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Title: Gonadotropin-releasing hormone targets Wnt signalling
Author: Gardner, Samantha
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2008
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This thesis describes a potential mechanism by which GnRH promotes the nuclear accumulation of β-catenin, activation of TCF-dependent transcription and up-regulation of Wnt target genes, c-Jun, Fra-1, Cyclin D1 and c-Mye. GnRH-induced nuclear accumulation of β-catenin and activation of β-catenin/TCF-dependent transcription was found to be dependent on a pathway utilising Gq-Phospholipase C (PLC)-Diacylglycerol (DAG)/Protein kinase C (PKC), and was found to be specifically dependent on the PKC δ isoform. GnRH was found to mediate the inactivation of Glycogen Synthase Kinase-3 (GSK-3), a protein serine/threonine kinase that regulates β-catenin degradation within the canonical Wnt signalling pathway. These results were observed in HEK293/GnRH receptor expressing cells and have been recapitulated in LβT2 and αT3-1 mouse gonadotrope cells, and then extended to various peripheral cell lines, sub-cultured prostate cells and whole prostate organ cultures. A potential mechanism of non-canonical Wnt/Ca2+ pathway activation by GnRH is described. GnRH was found to activate NFAT, a potential effecter of the non-canonical Wnt/Ca2+ pathway. GnRH-induced NFAT activation was found to be dependent on important mediators of the non-classical Wnt/Ca2+ pathway, including Gq, Ca2+, Calcineurin and PKC δ.  Intriguingly, by expression of a dominant negative TCF construct, GnRH-induced NFAT activation was found to be TCF-dependent, thereby implicating TCF in targeting both Wnt/β-catenin and Wnt/Ca2+ signalling. This novel finding suggests that a TCF-NFAT interaction may exist that functions either, to inhibit β-catenin/TCF-dependent transcription through competition for nuclear TCF, or to synergistically regulate TCF- and NFAT-target gene expression.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available