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Title: Regulation of cholecystokinin receptor 2 (CCK2R) expression
Author: Ashurst, Helen Louise
ISNI:       0000 0001 3430 6209
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2007
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The CCK2 receptor (CCK2R) mediates the physiological functions of gastrin in the stomach including stimulation of acid secretion and cellular proliferation and migration, but little is known about the factors that regulate its expression. The current study identified endogenous CCK2R expression in several cell lines and used luciferase promoter-reporter constructs to define the minimal promoter required for CCK2R transcription in human gastric adenocarcinoma derived, AGS, and rat gastric mucosa derived, RGM-I, cells. Consensus binding sites for SPI, CIEBPP and GATA within the -196bp proximal promoter were for activity. CCK2R transcription was also increased in AGS-GR and RGM-I cells by gastrin through mechanisms partly dependent upon PKC and MEK. Gastrin significantly increased endogenous CCK2R mRNA and protein expression in RGM-I cells and CCK2R protein expression was elevated in the stomach of hypergastrinaemic animals and decreased in the stomach of gastrin knockout mice. Following serum withdrawal from RGM-I and AR42J cells, endogenous CCK2R mRNA abundance and activity of a CCK2R promoter-reporter construct were significantly elevated. Additionally, following scratch wounding of RGM-I cells there was time dependent increases in CCK2R expression at the leading wound edge. These data suggest that the CCK2R can be regulated by cellular stress or damage in vitro. To study this phenomenon in vivo cryoulcers were generated in the acid secreting mucosa of C57BL/6 mice. CCK2R expression increased progressively In the regenerating mucosa adjacent to the ulcer repair margin, evident at six days post injury and maximal at 13 days. De novo expression of CCK2R was observed in the submucosa beneath the repairing ulcer crater 6-9 days post injury. Many of the cells in mucosa and submucosa that expressed CCK2R in response to cryoinjury were identified as myofibroblasts since they co-expressed vimentin and smooth muscle actin bu~ not desmin. Additionally, in human antral erosions there was increased CCK2R expression compared to non~al antral tissue. Many of the CCK2R expressing cells were identified as myofibroblasts. The in vivo data from these two lines of evidence suggests that increased CCK2R expression might be important in influencing the outcome of epithelial inflammation or injury and that the response may be mediated in part by direct stimulation of myofibroblasts by gastrin.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available