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CO-CHAPERONE INFLUENCE ON ANDROGEN RECEPTOR SIGNALING
AND IDENTIFICATION OF ANDROGEN RECEPTOR GENES IN
PROSTATE CANCER
by
Jennifer Prescott
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 Jennifer Prescott
Object Description
| Title | Co-chaperone influence on androgen receptor signaling and identification of androgen receptor genes in prostate cancer |
| Author | Prescott, Jennifer |
| Author email | jstepcic@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Epidemiology |
| School | Keck School of Medicine |
| Date defended/completed | 2007-03-28 |
| Date submitted | 2007 |
| Restricted until | Unrestricted |
| Date published | 2007-04-21 |
| Advisor (committee chair) | Coetzee, Gerhard A. |
| Advisor (committee member) |
Ingles, Sue A. Frenkel, Baruch Ursin, Giske Garner, Judy A. |
| Abstract | The androgen receptor (AR) plays pivotal roles in the initiation and progression of prostate cancer, which is a major health burden worldwide. Initially, the disease is androgen-dependent and readily responds to androgen-ablation therapies. However, after a relatively short period of ablation therapy, the tumor returns as a more aggressive androgen-ablation resistant disease for which there are no effective therapies. Thus, the detection of prostate cancer at an early curable stage, as well as understanding the mechanisms of cancer progression are of utmost importance.; Though ablation-resistant prostate tumors often respond to alternate ablation therapies, eventually such tumors become refractile to all. This occurs not from a loss of AR, but rather the acquired ability of the AR to signal at subphysiologic levels of androgen. While various mechanisms have been proposed, the details and the relative contribution of each mechanism are poorly understood. The following thesis attempts to enhance our knowledge of progression to advanced prostate cancer by examining an upstream factor as well as downstream effectors of AR signaling.; AR activation requires the proper high ligand-binding affinity conformation assembled by molecular chaperones to unfold and maintain accessibility to the ligand-binding pocket. The core complex of molecular chaperones are assisted and regulated by accessory proteins, including TPR-containing proteins. In collaboration with Dr. Wayne Tilley's group (Adelaide, Australia), we were able to demonstrate modulation of AR function by a novel TPR-containing protein, alphaSGT. The effect appeared to be the result of an influence on nuclear translocation.; With a relatively small number of known AR-regulated genes, it is difficult to understand the biological effects of AR signaling in normal, let alone advanced prostate tumors. Using ChIP Display, we identified several new AR binding sites, which were in the vicinity of androgen-regulate |
| Keyword | prostate cancer; androgen receptor; chaperone; repression |
| 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-m435 |
| Rights | Prescott, Jennifer |
| 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-Prescott-20070421 |
| Archival file | uscthesesreloadpub_Volume48/etd-Prescott-20070421.pdf |
Description
| Title | Page 1 |
| Full text | CO-CHAPERONE INFLUENCE ON ANDROGEN RECEPTOR SIGNALING AND IDENTIFICATION OF ANDROGEN RECEPTOR GENES IN PROSTATE CANCER by Jennifer Prescott 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 Jennifer Prescott |
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