Bartholomew, Janine Nicole
(2009)
Caveolin-1 mediated p53 activation in stress induced premature senescence and its antagonistic pleiotropic implications in cancer.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Caveolin-1 (Cav-1) is a membrane associated scaffolding protein that regulates a myriad of signaling molecules. It has been implicated as both a tumor suppressor and promoter. Here, we examine the protein's link to senescence and cancer, and identify a novel pathway through which Cav-1 mediates stress induced premature senescence (SIPS) through p53 activation. Oxidative stress triggers p38MAPK , which activates the transcription factor Sp1. Sp1 binds to two GC-rich regions in the caveolin-1 promoter up-regulating the protein. Cav-1 binds to p53's negative regulator, MDM2, sequestering the E3 ligase to allow p53 to become active. p53 activates its downstream targets, such as p21WAF/CIP1, which initiates SIPS. This pathway is dysfunctional in many cancers that have a downregulated Cav-1 gene. The effects of oxidative stress in Cav-1 null backgrounds were examined. Breast cancer cells that do not express Cav-1 cannot undergo oxidatively induced SIPS. However, upon re-expression of Cav-1, the SIPS phenotype is restored. Utilization of Cav-1 knockout mouse embryonic fibroblasts show that without Cav-1 to sequester MDM2, allowing for the upregulation of p53 leading to SIPS, cells continued to proliferate. These results distinguish Cav-1 as a molecular "senescence switch," because in its absence oxidative SIPS does not occur, but in its presence it does. This effect is also not specific to a particular cell type; data supports Cav-1 as a molecular switch in epithelial and fibroblast cell lines. Finally, senescence is known to have antagonistic pleiotropic effects on an organism. That is, cell senescence is beneficial for younger organisms, as it prevents the proliferation of mutated genomes through growth arrest. However, an accumulation of senescent cells can lead to aging and become detrimental. Cav-1's role in the antagonistic pleiotropic effects of senescent fibroblasts on neoplastic epithelial cells is also explored. Data shows that senescence of fibroblasts depends upon Cav-1 sequestering MDM2, which activates p53 and induces SIPS. These fibroblasts can secrete factors that make it advantageous for NIH 3T3 RasG12V transformed fibroblasts and MDA-MB-231 breast cancer epithelial cells to proliferate in vitro and in vivo. Hence, we propose that the Cav-1 gene functions with antagonistic pleiotropy.
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Details
Item Type: |
University of Pittsburgh ETD
|
Status: |
Unpublished |
Creators/Authors: |
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ETD Committee: |
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Date: |
20 February 2009 |
Date Type: |
Completion |
Defense Date: |
12 November 2008 |
Approval Date: |
20 February 2009 |
Submission Date: |
5 February 2009 |
Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
Institution: |
University of Pittsburgh |
Schools and Programs: |
School of Medicine > Molecular Pharmacology |
Degree: |
PhD - Doctor of Philosophy |
Thesis Type: |
Doctoral Dissertation |
Refereed: |
Yes |
Uncontrolled Keywords: |
antagonistic pleiotropy; breast cancer; cancer; caveolin-1; MDM2; p53; senescence |
Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-02052009-225705/, etd-02052009-225705 |
Date Deposited: |
10 Nov 2011 19:31 |
Last Modified: |
15 Nov 2016 13:36 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/6333 |
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