Characterisation of small G protein regulation and survival signaling by the human sphingosine-1-phosphate receptor S1P1

Childs, Shona (2006) Characterisation of small G protein regulation and survival signaling by the human sphingosine-1-phosphate receptor S1P1. PhD thesis, University of Glasgow.

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Abstract

The lipid mediator sphingosine-1-phosphate (S1P) is involved in many growth-related processes including migration, angiogenesis and survival. S1P exerts its effects through the G protein-coupled receptors named SIP1-5. SIP1, 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. SIP-mediated signaling 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 SIP1 receptor, S1P-mediated Rac and Cdc42 activation was not detected. SIP2 which inhibits Rac activation was not detected and the selective inhibitor which binds all S1P receptors except SIP2 did not rescue this effect. Using CCL39mycS1P1 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 S1P production. Inhibition of S1P1-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 SIP1 receptor signaling 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.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Tim Palmer
Keywords: Molecular biology
Date of Award: 2006
Depositing User: Enlighten Team
Unique ID: glathesis:2006-71122
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 10:49
Last Modified: 10 May 2019 10:49
URI: http://theses.gla.ac.uk/id/eprint/71122

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