Androgen receptor modulation by non-androgenic factors and the basal transcription factor TAF1
department or school: Medicine, Faculty of
department or school: Pathology and Laboratory Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Tavassoli, Peyman
issued: 2010-01-15T22:10:15Z
issued: 2010
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: There is considerable evidence to suggest that progression of prostate cancers to castration-resistant is due to inappropriate activation of the androgen receptor (AR) and hence, the AR is a good target for the treatment of this disease. In this study we used two approaches to investigate AR activation and inhibition. First, we developed high-throughput, non-invasive, cell-based screening assays to rapidly and biologically assess factors that modulate prostate cancer growth and affect AR activity. Using these assays, we found that differentiated osteoblast-like condition media enhanced prostate cancer cell growth, but not AR activity. In addition, we applied this system to screen compounds, selected through in silico approaches against a crucial pocket on the AR protein. The application of our in silico tools and our cell based screening assay resulted in identification of 17 compounds out of 4 millions that can inhibit AR activity. Importantly, some of these compounds are more potent than bicalutamide, which is one of the most potent antiandrogen drugs currently used to treat patients with metastatic prostate cancer. In the context of AR transcription target genes, the presence of AR coactivators is essential for AR activity. Using the repressed transactivator yeast two-hybrid system, we found that TATA binding protein-associated factor 1 (TAF1) interacted with the AR. In tissue microarrays, TAF1 was shown to steadily increase with duration of neoadjuvant androgen withdrawal and with progression to castration resistance. GST pull-down assays established TAF1/AR interaction and co-immunoprecipitation and ChIP assays revealed colocalization of TAF1 and AR on the prostate specific antigen (PSA) promoter in prostate cancer cells. With respect to modulation of AR activity, while full-length TAF1 showed enhancement of both AR and some generic gene transcriptional activity, selective AR coactivator activity was demonstrated in transactivation experiments using cloned TAF1…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/18163
note: i Androgen Receptor Modulation by non-Androgenic Factors and the Basal Transcription Factor TAF1 by Peyman Tavassoli MD, Shahid Beheshti University of Medical Sciences, 1994 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Pathology and Laboratory Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) January 2010 © Peyman Tavassoli 2009 ii Abstract There is considerable evidence to suggest that progression of prostate cancers to castration- resistant is due to inappropriate activation of the androgen receptor (AR) and hence, the AR is a good target for the treatment of this disease. In this study we used two approaches to investigate AR activation and inhibition. First, we developed high-throughput, non-invasive, cell-based screening assays to rapidly and biologically assess factors that modulate prostate cancer growth and affect AR activity. Using these assays, we found that differentiated osteoblast-like condition media enhanced prostate cancer cell growth, but not AR activity. In addition, we applied this system to screen compounds, selected through in silico approaches against a crucial pocket on the AR protein. The application of our in silico tools and our cell based screening assay resulted in identification of 17 compounds out of 4 millions that can inhibit AR activity. Importantly, some of these compounds are more potent than bicalutamide, which is one of the most potent antiandrogen drugs currently used to treat patients with metastatic prostate cancer. In the context of AR transcription target genes, the presence of AR coactivators is essential for AR activity. Using the repressed transactivator yeast two-hybrid system, we found that TATA binding protein-associated factor 1 (TAF1) interacted with the AR. In tissue microarrays, TAF1 was shown to steadily increase with duration of neoadjuvant androgen withdrawal and with progression to castration resistance. GST pull-…
has type: Thesis/Dissertation
date issued: 2010-05
is shown at: 10.14288/1.0069011
language: eng
degree discipline: Pathology
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/18163