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INVESTIGATING THE ROLES OF BMI-1
AND IGF-1 IN PROMOTING ESFT SURVIVAL
by
Darren Jason Russell
___________________________________________________________
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(EXPERIMENTAL AND MOLECULAR PATHOLOGY)
May 2011
Copyright 2011 Darren Jason Russell
Object Description
| Title | Investigating the roles of BMI-1 and IGF-1 in promoting ESFT survival |
| Author | Russell, Darren Jason |
| Author email | darrussell@gmail.com; djrussel@usc.edu |
| Degree | Master of Science |
| Document type | Thesis |
| Degree program | Experimental & Molecular Pathology |
| School | Keck School of Medicine |
| Date defended/completed | 2010-07-21 |
| Date submitted | 2011 |
| Restricted until | Unrestricted |
| Date published | 2011-01-19 |
| Advisor (committee chair) | Erdreich-Epstein, Anat |
| Advisor (committee member) |
Widelitz, Randall Hofman, Florence Roy-Burman, Pradip |
| Abstract | Purpose: Ewing sarcoma family tumors (ESFT) are highly aggressive pediatric and young adult stem cell tumors for which prognostic biomarkers and novel treatments are needed. New treatments targeting the IGF-1R signaling pathway show promise, but may not be effective in treating all patients. We have assessed the potential clinical significance of BMI-1 expression level on treatments utilizing IGF-1R inhibition.; Experimental Design: BMI-1-positive and –negative ESFT cell lines were identified using PCR, Q-RT-PCR, and western blot analysis. Sensitivity to IGF1-R inhibition was determined using MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assays. Performing gain and loss of function studies assessed the role of BMI-1 on IGF-1R inhibition. The effect of IGF-1 inhibition on cell viability was evaluated by PARP cleavage western blots. Cooperation between BMI-1 and IGF-1 was assessed by performing immunoblotting to detect Akt phosphorylation.; Results: BMI-1 expression is negatively correlated with IGF-1R axis signaling in ESFT. Significantly, although BMI-1-positive cell lines are more sensitive to IGF-1R inhibition than BMI-1-negative cells, overexpressing BMI-1 decreased this sensitivity, while knocking down BMI-1 expression increased the effects of IGF-1R inhibition. PARP cleavage western blots showed that the likely mechanism of decreased viability in cell lines treated with IGF-1R inhibition is apoptosis. Consistent with these data, we have shown that BMI-1 and IGF-1 cooperate to promote Akt phosphorylation.; Conclusion: BMI-1 and IGF-1 signaling cooperate to promote ESFT survival and tumorigenesis through activation of the PI3K/Akt survival pathway. |
| Keyword | Ewing's sarcoma; ESFT; cancer; BMI-1, IFG-1; IGF-1R |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m3616 |
| Rights | Russell, Darren Jason |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Russell-4265 |
| Archival file | uscthesesreloadpub_Volume17/etd-Russell-4265.pdf |
Description
| Title | Page 1 |
| Full text | INVESTIGATING THE ROLES OF BMI-1 AND IGF-1 IN PROMOTING ESFT SURVIVAL by Darren Jason Russell ___________________________________________________________ A Thesis Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (EXPERIMENTAL AND MOLECULAR PATHOLOGY) May 2011 Copyright 2011 Darren Jason Russell |
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