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Title: Protein kinase pathways involved in nutrient- and hormone-induced insulin gene transcriptions
Author: Wu, H.
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1999
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In this study we show that PDX1, a homeodomain transcription factor in pancreatic β-cell, binds to the promoter region of the human insulin gene in a glucose-or nutrient-responsive manner. Threshold concentrations of glucose or nutrients are necessary for the regulatory effects. Furthermore, we show that the metabolism of glucose or nutrients is required for glucose- or nutrient-induced PDX1 DNA-binding activity, while non-metabolisable nutrients, e.g. L-glucose, D-galactose, and 3-O-methyl-D-glucose, elicited no stimulation of PDX1 DNA-binding activity. However, 2-deoxy glucose, which undergoes phosphorylation but not further metabolism, was found to stimulate PDX1 DNA-binding activity. We also show that nutrient-induced PDX1 phosphorylation occurs through the activation of PI-3 kinase and p38 MAP kinase. The results revealed that PI-3 kinase is required for the regulation of PDX1 DNA-binding activity in human β cells. In addition, we have shown that the intracellular calcium concentration did not affect the cell signalling events involved in glucose-induced PDX1 DNA-binding. We have also observed that insulin induced PDX1 DNA-binding in a dose-dependent manner. This was completely inhibited by wortmannin and LY294002, the specific inhibitors of PI-3 kinases. Also, we have demonstrated that IGF-I can stimulate PDX1 DNA-binding activity in isolated human islets in a dose-dependent fashion. Interestingly, platelet-derived growth factor (PDGF), which also activates PI-3 kinase by binding to PDGF-receptor, did not significantly affect the PDX1 DNA-binding activity in isolated human islets. The study provided detailed evidence that demonstrated that transcription factor PDX1 binds to the human insulin promoter and triggers glucose-, nutrient-, and hormone-induced insulin gene transcription. Furthermore, the present study also provided evidence that glucose-induced PDX1-dependent insulin gene transcription was associated with a time-dependent responsive increase in insulin mRNA levels.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available