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dc.contributor.authorMooney, Patrick
dc.contributor.otherQueen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.))en
dc.date2010-01-09 21:57:30.056en
dc.date.accessioned2010-01-11T16:01:56Z
dc.date.available2010-01-11T16:01:56Z
dc.date.issued2010-01-11T16:01:56Z
dc.identifier.urihttp://hdl.handle.net/1974/5381
dc.descriptionThesis (Master, Biochemistry) -- Queen's University, 2010-01-09 21:57:30.056en
dc.description.abstractCell migration and invasion are essential physiological processes required for the growth and development of all multicellular organisms. However, they have also been implicated in the pathogenesis of certain vascular system diseases and invasive cancers. In this study, we investigate two proteins involved in cell proliferation and survival signaling, p53 and Stat3, which have been found misregulated in atherosclerosis and cancer, to establish what effect they have on the development of Src-induced invasive phenotypes in aortic vascular smooth muscle cells (VSMC) and NIH 3T3 fibroblasts. In the first stage of this experiment, we investigated the tumor suppressor p53. Once believed to act primarily as a regulator of the cell cycle, DNA repair, senescence and apoptosis, current evidence suggests that p53 can also regulate cell migration and invasion. For our study, we stably transduced VSMC and NIH 3T3 fibroblasts with constitutively active Src (SrcY527F) to generate invasive cell lines with pronounced podosome and rosette formation. We established for the first time that p53 suppresses Src-induced podosome and rosette formation, extracellular matrix degradation, cell migration and invasion in these cells. We also present novel data showing that p53 suppresses these invasive phenotypes, at least in part, by up-regulating the expression of caldesmon, an actin binding protein which stabilizes stress fibers and inhibits podosome and rosette formation. In the second part of this study, we show that Stat3, a pro-survival and pro-metastatic transcription factor, is required downstream of Src for the promotion of invasive phenotypes in VSMC and NIH 3T3 fibroblasts. Interestingly we have also shown for the first time that Stat3 can localize to podosomes and rosettes in these cells. The exact physiological reasoning for this localization, however, remains to be determined. This study provides strong evidence suggesting that mutual antagonism between the anti-invasive ‘p53-caldesmon’ and pro-invasive ‘Src-Stat3’ pathways dictates the outcome of Src-induced invasive phenotypes in VSMC and NIH 3T3 fibroblasts.en
dc.format.extent2949757 bytes
dc.format.mimetypeapplication/pdf
dc.languageenen
dc.language.isoenen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectCell migrationen
dc.subjectCell Invasionen
dc.subjectp53en
dc.subjectStat3en
dc.subjectSrcen
dc.subjectcaldesmonen
dc.titleA balancing act between the 'Src-Stat3' and 'p53-caldesmon' pathways dictates the outcome of Src-induced invasive phenotypesen
dc.typeThesisen
dc.description.degreeMasteren
dc.contributor.supervisorMak, Alanen
dc.contributor.departmentBiochemistryen


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