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Title: The role of spatially distinct calcium signals in the control of gene expression
Author: Hardingham, G. E.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1998
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This thesis is devoted to investigating the mechanisms by which calcium signals activate gene expression. As a model for calcium-activated gene expression, I study the activation of the c-fos gene, whose expression is induced rapidly by calcium influx into neurons. The c-fos promoter contains two elements that mediate the effect of calcium on transcription: the serum response element (SRE) that can bind two transcription factors, serum response factor (SRF), and ternary complex factor (TCF) and the cyclic adenosine monophosphate (cAMP) response element (CRE) that binds, among others, the CRE binding protein, CREB. Cells do not respond stereotypically to calcium; different patterns of electrical activity result in different transcriptional responses. I investigated the possibility that calcium in different areas of the cell can activate different pathways, since this would conceivably provide a mechanism by which a single second messenger could mediate different responses. I have shown that following electrical activity, calcium concentration rises in the nucleus as well as the cytoplasm. I therefore investigated the relative contribution of these spatially distinct pools of calcium to the activation of the c-fos promoter. I injected a calcium chelator into the nucleus of electrically excitable cells, that remained in the nucleus due to it being coupled to a high molecular weight dextran. This chelator blocked activity-induced increases in nuclear calcium without affecting the increase in cytoplasmic calcium. I found that this nuclear chelator blocked activation of CREB, bound to the CRE. Strikingly, I found that transcription activated through the SRB was unaffected and is therefore independent of nuclear calcium, requiring only an increase in cytoplasmic calcium. I have unearthed two calcium-activated signalling pathways that differed in their spatial requirements for calcium. This represents a significant conceptual, as well as technical, advance in the field of cell signalling, for it was the first time a single second messenger had been shown to exert differential effects, depending on its location in the cell.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available