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THE NONCANONICAL ROLE OF TELOMERASE IN PROSTATE CANCER CELLS:
EXPLORING A NON-TELOMERIC SIGNALING ROLE FOR TELOMERASE PROTEIN (TERT) IN A CANCER CELL LINE
by
Anisha Madhav
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
May 2012
Copyright 2012 Anisha Madhav
Object Description
| Title | The noncanonical role of telomerase in prostate cancer cells: exploring a non-telomeric signaling role for telomerase protein (TERT) in a cancer cell line |
| Author | Madhav, Anisha |
| Author email | anishama@usc.edu;anishama@usc.edu |
| Degree | Master of Science |
| Document type | Thesis |
| Degree program | Biochemistry and Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2012-03-22 |
| Date submitted | 2012-05-04 |
| Date approved | 2012-05-04 |
| Restricted until | 2012-05-04 |
| Date published | 2012-05-04 |
| Advisor (committee chair) | Tokes, Zoltan A. |
| Abstract | The telomerase reverse transcriptase (TERT) component of telomerase has reverse transcriptase activity capable of elongating telomeres during each replication cycle of the cell. TERT plays a dual role in activating normal stem cell niches and in potentiating tumorigenicity and malignancy. Recently, there has been mounting evidence that TERT may exert some of its effects in stem cells through functions independent of its ability to maintain telomere ends. Therefore, we hypothesized that TERT has a non-canonical (non-telomeric) cancer signaling role that potentiates and expands a highly tumorigenic and drug resistant subpopulation of cancer stem-like cells. To test this hypothesis, we ectopically expressed either a wild type or a catalytically dead TERT (or control vector) in DU145 prostate cancer cells and measured the effects on a spectrum of cancer stem-like related phenotypes. We found that ectopically expressing TERT resulted in a slower overall rate of proliferation with downregulation of the cell cycle checkpoint proteins c-myc and cyclinD1. At the same time TERT-expressing DU145 had a significant increase in a CD44+CD24- subpopulation, which has been associated with a cancer stem-like tumorigenic, clonogenic, and metastatic phenotype. TERT-expressing DU145 was also more invasive and expressed lower transcript levels of E-cadherin, an important mediator of cell-cell adhesion. Furthermore, TERT-expressing DU145 had an overall trend, although not significant, in the cancer stem-like ability to form spheres, and had significant downregulation of axin2, a transcriptional target of β-catenin previously shown to be regulated by TERT in stem cell models. Most remarkably, this spectrum of phenotypic changes (surface markers, proliferation, sphere formation, invasiveness, gene expression) occurred in response to either wild type or catalytically dead TERT, suggesting that TERT may indeed potentiate a phenotypic shift towards a cancer-stem like state that is independent of its enzymatic telomere-lengthening role. |
| Keyword | telomerase; TERT; prostate cancer; cancer stem cells |
| 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 |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | Madhav, Anisha |
| 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 |
| Archival file | uscthesesreloadpub_Volume4/etd-MadhavAnis-764-0.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | THE NONCANONICAL ROLE OF TELOMERASE IN PROSTATE CANCER CELLS: EXPLORING A NON-TELOMERIC SIGNALING ROLE FOR TELOMERASE PROTEIN (TERT) IN A CANCER CELL LINE by Anisha Madhav A Thesis Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (BIOCHEMISTRY AND MOLECULAR BIOLOGY) May 2012 Copyright 2012 Anisha Madhav |
