Loss of Id2 potentiates the tumorigenic effect of Rb inactivation in a mouse model of retinoblastoma.
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.
Landreville
Solange
S
Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA.
Ma
Duanduan
D
Wu
Jun
J
Harbour
J William
JW
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*
C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins
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