Initial work carried out in this study, set out to develop a suitable cellular model for Bcl-2 over-expression that could be employed in later studies to characterise the interaction between Bcl-2 and calcium signaling. An established anti-apoptotic effect of Bcl-2, is reduction of calcium release from the ER. As a consequence of this reduction, mitochondrial calcium uptake and apoptosis is suppressed. These effects of Bcl-2 were observed in my experimental model of stable over-expression. Examination of the mechanism responsible, for this reduction in calcium release, revealed that it was not due to a decrease in ER store loading, but due to a decrease in sensitivity of the calcium release process. In agreement with previous studies which demonstrate that calcium release from the ER is inhibited as a result of a functional interaction between Bcl-2 and the inositol 1,4,5-trisphosphate (InsP<sub>3</sub>) receptor, Bcl-2 was shown to interact with the InsP<sub>3</sub>R in HEK-293 cells. Since lumenal calcium concentration was shown to be unaffected by Bcl-2, there is a high likelihood that this interaction was contributing to the inhibition of ER calcium release observed in this study. In addition to regulating ER calcium signalling, Bcl-2 modulates mitochondrial calcium homeostasis. Bcl-2 has been shown to increase the calcium buffering and storage capacity of the mitochondria, allowing higher calcium concentrations to be reached before mitochondrial calcium overload occurs. Results presented in this thesis, showed that Bcl-2 also functions to reduce the sensitivity of mitochondrial calcium uptake. Over-expressed Bcl-2 increased the cytosolic calcium concentration required to trigger mitochondrial calcium uptake, in response to ER calcium release and store operated calcium entry.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:603668 |
| Date | January 2007 |
| Creators | Hanson, C. J. |
| Publisher | University of Cambridge |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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