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THE MECHANISM BY WHICH EXTRACELLULAR HSP90α PROMOTES CELL
MIGRATION: IMPLICATIONS IN WOUND HEALING AND CANCER
PROGRESSION
by
Shao-Hung Fred Tsen
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERISTY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(GENETIC, MOLECULAR, AND CELLULAR BIOLOGY)
May 2013
Copyright 2013 Shao-Hung Fred Tsen
Object Description
| Title | The mechanism by which extracellular Hsp90α promotes cell migration: implications in wound healing and cancer |
| Author | Tsen, Shao Hung Fred |
| Author email | stsen@usc.edu;f9xtudios@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Genetic, Molecular and Cellular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2013-03-22 |
| Date submitted | 2013-04-15 |
| Date approved | 2013-04-15 |
| Restricted until | 2013-04-15 |
| Date published | 2013-04-15 |
| Advisor (committee chair) | Li, Wei |
| Advisor (committee member) |
Hong, Young-Kwon Chuong, Cheng-Ming Kobielak, Agnieszka |
| Abstract | Extracellular heat shock protein-90 (eHsp90) proteins, which include the membrane-bound, released and secreted forms were first cited in scientific literature late in the 70s. It was not until the recent decade that researchers began to understand the role of exported Hsp90 in normal and tumor cells. In normal cells, Hsp90 is secreted in response to tissue injury. Tumor cells, on the other hand, have managed to constitutively secrete Hsp90 for the purpose of tissue invasion. Cells abundantly store Hsp90 in their cytoplasm, insuring a sufficient supply of extracellular Hsp90 at a moment’s notice. A well-characterized function of secreted Hsp90α is to promote cell motility, a crucial event in both wound healing and cancer. One of the primary targets for extracellular Hsp90α is the cell surface LRP-1 receptor. The promotility activity of secreted Hsp90α resides within a fragment at the boundary between linker region and middle domain. Inhibiting Hsp90α secretion, neutralizing its extracellular function or blocking its signaling through the LRP-1 receptor prevent wound healing and tumor invasion both in vitro and in vivo. ❧ In regards to wound healing, topical application of F-5 promotes acute and diabetic wound healing far more effectively than US FDA-approved conventional growth factor therapy in mice. Moreover we demonstrated that, mechanistically, eHsp90α functions as signaling molecule to promote wound closure. eHsp90α binds to the subdomain II of the LRP-1 receptor and transmits the promotility signal through its NPVY motif located in its cytoplamic tail. The NPVY motif then relays the eHsp90α signal to the Akt1 and Akt2 kinases. We confirmed our findings using cross-rescuing experiments that suggest Akt1 and Akt2 work cooperatively to create a threshold of Akt kinase activity and promote cell migration. In vivo, eHsp90α accelerated wound closure in wild type mice, but not in its Akt1- and Akt2- knockout counterparts. ❧ In cancer, despite extensive efforts in the clinical and research fronts over the lasts two decades, it is still not clear why cancer cells are more susceptible to the toxicity of Hsp90 inhibitors compared to normal cells. We also do not understand why all cancer cell lines do not share this heightened sensitivity to Hsp90 inhibitors. Based on recent findings, we reason that the selected sensitivity of cancer cells to Hsp90 inhibitors, like17-AAG, is likely due to inhibition of the extracellular Hsp90 rather than intracellular Hsp90 action. Since not all tumor cells utilize eHsp90 for motility, invasion and metastasis, only eHsp90 dependent cancer cells display sensitivity to Hsp90 inhibitors. Based on this notion, pharmaceutical agents that specifically target eHsp90 function should be more effective on treating tumor cells and less toxic on normal cells than current inhibitors that do not discriminate between the extracellular Hsp90 promotility action from its intracellular ATPase dependent function. |
| Keyword | wound healing; cell motility; cancer progression; secreted Hsp90; and LRP-1 |
| Language | English |
| Format (imt) | application/pdf |
| 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 | Tsen, Shao Hung Fred |
| Physical access | 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@lib.usc.edu |
| Filename | etd-TsenShaoHu-1550.pdf |
| Archival file | uscthesesreloadpub_Volume7/etd-TsenShaoHu-1550.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | THE MECHANISM BY WHICH EXTRACELLULAR HSP90α PROMOTES CELL MIGRATION: IMPLICATIONS IN WOUND HEALING AND CANCER PROGRESSION by Shao-Hung Fred Tsen A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERISTY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (GENETIC, MOLECULAR, AND CELLULAR BIOLOGY) May 2013 Copyright 2013 Shao-Hung Fred Tsen |
