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 proteins 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 p53s 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-1s 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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-02052009-225705 |
| Date | 20 February 2009 |
| Creators | Bartholomew, Janine Nicole |
| Contributors | Donald B. DeFranco, Ferruccio Galbiati, Baskaran Rajasekaran, Daniel E. Johnson, Daniel L. Altschuler |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-02052009-225705/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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