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A Synthetic Lethal Screen for NF-kB-Dependent Plasma Cell Disorders
By
Waiel Halabi
A Thesis Presented to FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
December 2012
Copyright 2012 Waiel Halabi
Object Description
| Title | A synthetic lethal screen for NF-κB-dependent plasma cell disorders |
| Author | Halabi, Waiel |
| Author email | wael_halabi@hotmail.com;wael_halabi@hotmail.com |
| Degree | Master of Science |
| Document type | Thesis |
| Degree program | Biochemistry and Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2012-10-21 |
| Date submitted | 2012-11-27 |
| Date approved | 2012-11-28 |
| Restricted until | 2012-11-28 |
| Date published | 2012-11-28 |
| Advisor (committee chair) | Tokes, Zoltan |
| Advisor (committee member) |
Chaudhary, Preet Hong, Young |
| Abstract | Nuclear factor- kappa B (NF-κB) was first described as a transcription factor in B cells that binds to the enhancer element controlling immunoglobulin kappa light chain expression. Since its discovery in 1986, NF-κB and its role in inflammatory responses, immune reactions, and tumorigenesis has been extensively studied. Although the abnormal activation of the NF-κB pathway plays a key role in the pathogenesis of several cancers, inflammatory and autoimmune disorders, no specific NF-κB inhibitor is currently in clinical use or in clinical trial. Additionally, to date, efforts to target NF-κB signaling have been focused mostly on IKK2-based, in vitro screening. However, NF-κB pathway activates the expression of a large number of genes, and it is possible that distal downstream components of the NF-κB-signaling network could be targets for drug discovery. A strategy that could be used for revealing such NF-κB-linked targets is synthetic lethal screening. To test this hypothesis, we carried out a screen with an isogenic pair of cell lines derived from IL6-dependent T1165 mouse plasmacytoma. A derivative of T1165 cells stably expressing Kaposi's sarcoma associated herpesvirus encoded viral FLICE inhibitory protein (vFLIP) K13 possess increased NF-κB activity and is independent of IL6. We screened T1165-K13 and T1165-vector cells using libraries of small molecule compounds and identified Fenretinide as a compound with synthetic lethality against plasmacytomas with increased NF-κB activity. |
| Keyword | hematology; plasma cell disorders |
| 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-m |
| Rights | Halabi, Waiel |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume6/etd-HalabiWaie-1359.pdf |
Description
| Title | Page 1 |
| Full text | A Synthetic Lethal Screen for NF-kB-Dependent Plasma Cell Disorders By Waiel Halabi A Thesis Presented to FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (BIOCHEMISTRY AND MOLECULAR BIOLOGY) December 2012 Copyright 2012 Waiel Halabi |
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