TY - JOUR
T1 - Loss of Id2 potentiates the tumorigenic effect of Rb inactivation in a mouse model of retinoblastoma
AU - Landreville, Solange
AU - Ma, Duanduan
AU - Wu, Jun
AU - Harbour, J. William
N1 - Funding Information:
The authors wish to thank the Immunomorphology Core Lab for preparation of histopathologic sections. This research was supported by Grant R01 EY1316905 from the National Eye Institute, Knights Templar Eye Foundation (Postdoctoral Training Award; DM), Research to Prevent Blindness, Horncrest Foundation (JWH), Fonds de la recherche en santé du Québec (Postdoctoral Training Award; SL), and departmental grants from Research to Prevent Blindness and National Eye Institute Vision Core Grant P30 EY 02687.
PY - 2010/5
Y1 - 2010/5
N2 - Purpose: 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. LHβ-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.
AB - Purpose: 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. LHβ-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.
KW - Id2
KW - Pocket proteins
KW - Rb protein
KW - Retinoblastoma
KW - Tumor suppressor
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U2 - 10.3109/02713680903509428
DO - 10.3109/02713680903509428
M3 - Article
C2 - 20450257
AN - SCOPUS:77952155969
SN - 0271-3683
VL - 35
SP - 435
EP - 439
JO - Current Eye Research
JF - Current Eye Research
IS - 5
ER -