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THE ROLE OF GRP78 IN THE REGULATION OF APOPTOSIS AND PROSTATE CANCER PROGRESSION
by
Yong Fu
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 & MOLECULAR BIOLOGY)
May 2008
Copyright 2008 Yong Fu
Object Description
| Title | The role of GRP78 in the regulation of apoptosis and prostate cancer progression |
| Author | Fu, Yong |
| Author email | yongfu@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2008-03-19 |
| Date submitted | 2008 |
| Restricted until | Restricted until 17 Apr. 2010. |
| Date published | 2010-04-17 |
| Advisor (committee chair) | Lee, Amy S. |
| Advisor (committee member) |
Stallcup, Michael R. Stellwagen, Robert H. Kaplowitz, Neil |
| Abstract | Glucose-regulated protein 78 (GRP78), a molecular chaperone at the endoplasmic reticulum (ER), is a master regulator of ER stress and an important survival factor for cell. GRP78 protein level is highly elevated in malignant tumors and correlates with severe pathological grade and poor prognosis. It has been well established that GRP78 can affect apoptosis by regulating ER Ca2+ signaling and unfolded protein response pathway, but whether other mechanism exists remains unknown. Searching for novel partners that interact with GRP78 at the ER, we discovered that BIK, an apoptotic BH-3-only protein located principally at ER, selectively forms a complex with GRP78. GRP78 overexpression decreases apoptosis of 293T cells induced by ER-targeted BIK. For the MCF-7/BUS breast cancer cells that require BIK to mediate estrogen starvation-induced apoptosis, overexpression of GRP78 inhibits estrogen-starvation induced BAX activation, mitochondrial permeability transition, and consequent apoptosis. Further, knockdown of endogenous GRP78 by siRNA sensitizes MCF-7/BUS cells to estrogen-starvation induced apoptosis. This effect was substantially reduced when the expression of BIK was also reduced by siRNA. In addition to in vitro investigations, an in vivo study in a Pten conditional knockout mouse model of prostate cancer reveals that homozygous deletion of Grp78 blocks prostate cancer formation and progression initiated by Pten nullification. Our results provide multiple lines of evidence that GRP78 is a critical player in the regulation of apoptosis and the formation and progression of cancer. These results further support the concept that GRP78 represents a novel marker for cancer progression and chemo-responsiveness, as well as a novel target for cancer therapy. |
| Keyword | GRP78; BIK; apoptosis; prostate cancer; BiP; PTEN |
| 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-m1145 |
| Rights | Fu, Yong |
| 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-Fu-20080417 |
| Archival file | uscthesesreloadpub_Volume14/etd-Fu-20080417.pdf |
Description
| Title | Page 1 |
| Full text | THE ROLE OF GRP78 IN THE REGULATION OF APOPTOSIS AND PROSTATE CANCER PROGRESSION by Yong Fu 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 & MOLECULAR BIOLOGY) May 2008 Copyright 2008 Yong Fu |
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