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THE TRANSCRIPTIONAL REGULATION OF THE PRO-SURVIVAL PROTEIN
GRP78 BY ACTIVATING TRANSCRIPTION FACTORS AND CHROMATIN-MODIFYING
ENZYMES: ITS UPREGULATION IN RESPONSE TO HDAC-INHIBITOR
TREATMENT AND THE THERAPEUTIC CONSEQUENCES
by
Peter J. Baumeister
______________________________________________________________________
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
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
December 2008
Copyright 2008! ! ! ! ! ! ! Peter J. Baumeister
Object Description
| Title | The transcriptional regulation of the pro-survival protein Grp78 by activating transcription factors and chromatin-modifying enzymes: its upregulation in response to HDAC-inhibitor treatment and the therapeutic consequences |
| Author | Baumeister, Peter J. |
| Author email | baumeist@usc.edu; pjbethcal@mac.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2008-08-27 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-11-19 |
| Advisor (committee chair) | Lee, Amy S. |
| Advisor (committee member) |
Ladner, Robert D. Johnson, Deborah L. |
| Abstract | The unfolded protein response (UPR) is an evolutionarily conserved mechanism whereby cells respond to stress conditions that target the endoplasmic reticulum (ER). One of the major targets of the UPR is the 78kDa Glucose Regulated Protein Grp78 (BiP). The transcriptional activation of the promoter of GRP78 has been used extensively as an indicator of the onset of the UPR. The transcriptional activation of Grp78 in response to ER stress has been well documented. It is characterized by multiple transcription factors such as YY1, TFII-I, ATF6(N), and NF-Y binding to conserved promoter sequences at the onset of ER stress.; There are also epigenetic changes that occur during the activation of the Grp78 promoter. We have observed ER-stress induced binding of the histone acetyltransferase p300 to the Grp78 promoter and histone H4 acetylation. We have also seen the arginine methyltransferase PRMT1, and evidence of its action through methylation of the arginine 3 residue on histone H4. We show the involvement of histone deacetylase 1 (HDAC1) in the negative regulation of the Grp78 promoter not only by its induction in the presence of the HDAC inhibitors trichostatin A, valproic acid, MS-275 and SAHA, but also by exogenous overexpression and siRNA knockdown of specific HDACs, and ChIP analysis that reveals the binding of HDAC1 to the Grp78 promoter before but not after ER stress.; This dissertation seeks to expand on what is currently known about the ER stress inducible promoter of Grp78 by characterizing the role of activating transcription factors and histone-modifying enzymes in Grp78 promoter regulation. We report that HDAC-inhibition employs a novel mechanism for induction, independent of the ER stress response. We show that overexpression of GRP78 confers resistance to, and suppression of GRP78 enhances the efficacy of HDAC inhibitor-based therapy. |
| Keyword | transcription; histone; deacetylases; grp78; endoplasmic reticulum stress |
| 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-m1773 |
| Contributing entity | University of Southern California |
| Rights | Baumeister, Peter J. |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@dots.usc.edu |
| Filename | etd-Baumeister-2436 |
| Archival file | uscthesesreloadpub_Volume14/etd-Baumeister-2436.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | THE TRANSCRIPTIONAL REGULATION OF THE PRO-SURVIVAL PROTEIN GRP78 BY ACTIVATING TRANSCRIPTION FACTORS AND CHROMATIN-MODIFYING ENZYMES: ITS UPREGULATION IN RESPONSE TO HDAC-INHIBITOR TREATMENT AND THE THERAPEUTIC CONSEQUENCES by Peter J. Baumeister ______________________________________________________________________ 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 (BIOCHEMISTRY AND MOLECULAR BIOLOGY) December 2008 Copyright 2008! ! ! ! ! ! ! Peter J. Baumeister |
