Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558096
Title: Investigating the role of ERK in microtubule-interferin agent-induced cell survival and death
Author: Gopar, Priti
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2012
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Abstract:
Activation of the mitotic checkpoint by microtubule-interfering drugs (MIAs) such as r- axol causes mammalian cells to undergo apoptosis. Previous studies have shown that tr atment with such drugs activate the extra-cellular regulated kinase (ERK) pathway, causing the cells to arrest in mitosis and then undergo apoptosis. ERK1I2 activation in response to MIAs has been implicated as having a role in mediating MIA-induced cell survival in certain cancer cell types such as lung cancers. Using Hela cells, the results in this project confirm the activation of ERK1I2 upon introduction of MIAs such as Nocodazole, Taxol, Vinblastine and Vincristine. GFP-Erk 1 expression showed a rapid cytoplasmic to nuclear translocation of ERK1I2 in response to MIAs, further suggesting a direct role for ERK1I2 in cell survival. Quantifying cell death in response to MIAs with or without the MEKlERK inhibitor U0126 showed that ERK1/2 inhibition may increase cell death in comparison to MIA treatment alone. Subsequent data has shown, for the first time, that upon ERK1I2 inhibition by U0126, cell death occurs via the intrinsic apoptotic pathway, as seen by caspase-9 and caspase-3 cleavage after 12 hours of treatment with Taxol plus U0126. Furthermore, inhibiting ERK1I2 activation in Taxol- induced mitotic cells using the UO 126 compound increases cell death suggesting that cells need to reach mitosis before the onset of apoptosis. Preliminary data in this report also supports a role for active ERK 112 in mediating cell survival via phosphorylation of the pro-apoptotic protein Bim and possibly caspase-9. Collectively, the results shown in this report provides potential new targets in the development of anti-cancer therapies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.558096  DOI: Not available
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