A characterization of NR0B1 in the pathogenesis of Ewing's sarcoma

Update Item Information
Publication Type dissertation
School or College School of Medicine
Department Oncological Sciences
Author Kinsey, Michelle Vitek
Title A characterization of NR0B1 in the pathogenesis of Ewing's sarcoma
Date 2010-04
Description 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.
Type Text
Publisher University of Utah
Subject Ewing's Sarcoma
Subject MESH Sarcoma, Ewing's
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
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.
Rights Management © Michelle Vitek Kinsey
Format Medium application/pdf
Format Extent 2,128,626 bytes
Source Original: University of Utah Spencer S. Eccles Health Sciences Library
Conversion Specifications Original scanned on Fujitsi fi-5220G as 400 dpi to pdf using ABBYY FineReader 10
ARK ark:/87278/s6sb4m93
Setname ir_etd
ID 193262
Reference URL https://collections.lib.utah.edu/ark:/87278/s6sb4m93
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