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ONE PLAY, MANY ACTORS:
THE MANY ROLES COREGULATORS PLAY IN NUCLEAR RECEPTOR MEDIATED TRANSCRIPTION
by
Irina Ianculescu
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(GENETIC, MOLECULAR AND CELLULAR BIOLOGY)
December 2011
Copyright 2011 Irina Ianculescu
Object Description
| Title | One play, many actors: the many roles coregulators play in nuclear receptor mediated transcription |
| Author | Ianculescu, Irina |
| Author email | iiancule@usc.edu;irinaianculescu@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Genetic, Molecular and Cellular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2011-07-26 |
| Date submitted | 2011-10-06 |
| Date approved | 2011-10-06 |
| Restricted until | 2011-10-06 |
| Date published | 2011-10-06 |
| Advisor (committee chair) | Stallcup, Michael R. |
| Advisor (committee member) |
Coetzee, Gerhard A. Rice, Judd C. |
| Abstract | It is becoming increasingly evident that transcriptional coregulators are a diverse group of proteins of central importance to gene expression. Although some appear to be just scaffold proteins used to tether the nuclear receptor to RNA polymerase quite a few possess enzymatic activities that are required for gene expression. Here we explored the roles of various coactivators in nuclear receptor mediated transcription. ❧ Hic-5 is perhaps the least well studied coactivator of the group investigated. A coactivator for both the androgen receptor (AR) and glucocorticoid receptor (GR), its depletion in A549 lung cancer cells failed to show any changes in GR target gene expression for the 25 genes that we examined. Similar results were observed for the depletion of the well known histone and protein methyltransferase PRMT1 in A549 and MCF-7 cells. ❧ The histone acetyltransferases p300 and CBP appeared to be selectively required for androgen-regulated genes in the C4-2B prostate cancer cells. Illumina microarray expression data showed that 47% of androgen regulated genes are p300 dependent, while only 0.3% are CBP dependent. Actually, p300 is important for both androgen dependent pol II and TBP recruitment to the AR target genes, TMPRSS2 and PSA. CBP expression cannot compensate for the loss of p300 on these two genes. Likewise, androgen induced increases in histone H3 Lys 18, Lys 27 and histone H4 acetylation rely on the presence of p300. Although previously thought to have many overlapping functions in gene expression, our data suggests that in C4-2B cells they exhibit many separate and defining roles critical for proper androgen regulated gene expression. Our data also suggests that p300 is the dominant member of the pair, appearing to be more important for androgen-mediated gene expression. CBP depletion in our cell line did not affect the androgen regulated expression of nearly as many genes as loss of p300 did. This suggests a distinct role for p300 in an advanced prostate cancer cell model. |
| Keyword | transcriptional regulation; nuclear receptor coactivators; p300/CBP |
| 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-m |
| Contributing entity | University of Southern California |
| Rights | Ianculescu, Irina |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume6/etd-Ianculescu-320.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Full text | ONE PLAY, MANY ACTORS: THE MANY ROLES COREGULATORS PLAY IN NUCLEAR RECEPTOR MEDIATED TRANSCRIPTION by Irina Ianculescu A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (GENETIC, MOLECULAR AND CELLULAR BIOLOGY) December 2011 Copyright 2011 Irina Ianculescu |
