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Investigating the role of ERK in microtubule-interfering agent-induced cell survival and death

By Priti Gopar

Abstract

Activation of the mitotic checkpoint by microtubule-interfering drugs (MIAs) such as Taxol causes mammalian cells to undergo apoptosis. Previous studies have shown that treatment with such drugs activate the extra-cellular regulated kinase (ERK) pathway, causing the cells to arrest in mitosis and then undergo apoptosis. ERK1/2 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.\ud Using Hela cells, the results in this project confirm the activation of ERK1/2 upon introduction of MIAs such as Nocodazole, Taxol, Vinblastine and Vincristine. GFP-Erk1 expression showed a rapid cytoplasmic to nuclear translocation of ERK1/2 in response to MIAs, further suggesting a direct role for ERK1/2 in cell survival. Quantifying cell death in response to MIAs with or without the MEK/ERK 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 ERK1/2 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 ERK1/2 activation in Taxol-induced mitotic cells using the U0126 compound increases cell death suggesting that cells need to reach mitosis before the onset of apoptosis.\ud Preliminary data in this report also supports a role for active ERK1/2 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

Publisher: University of Leicester
Year: 2009
OAI identifier: oai:lra.le.ac.uk:2381/9929

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