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MODULATION OF RUNX PROTEINS BY STEROID HORMONE RECEPTORS
by
Omar Khalid
_____________________________________________________________________
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
(PHARMACEUTICAL SCIENCES)
May 2009
Copyright 2009 Omar Khalid
Object Description
| Title | Modulation of Runx proteins by steroid hormone receptors |
| Author | Khalid, Omar |
| Author email | khalid@usc.edu; pageplant99@yahoo.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pharmaceutical Sciences |
| School | School of Pharmacy |
| Date defended/completed | 2008-12-03 |
| Date submitted | 2009 |
| Restricted until | Unrestricted |
| Date published | 2009-03-02 |
| Advisor (committee chair) | Hamm-Alvarez, Sarah |
| Advisor (committee member) |
Coetzee, Gerhard A. Frenkel, Baruch Okamoto, Curtis T. |
| Abstract | Estrogen receptor α (ER α) and androgen receptor (AR) are master transcription factors in the breast and prostate, respectively. They are commonly known in development of sexual characteristics. However, both ERα and AR have been known to be involved in breast cancer (BCa) and prostate cancer (PCa) progression, respectively. The Runx family of transcription factors plays a role in hematopoiesis (Runx1), skeletogenesis (Runx2) and neurogenesis (Runx3). In addition, Runx proteins inhibit cell cycle progression, and have been assigned tumor suppressor roles in various contexts. Because both BCa and PCa cells metastasize to bone at high frequency, investigators have interrogated the possibility that they share characteristics with osteoblasts. Indeed, BCa and PCa cells were found to have "osteomimetic" properties, including expression of Runx2 and Runx2-target genes otherwise expressed by osteoblasts. Provoked by the reported physical interaction between AR and Runx2, we initiated a study to test whether ERα and AR might promote BCa and PCa progression (respectively) by inhibiting Runx2 activity through direct protein-protein interactions. We report here that ERα and AR both inhibit Runx2 transcriptional activity via interaction through specific domains in a receptor specific and ligand specific manner. In addition, it was revealed to a lesser extent that AR was able to strongly inhibit Runx1 transcriptional activity, but ERα was not. Immunohistochemistry analyses revealed that both ERα and Runx2 colocalize in the nucleus in specific subnuclear domains as well as AR and Runx2.; An inverse relationship was observed of Runx2 target genes and ERα target genes in BCa patient tumor samples. Similarly an inverse relationship was also observed of Runx2 target genes and AR target genes in PCa patient tumor samples, suggesting that the molecular biology that we observe in vitro may be occurring within patients. Molecular characterization of ERα/Runx2 and AR/Runx2 interaction and the functional consequences of this interaction may form the basis for novel therapeutic approaches to treat both BCa and PCa patients. |
| Keyword | Runx; steroids; breast cancer; prostate cancer; estrogen receptor; androgen receptor; bone |
| 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-m1991 |
| Rights | Khalid, Omar |
| 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-Khalid-2586 |
| Archival file | uscthesesreloadpub_Volume44/etd-Khalid-2586.pdf |
Description
| Title | Page 1 |
| Full text | MODULATION OF RUNX PROTEINS BY STEROID HORMONE RECEPTORS by Omar Khalid _____________________________________________________________________ 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 (PHARMACEUTICAL SCIENCES) May 2009 Copyright 2009 Omar Khalid |
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