title: Loss of Id2 potentiates the tumorigenic effect of Rb inactivation in a mouse model of retinoblastoma.
abstract: OBJECTIVE
  In some cancers, the oncogenic consequences of inactivating the retinoblastoma protein (Rb) appear to be mediated by unrestrained activity of the inhibitor of DNA binding protein Id2. The role of Id2 has not yet been investigated in the prototype cancer Rb-defective cancer, retinoblastoma itself. This study investigated whether loss of Id2 modified the effects of Rb inactivation in a mouse model of retinoblastoma.
  
  
  METHODS
  Id2 was analyzed in cultured cells using qPCR, Western blot, and colony formation assays. LH beta-Tag transgenic mice were crossed with Id2 heterozygotes to obtain mice with all three Id2 genotypes. Intraocular tumors were assessed for size, degree of differentiation, mitotic index, and tumor vascular density at 15 weeks of age.
  
  
  RESULTS
  Retinoblastoma cell lines expressed low levels of Id2 mRNA and protein. Depletion of Id2 in Rb-inactivated cells increased clonogenic activity. Id2-deficient tumors in vivo were significantly larger, less differentiated, and more vascularized than Id2-wild-type tumors (P = 0.02, P = 0.01, P = 0.0001, respectively). There was a dosage effect for loss of each Id2 allele with respect to differentiation and vascular density.
  
  
  CONCLUSIONS
  Id2 suppresses rather than promotes tumor progression in this mouse model of retinoblastoma. Id2 can act as either an oncogene or a tumor suppressor depending on context.
authors.affiliation: Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Solange
authors.initials: S
authors.lastname: Landreville
authors.forename: Duanduan
authors.initials: D
authors.lastname: Ma
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: J William
authors.initials: JW
authors.lastname: Harbour
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D018450:Disease Progression; D005838:Genotype; D051797:Inhibitor of Differentiation Protein 2 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D019572:Retinal Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D012175:Retinoblastoma / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins
references.citation: Nature. 1990 Feb 15;343(6259):665-9
references.pmid: 1689463
references.citation: Genomics. 2007 Sep;90(3):344-53
references.pmid: 17604597
references.citation: Nature. 1999 Feb 25;397(6721):702-6
references.pmid: 10067894
references.citation: Cancer Res. 2004 Oct 15;64(20):7296-301
references.pmid: 15492249
references.citation: Cell. 1999 Sep 17;98(6):859-69
references.pmid: 10499802
references.citation: Nature. 2000 Oct 5;407(6804):592-8
references.pmid: 11034201
references.citation: Mol Cell Biol. 2004 May;24(10):4241-54
references.pmid: 15121845
references.citation: Surv Ophthalmol. 2002 Jan-Feb;47(1):1-16
references.pmid: 11801265
references.citation: Cancer Cell. 2003 Jun;3(6):525-30
references.pmid: 12842081
references.citation: Arch Pathol Lab Med. 2009 Aug;133(8):1203-9
references.pmid: 19653710
references.citation: Cancer Res. 2002 Jan 1;62(1):301-6
references.pmid: 11782392
references.citation: Cancer Res. 2004 Oct 15;64(20):7220-5
references.pmid: 15492237
references.citation: Oncogene. 1999 Jul 8;18(27):3930-5
references.pmid: 10435615
references.citation: Genes Chromosomes Cancer. 2007 Jul;46(7):617-34
references.pmid: 17437278
references.citation: J Biol Chem. 2001 Apr 6;276(14):11362-70
references.pmid: 11152455
references.citation: Invest Ophthalmol Vis Sci. 2006 Apr;47(4):1264-8
references.pmid: 16565356
references.citation: Mol Cell Biol. 1996 Jun;16(6):2570-8
references.pmid: 8649364
references.citation: Oncogene. 2001 Dec 20;20(58):8290-8
references.pmid: 11840321
references.citation: Clin Cancer Res. 2008 Feb 15;14(4):1025-31
references.pmid: 18281534
references.citation: Mol Cell Biol. 2004 Mar;24(5):2083-90
references.pmid: 14966287
references.citation: J Biol Chem. 2003 May 23;278(21):19358-66
references.pmid: 12646568
references.citation: Exp Eye Res. 1996 Nov;63(5):511-8
references.pmid: 8994354
references.citation: Cancer Res. 1998 Sep 1;58(17):3769-72
references.pmid: 9731481
references.citation: Prostate. 2005 Aug 1;64(3):253-64
references.pmid: 15717313
references.citation: Genes Dev. 1994 Jun 1;8(11):1270-84
references.pmid: 7926730
references.citation: Cancer Res. 2003 Nov 1;63(21):7098-105
references.pmid: 14612502
references.citation: Oncogene. 2001 Dec 20;20(58):8326-33
references.pmid: 11840325
references.citation: Cancer Res. 2006 May 1;66(9):4602-9
references.pmid: 16651410
references.citation: Oncogene. 2006 Aug 28;25(38):5326-32
references.pmid: 16936754
references.citation: Mol Cell Biol. 2005 May;25(9):3563-74
references.pmid: 15831462