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Title: Mechanisms controlling calcium-activated transcription in neuronal cells
Author: Chawla, S.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1997
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This thesis describes the finding that changes in calcium concentration in different cellular compartments, the cytoplasm and the nucleus, activate transcription through different DNA regulatory elements in the promoter of the c-fos gene. Transcriptional activation following increases in nuclear calcium concentrations is mediated by the cAMP response element (CRE). A second signalling pathway activates transcription through the serum response element (SRE), is triggered by increases in cytoplasmic calcium and does not require an increase in nuclear calcium. I have also shown that c-fos transcriptional induction mediated through the SRE, is independent of ternary complex formation in AtT20 cells and primary hippocampal neurons. To further characterise nuclear calcium-dependent transcription of c-fos, I identified the transcription factors and coactivators. I showed that the CRE binding protein CREB can mediate a nuclear calcium-dependent response. It is well established that transcriptional activation by CREB requires its phosphorylation on serine 133. This phosphorylation event can occur independently of nuclear calcium transients, indicating that other regulatory steps are necessary for nuclear calcium dependent transcription. These may involve the CREB binding protein CBP. Recruitment of CBP by CREB phosphorylated on serine 133 is critical for CREB-mediated transcriptional responses, raising the possibility that a post-translational modification of CBP may represent a crucial regulatory step in calcium induced transcription. I have shown that the CBP protein when directly tethered to the promoter can confer calcium inducibility to a c-fos based reporter gene and CBP-mediated transcriptional activation requires nuclear calcium transients.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available