol Dis. 2006 Mar-Apr;36(2):283-7
references.pmid: 16480904
references.citation: EMBO J. 2004 Jan 28;23(2):386-95
references.pmid: 14726953
references.citation: Science. 2009 Oct 30;326(5953):722-6
references.pmid: 19762597
references.citation: J Nutr. 1997 Feb;127(2):238-48
references.pmid: 9039823
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12345-50
references.pmid: 12209011
references.citation: Science. 1999 Jan 29;283(5402):676-9
references.pmid: 9924025
references.citation: Carcinogenesis. 2007 Apr;28(4):785-91
references.pmid: 17127713
references.citation: BMC Mol Biol. 2008 Jan 28;9:15
references.pmid: 18226225
references.citation: Science. 2009 Oct 30;326(5953):718-21
references.pmid: 19762596
references.citation: J Trace Elem Med Biol. 2010 Jan;24(1):58-66
references.pmid: 20122582
references.citation: Nat Chem Biol. 2006 Aug;2(8):406-14
references.pmid: 16850017
references.citation: Methods Enzymol. 2002;348:324-37
references.pmid: 11885287
references.citation: Mol Cell. 2008 Dec 26;32(6):838-48
references.pmid: 19111663
references.citation: Cell Metab. 2008 Jan;7(1):79-85
references.pmid: 18177727
references.citation: Nat Struct Mol Biol. 2007 May;14(5):420-6
references.pmid: 17417656
references.citation: Blood. 2005 Aug 1;106(3):1084-91
references.pmid: 15831703
references.citation: Science. 2004 Dec 17;306(5704):2087-90
references.pmid: 15604406