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ROLE OF GRP78 AND ITS NOVEL CYTOSOLIC ISOFORM GRP78VA
IN REGULATING THE UNFOLDED PROTEIN RESPONSE IN CANCER
by
Min Ni
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)
August 2008
Copyright 2008 Min Ni
Object Description
| Title | Role of GRP78 and its novel cytosolic isoform GRP78va in regulating the unfolded protein response in cancer |
| Author | Ni, Min |
| Author email | mni@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2008-06-17 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-06-27 |
| Advisor (committee chair) | Lee, Amy S. |
| Advisor (committee member) |
Coetzee, Gerhard Farley, Robert Laird-Offringa, Ite Duncan, Roger |
| Abstract | The endoplasmic reticulum (ER) is an essential cellular compartment for protein synthesis and maturation and also functions as a Ca2+ storage organelle. The failure of the ER to cope with the excessive protein load due to perturbation of ER functions leads to ER stress. In response to ER stress, the unfolded protein response (UPR) is activated to reduce the unfolded protein load and meanwhile increase protein folding capacity. Activation of PERK (PKR-like eIF2a kinase) signaling and induction of ER chaperone GRP78/BiP (78kDa glucose-regulated protein) represent two major survival arms of the UPR. In this thesis, the fortuitous discovery of a novel cytosolic isoform of GRP78 is reported. This GRP78 isoform, designated as GRP78va, is generated by alternative splicing and alternative translational initiation. Expression of GRP78va is enhanced by ER stress and is notably elevated in human leukemic cells and leukemia patients. Unlike the canonical form of GRP78 which is primarily localized in the ER lumen, GRP78va is located in the cytosol. GRP78va is a potent promoter of cell survival under ER stress, which could be in part due to a previously undocumented positive feedback of the PERK pathway through interacting with PERK inhibitor, P58IPK.; Finally, several novel observations and mechanisms on the protective role of GRP78 in cancer and ER-stress-induced autophagy are presented. Mouse mammary tumors with Grp78 heterozygosity exhibit activated CHOP and capspases, which contribute to impeded tumor growth. Downregulation of GRP78 by siRNA results in impaired cell viability and the blockage of autophagosome formation induced by ER stress as well as nutrition starvation, despite spontaneous activation of the UPR. Electron microscopic analysis reveals that the ER, a putative membrane source for autophagosome, was massively expanded and disorganized in cells where GRP78 was knocked down. ER expansion is dependent on the UPR transcription factor XBP-1. Simultaneous knockdown of GRP78 and XBP-1 recovered normal levels of stress-induced autophagosome formation. Thus, these studies provide the first evidence of modulation of UPR signaling via alternative pre-mRNA splicing of Grp78 and reveal a few lines of new evidence for understanding survival mechanisms in cells, especially cancer cells, by induction of GRP78 and GRP78va. |
| Keyword | Robert Farley |
| 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 |
| Type | texts |
| Legacy record ID | usctheses-m1302 |
| Rights | Ni, Min |
| 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-Ni-20080627 |
| Archival file | uscthesesreloadpub_Volume17/etd-Ni-20080627.pdf |
Description
| Title | Page 1 |
| Full text | ROLE OF GRP78 AND ITS NOVEL CYTOSOLIC ISOFORM GRP78VA IN REGULATING THE UNFOLDED PROTEIN RESPONSE IN CANCER by Min Ni 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) August 2008 Copyright 2008 Min Ni |
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