Abstract/Details

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


2008 2008

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Abstract (summary)

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.

Indexing (details)


Subject
Molecular biology
Classification
0307: Molecular biology
Identifier / keyword
Biological sciences; Cancer; Chromatin; Drug resistance; Epigenetics; Grp78; HDAC1; Transcriptional regulation
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.
Number of pages
123
Publication year
2008
Degree date
2008
School code
0208
Source
DAI-B 70/01, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780549981589
Advisor
Lee, Amy S.
Committee member
Johnson, Deborah; Ladner, Robert D.
University/institution
University of Southern California
Department
Biochemistry and Molecular Biology
University location
United States -- California
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3341884
ProQuest document ID
304461768
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304461768
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