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Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/18965

Title: Role of the Tumor Suppressor ARF and the p53-pathway in Retinoblastoma Development
Authors: To, Kwong Him
Advisor: Gallie, Brenda L.
Department: Molecular and Medical Genetics
Keywords: Cancer
Retinoblastoma
INK4a/ARF
p53
Retina
Tumor suppressor
Oncogene
Therapy
Issue Date: 16-Feb-2010
Abstract: Retinoblastoma development is a multistep process, and inactivation of the RB1 gene is not sufficient for tumorigenesis. Previous studies suggest that the p53-tumor suppressor is inactivated due to overexpression of p53-antagonists MDM4 and MDM2. This thesis evaluates the importance of ARF, a p53-activator that inhibits MDM2. In retinoblastomas, ARF protein is nearly undetectable despite robust mRNA expression. Chemical inhibition of the proteasome, which regulates ARF protein-turnover, did not result in ARF accumulation in retinoblastoma cells, indicating that ARF protein was not aberrantly degraded by the proteasome. During mouse retinoblastoma development, Arf protein was expressed at low level, and p53-target genes involved in cell cycle arrest and autoregulation were not activated. Overexpression of ARF in retinoblastoma cells led to growth inhibition, accompanied by increased expression of p53 and p53-transcriptional targets. Taken together, our data suggests that low ARF protein is an important factor in silencing of the p53-pathway during retinoblastoma development.
URI: http://hdl.handle.net/1807/18965
Appears in Collections:Master
Department of Molecular Genetics - Master theses

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