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Title: Characterisation of Small G protein Regulation and Survival Signalling by the Human Sphingosine-1- phosphate receptor S1P1
Author: Childs, Shona
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2006
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The lipid mediator sphingosine-1-phosphate (81 P) is involved in many growth-related processes including migration, angiogenesis and survival. 51 P exerts its effects through the G protein-coupled receptors named 81 P1-S. 81 Pi, the first receptor to be identified is associated with regulation of cytoskeletal dynamics by differential regulation of small G proteins such as Rac, Rho and Cdc42 which are crucial mediators of migration. 81 P-mediated signaliing has long been associated with cell survival but the mechanisms are not completely understood. However, using the model system of Chinese hamster lung fibroblasts (CCL39) stably expressing the 81 P1 receptor, 51 P-mediated Rac and Cdc42 activation was not detected. 81 P2 which inhibits Rac activation was not detected and the selective inhibitor which binds all 81 P receptors except 81 P2 did not rescue this effect. Using CCL39myc51 Pi cells it was demonstrated that the presence of this receptor has a protective effect against apoptosis caused by the removal of trophic factors. Control CCL39 cells showed increased levels of apoptotic initiator protein, Bim and the executioner protein active caspase-3. This effect is not ERK-dependent nor is it dependent on total levels of the pro-apoptotic mediator Bim. This also occurred in the absence of agonist or endogenous 81 P production. Inhibition of 81 P1-mediated signalling pathways such as PI 3-kinase/PKB pathway and PKC completely attenuated this protective effect. Furthermore, blocking protein synthesis by emetine treatment is also reversed the protective which strongly suggests that 51 P1 receptor signalling is the driving force behind the up-regulation of one or more anti-apoptotic proteins which bind and sequester Bim. Understanding the mechanisms by which control growth patterns are regulated is important in the development of new drugs to combat growth-related diseases such as cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available