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CYTOCHROME C CATIONIC OLIGOPEPTIDE CONJUGATES:
THEIR CELLULAR UPTAKE, INTRACELLULAR PROCESSING
AND BIOLOGICAL ACTIVITY
by
Maureen P. Barnes
____________________________________________________________________
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
(PHARMACEUTICAL SCIENCES)
May 2007
Copyright 2007 Maureen P. Barnes
Object Description
| Title | Cytochrome c cationic oligopeptide conjugates: their cellular uptake, intracellular processing and biological activity |
| Author | Barnes, Maureen P. |
| Author email | mbarnes@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pharmaceutical Sciences |
| School | School of Pharmacy |
| Date defended/completed | 2006-12-14 |
| Date submitted | 2007 |
| Restricted until | Restricted until 14 Feb. 2009. |
| Date published | 2009-02-14 |
| Advisor (committee chair) | Shen, Wei-Chiang |
| Advisor (committee member) |
Wang, Clay Garner, Judy Okamoto, Curtis Hamm-Alvarez, Sarah F. |
| Abstract | Peptides characterized as protein transduction domain peptides (PTD) or membrane transduction peptides (MTP) have recently attracted attention as a novel approach for the efficient intracellular delivery of oligopeptides, oligonucleotides and other bioactive macromolecules, primarily into the cytoplasm of mammalian cells. However, the effect of the linkage between cargo and its cationic oligopeptide carrier on the internalization, intracellular processing and biological activity of the cargo has not been fully deliberated. In this thesis, the cellular processing of conjugates of PTDs and the nuclear encoded apoptotic protein cytochrome c prepared with either a disulfide or a thioether linkage is studied and the conjugates used as a tool to learn more about the intracellular fate of cationic oligopeptides. The results from this work, performed in multiple cell lines, including CHO, U937 and HeLa, show that the uptake of the conjugates is increased when compared to that of cytochrome c alone. In HeLa cells, apoptotic activity of cytochrome c is observed only in the thioether conjugate, but not in the cytochrome c or the disulfide conjugate. However, apoptosis is restored in the disulfide conjugate with the addition of the proteasome inhibitor, MG132. Furthermore, the addition of MG132 resulted in an increase of apoptotic activity in cytochrome c. Conceivably, MG132 can protect cytochrome c, either in the native form or as a product released from the disulfide conjugate, from degradation by proteasomes. This model is further supported by the finding that treatment with acetaminophen, a glutathione depleting agent, markedly enhances the apoptotic effect of the disulfide conjugate, but not of the cytochrome c or the thioether conjugate. This result suggests that not only does the preservation of the cargo-carrier complex not hinder the cargo's biological activity, it is required for the retention of the conjugate's biological activity. |
| Keyword | Barnes |
| 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-m255 |
| Rights | Barnes, Maureen P. |
| 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-Barnes-20070214 |
| Archival file | uscthesesreloadpub_Volume29/etd-Barnes-20070214.pdf |
Description
| Title | Page 1 |
| Full text | CYTOCHROME C CATIONIC OLIGOPEPTIDE CONJUGATES: THEIR CELLULAR UPTAKE, INTRACELLULAR PROCESSING AND BIOLOGICAL ACTIVITY by Maureen P. Barnes ____________________________________________________________________ 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 (PHARMACEUTICAL SCIENCES) May 2007 Copyright 2007 Maureen P. Barnes |
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