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Title: Jagged shedding : elucidating the biochemical mechanisms and its physiological relevance in prostate cancer
Author: Parr-Sturgess, Catherine
Awarding Body: Lancaster University
Current Institution: Lancaster University
Date of Award: 2011
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Notch signalling is an ancient and highly conserved pathway responsible for many cell fate determinations. Like the Notch receptor, its ligand, Jagged1, undergoes regulated intramembrane proteolysis (RIP) to yield a soluble extracellular ectodomain and an intracellular domain capable of regulating gene transcription. Increased Jagged1 expression has previously been linked with the pathogenesis of a range of cancers, in particular prostate cancer; the most commonly diagnosed cancer in males in the UK. However, whilst a role for the Jagged1 holoprotein in cancer pathogenesis is clear, nothing is known of the role played by Jagged1 RIP and its proteolytic fragments in the disease. The aim of the current study was to characterise the mechanisms and enzymes involved in Jagged1 proteolysis and the role played by this phenomenon in prostate cancer. The results demonstrated that Jagged1 was constitutively cleaved by the zinc metalloproteinase, ADAM-17, in a manner independent of cholesterol-rich lipid rafts and of the former protein's cytosolic domain. Furthermore, the investigation showed that Jagged1 proteolysis was regulated by the divalent metal copper, possibly by the activation of an ADAM distinct from ADAM-17. In addition, the shed form of Jagged 1 enhanced the proliferation of a prostate cancer cell line. Finally, a model system was developed for the purification of the Jagged1 C-terminal fragment with a view, ultimately, to sequencing the N-terminal residues of this fragment thereby identifying the ADAM-17 cleavage site. Collectively, these studies provide a detailed mechanistic insight into the RIP of Jaggedl and lay the foundations for future work aimed at resolving the exact roles of copper, the Jaggedl ectodomain and the protein's soluble intracellular domain in the pathogenesis and metastasis of prostate cancer
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available