title: Retinoblastoma has properties of a cone precursor tumor and depends upon cone-specific MDM2 signaling.
abstract: Retinoblastomas result from the inactivation of the RB1 gene and the loss of Rb protein, yet the cell type in which Rb suppresses retinoblastoma and the circuitry that underlies the need for Rb are undefined. Here, we show that retinoblastoma cells express markers of postmitotic cone precursors but not markers of other retinal cell types. We also demonstrate that human cone precursors prominently express MDM2 and N-Myc, that retinoblastoma cells require both of these proteins for proliferation and survival, and that MDM2 is needed to suppress ARF-induced apoptosis in cultured retinoblastoma cells. Interestingly, retinoblastoma cell MDM2 expression was regulated by the cone-specific RXRgamma transcription factor and a human-specific RXRgamma consensus binding site, and proliferation required RXRgamma, as well as the cone-specific thyroid hormone receptor-beta2. These findings provide support for a cone precursor origin of retinoblastoma and suggest that human cone-specific signaling circuitry sensitizes to the oncogenic effects of RB1 mutations.
authors.affiliation: Dyson Vision Research Institute, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Xiaoliang L
authors.initials: XL
authors.lastname: Xu
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Fang
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Lee
authors.forename: Douglas
authors.initials: D
authors.lastname: Forrest
authors.forename: Cheryl
authors.initials: C
authors.lastname: Gregory-Evans
authors.forename: Dena
authors.initials: D
authors.lastname: Almeida
authors.forename: Aihong
authors.initials: A
authors.lastname: Liu
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Jhanwar
authors.forename: David H
authors.initials: DH
authors.lastname: Abramson
authors.forename: David
authors.initials: D
authors.lastname: Cobrinik
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism; D012175:Retinoblastoma / Q000378:metabolism*; D047491:Retinoid X Receptor gamma / Q000378:metabolism; D015398:Signal Transduction; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D047491:Retinoid X Receptor gamma; D037042:Thyroid Hormone Receptors beta; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2