Abstract
BackgroundRetinoblastoma is caused by loss of the Rb protein in early retinal cells. Although numerous Rb functions have been identified, Rb effects that specifically relate to the suppression of retinoblastoma have not been defined.ResultsIn this study, we examined the effects of restoring Rb to Y79 retinoblastoma cells, using novel retroviral and lentiviral vectors that co-express green fluorescent protein (GFP). The lentiviral vector permitted transduction with sufficient efficiency to perform biochemical analyses. Wild type Rb (RbWT) and to a lesser extent the low penetrance mutant Rb661W induced a G0/G1 arrest associated with induction of p27KIP1 and repression of cyclin E1 and cyclin E2. Microarray analyses revealed that in addition to down-regulating E2F-responsive genes, Rb repressed expression of Brn-2 (POU3F2), which is implicated as an important transcriptional regulator in retinal progenitor cells and other neuroendocrine cell types. The repression of Brn-2 was a specific Rb effect, as ectopic p27 induced a G0/G1 block, but enhanced, rather than repressed, Brn-2 expression.ConclusionIn addition to Rb effects that occur in many cell types, Rb regulates a gene that selectively governs the behavior of late retinal progenitors and related cells.
Highlights
Retinoblastoma is caused by loss of the Rb protein in early retinal cells
Rb was expressed from the murine stem cell virus (MSCV) LTR and green fluorescent protein (GFP) from a PGK promoter 3' to the RB1 cDNA
Rb was expressed in Y79 cells using novel retroviral and lentiviral vectors
Summary
Retinoblastoma is caused by loss of the Rb protein in early retinal cells. numerous Rb functions have been identified, Rb effects that relate to the suppression of retinoblastoma have not been defined. Rb promotes differentiation through interactions with several widely expressed proteins [18,19], and may both promote differentiation and suppress tumorigenesis by inhibiting Ras [20]. Besides these general effects, Rb promotes osteogenic, adipogenic, thyroid, and melanocytic differentiation through interactions that are specific to the relevant cell types [21,22,23,24,25,26]. To understand how Rb suppresses retinoblastoma, it may be necessary to identify the cell type-specific functions of Rb in the cells that give rise to retinoblastoma tumors
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