|School or College
|School of Medicine
|Kinsey, Michelle Vitek
|A characterization of NR0B1 in the pathogenesis of Ewing's sarcoma
|Ewing's sarcoma is a devastating pediatric malignancy. Current treatments are highly toxic, invasive, and not sufficiently targeted or efficacious. It is hoped that knowledge of the molecular mechanisms required for disease development and maintenance willl assist in the generation of more directed and successful therapeutic options for Ewing's sarcoma patients. A breakthrough occurred with the observation that the majority of Ewing's tumors harbored a reciprocal translocation, t(ll;22)(q24;ql2). This chromosomal abnormality results in the synthesis of a fusion protein, EWS/FLI, which functions as an oncogenic aberrant transcription factor. Identifying and understanding the genes influenced by EWS/FLI may provide molecular insight into the transformed phenotype of Ewing's sarcoma. Using a loss-of-function approach targeting EWS/FLI in multiple patient-derived Ewing's sarcoma cells coupled with microarray analysis, we identified genes dysregulated by the fusion protein. Notably, NR0B1 was the most consistently upregulated target of EWS/FLI. NROB1 is a unique orphan member of the nuclear hormone receptor superfamily that functions throughout the steroidogenic axis. NR0B1 is expressed in Ewing's sarcoma patient tumor samples and cell lines, and is required for the transformed phenotype. Therefore, NROB] is a critical EWS/FLI target that has relevance to the bona fide disease. NR0B1 was identified as being directly regulated by EWS/FLI via a GGAA microsatellite in the NR0B1 promoter. This element was enriched in EWS/FLI upregulated genes, but not down-regulated targets. These data suggest the EWS/FLI downregulated gene signature may be modulated by EWS/FLI effector proteins. NR0B1 is a strong candidate to mediate this repression downstream of EWS/FLI. Microarray and whole genome localization studies were performed and NR0B1 was found to function both as a co-activator and a co-repressor. Furthermore, NR0B1 and EWS/FLI were found to co-occupy a subset of genomic loci. A direct interaction that appears to have transcriptional and transforming consequences was then identified between the two proteins. Taken together this work has identified NR0B1 as a critical direct target of EWS/FLI, whose protein product contributes to transformation by interacting with EWS/FLI and functioning as a co-factor for transcription. NR0B1 may then serve as a novel therapeutic target for the treatment of patients with Ewing's sarcoma.
|University of Utah
|University of Utah
|Relation is Version of
|Digital reproduction of "A Characterization of NR0B1 in the pathogenesis of ewing's sarcoma." Spencer S. Eccles Health Sciences Library." Print version of "A characterization of NR0B1 in the pathogenesis of ewing's sarcoma." available at J. Willard Marriott Library Special Collection. RC39.5 2009.K56.
|© Michelle Vitek Kinsey
|Original: University of Utah Spencer S. Eccles Health Sciences Library
|Original scanned on Fujitsi fi-5220G as 400 dpi to pdf using ABBYY FineReader 10