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MASS SPECTROMETRY-BASED PROTEOMIC ANALYSIS OF INHIBITOR OF KAPPA B KINASE BETA AND ITS ROLE IN CYTOKINE-INDUCED
DRUG RESISTANCE IN CANCER
by
Ling-Chi Wang
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR MICROBIOLOGY AND IMMUNOLOGY)
December 2007
Copyright 2007
Ling-Chi Wang
Object Description
| Title | Mass spectrometry-based proteomic analysis of inhibitor of kappa b kinase beta and its role in cytokine-induced drug resistance in cancer |
| Author | Wang, Ling-Chi |
| Author email | lingchiw@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Microbiology & Immunology |
| School | Keck School of Medicine |
| Date defended/completed | 2007-10-25 |
| Date submitted | 2007 |
| Restricted until | Restricted until 14 Nov. 2009. |
| Date published | 2009-11-14 |
| Advisor (committee chair) | Zandi, Ebrahim |
| Advisor (committee member) |
Lieber, Michael R. Chen, Jeannie |
| Abstract | IKKbeta is the key kinase in the TNFalpha-NF-kB pathway that phosphorylates IkBalpha and targets it for polyubiquitination and degradation. As a result, NF-kB is released and moves into the nucleus, where it binds to the promoters of target genes and activates transcription that increases cell proliferation or prevents apoptosis. In the chapter two of this dissertation, a novel role for the TNFalpha-IKK-NF-kB signaling pathway in anti-cancer drug resistance is described. Contrary to its physiological function, TNFalpha induced G0-G1 cell cycle arrest through IKK in cancer cells, which provided a mechanism for developing drug resistance to the purine and pyrimidine antimetabolites. A specific IKKbeta inhibitor prevented TNFalpha-induced drug resistance. Thus IKK inhibitors can enhance the effectiveness of antimetabolites in chemotherapy.; Phosphorylation regulates the kinase activity of IKKbeta. In chapters three and four of this dissertation, mass spectrometry-based proteomic methods was developed to analyze post-translational modifications of IKKbeta. A simple and inexpensive frit fabrication method for micro chromatography columns was developed to improve peptide separation in tandem liquid chromatography mass spectrometry. This technology simplifies the use of micro one- or multiple-dimensional chromatography. Using mass spectrometry, three novel phosphorylation sites S471, S474, and S476 in the leucine zipper of IKKbeta were identified. The potential role of these serines on IKKbeta kinase activity was studied. |
| Keyword | cancer drug resistance; frit fabrication; IKK; mass spectrometry; proteomics; tumor neurosis factor |
| 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 |
| Type | texts |
| Legacy record ID | usctheses-m924 |
| Rights | Wang, Ling-Chi |
| 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-Wang-20071114 |
| Archival file | uscthesesreloadpub_Volume32/etd-Wang-20071114.pdf |
Description
| Title | Page 1 |
| Full text | MASS SPECTROMETRY-BASED PROTEOMIC ANALYSIS OF INHIBITOR OF KAPPA B KINASE BETA AND ITS ROLE IN CYTOKINE-INDUCED DRUG RESISTANCE IN CANCER by Ling-Chi Wang A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR MICROBIOLOGY AND IMMUNOLOGY) December 2007 Copyright 2007 Ling-Chi Wang |
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