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Title: The integration of growth and stress signalling at the G₁→S transition
Author: Densham, Ruth Mary
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2005
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Progression through the mammalian cell cycle is a tightly controlled process influenced by changes in the expression and stability of both positive and negative regulators of the cell cycle. For example, dedicated cell cycle inhibitors, such as P21Cip1, are up-regulated following stress stimulation and are important for maintaining cell cycle arrest in G1. In contrast, the G1 cyclin, Cyclin D1 acts as a cell cycle sensor for mitogenic signalling and binds and activates cyclin dependent kinase-4 allowing subsequent phosphorylation and inactivation of the retinoblastoma protein and cell cycle progression. Over-expression of Cyclin D1 is observed in some breast cancers where it shortens G1, prompting interest in how Cyclin D1 levels are regulated. In this thesis I use the conditional kinase ΔMEKK3:ER*, which activates ERK1/2, JNK and p38 pathways in response to 4HT, to examine cell cycle progression in the context of conflicting growth and stress signalling. I demonstrate that co-operation of the ERK1/2 and p38 pathways up-regulates p21Cip1 mRNA and protein expression independently of the p53 pathway and consistent with a G1 cell cycle arrest. I also show that in Rat-1 cells, which lack p21Cip1, activation of ΔMEKK3:ER* causes a delay in cell cycle progression that is accompanied by down-regulation of Cyclin D1 mRNA and an increase in proteasome-dependent Cyclin D1 turnover. This increase in Cyclin D1 turnover requires phosphorylation at T286 and is mediated by ERK1/2 and p38 signalling but is independent of GSK3β. Finally, expression of a Cyclin D1-T286A mutant rescues cells from ΔMEKK3:ER*-induced delay in G1-S progression. Together these results show that co-operation of ERK1/2 and p38α/β signalling promotes a G1 cell cycle arrest by the rapid removal of Cyclin D1 and by the up-regulation of p21Cip1; the latter being necessary for sustained G1 arrest.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available