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FUNCTIONAL ANALYSES OF ANDROGEN RECEPTOR STRUCTURE
PERTAINING TO PROSTATE CANCER
by
Howard Chung-Hao Shen
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 EPIDEMIOLOGY)
May 2007
Copyright 2007 Howard Chung-Hao Shen
Object Description
| Title | Functional analyses of androgen receptor structure pertaining to prostate cancer |
| Author | Shen, Howard Chung-Hao |
| Author email | hcs@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Epidemiology |
| School | Keck School of Medicine |
| Date defended/completed | 2007-03-05 |
| Date submitted | 2007 |
| Restricted until | Unrestricted |
| Date published | 2007-04-19 |
| Advisor (committee chair) | Coetzee, Gerhard A. |
| Advisor (committee member) |
Ingles, Sue A. Stallcup, Michael R. |
| Abstract | Various peptide regions of the human androgen receptor (AR) were characterized for their potential role in mediating the androgenic signaling response that is integrally linked to prostate cancer development and resistance to treatment. A series of site-directed mutant AR constructs was created that targeted putative signaling motifs within the molecule, and was utilized in functional assays to determine how deviations from the wild-type AR sequence at these sites impacted receptor activity. It was shown that the AR amino-terminal transactivation domain (NTD) possesses great compensatory ability, as independent disruption of several sites had little impact on receptor function in prostate-cancer derived cell lines. Size modulations of the glycine trinucleotide repeat in the NTD had a direct effect on receptor signaling, suggestive of this region having important influence on NTD structure. It was determined that a motif located in the proximal region of the NTD contributes greatly to overall receptor function through mediating ligand-dependent interactions between the AR NTD and ligand-binding domains (LBD). In addition, it was revealed that one mechanism by which the p160 nuclear receptor coactivators enhance AR function is through enhancement of this inter-domain communication. In related studies it was shown that the AR Hinge domain imparts a pivotal contribution to normal AR signaling through mediating communication between AR and the 26S proteasome. Dual roles of the proteasome in AR signaling were characterized based on observations that separate signaling motifs within the AR Hinge control a balance between the apo-receptor and holo-receptor responses to proteasome influence.; These findings yield insight into how specific structural components of the AR cooperatively function within the entirety of the actively signaling receptor, and will contribute to new strategies for therapeutically targeting the AR molecule in the context of the aberrant androgen signaling axis that is evident in prostate cancer. |
| Keyword | androgen receptor; steroid receptor; nuclear receptor; prostate cancer |
| 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-m411 |
| Contributing entity | University of Southern California |
| Rights | Shen, Howard Chung-Hao |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-Shen-20070419 |
| Archival file | uscthesesreloadpub_Volume51/etd-Shen-20070419.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | FUNCTIONAL ANALYSES OF ANDROGEN RECEPTOR STRUCTURE PERTAINING TO PROSTATE CANCER by Howard Chung-Hao Shen 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 EPIDEMIOLOGY) May 2007 Copyright 2007 Howard Chung-Hao Shen |
