The role of c-jun/AP-1 in cholecystokinin induced pancreatic acinar cell growth in vivo and in vitro.
dc.contributor.author | Guo, Lili | |
dc.contributor.advisor | Williams, John A. | |
dc.date.accessioned | 2016-08-30T16:23:58Z | |
dc.date.available | 2016-08-30T16:23:58Z | |
dc.date.issued | 2008 | |
dc.identifier.uri | http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3304973 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/127015 | |
dc.description.abstract | The hypothesis of this thesis is that early response genes, particular c jun/AP-1, play an important role in CCK induced acinar cell growth. Adaptive pancreatic growth in response to diet and hormones involves division of differentiated acinar cells. We modeled this type of pancreatic growth by feeding the trypsin inhibitor camostat to increase plasma CCK. Camostat feeding induced expression of seventeen pancreatic early response genes. The acinar cell nuclear localization of newly synthesized c-jun, c-fos and Egr-1 was confirmed by immunohistochemistry. Camostat feeding increased the activity of JNKs and ERKs as well as AP-1 DNA binding. This increased AP-1 DNA binding and c-jun induction were dramatically reduced by the CCK<sub>A</sub> receptor antagonist IQM-95,333 and in CCK deficient mice, indicating that these effects are mainly CCK dependent. Pancreatic regeneration during experimental pancreatitis involves dedifferentiation and proliferation of acinar cells. We used primary cultures of acinar cells on collagen to model this form of acinar cell growth, to evaluate the effect of CCK and to determine the signaling pathway activation in this proliferation of acinar cells. Monolayer cultured acinar cells displayed embryonic characteristics with a reduced expression of digestive enzymes and an increased expression of duct cell and embryonic marker genes after 4 days culture. Genes active in pancreatic precursor cells including pdx-1 and nestin were also increased. CCK enhanced cellular spreading and DNA synthesis. BrdU incorporation visualized by immunohistochemistry further confirmed DNA synthesis occurred in the progeny of the original acinar cells. Cyclin D1 expression increased during culture and was further upregulated by CCK. When signaling pathways were evaluated, CCK stimulation increased JNKs and ERKs activity, c-jun induction, AP-1 DNA binding and AP-1 reporter gene transactivation. Pharmacological inhibition of JNKs and ERKs, dominant negative JNK, dominant negative c-jun, and siRNA targeting c-jun, dramatically inhibited CCK induced acinar cell thymidine incorporation. Dominant negative c-jun also inhibited CCK induced AP-1 transactivation and cyclin D1 expression. Furthermore, dominant negative c-jun reduced the dedifferentiation of acinar cells. In conclusion, we have confirmed through in vivo and in vitro studies that c-jun/AP-1 plays an essential role in two types of CCK induced acinar cell growth. | |
dc.format.extent | 179 p. | |
dc.language | English | |
dc.language.iso | EN | |
dc.subject | Ap-1 | |
dc.subject | C-jun | |
dc.subject | Cell | |
dc.subject | Cholecystokinin | |
dc.subject | Growth | |
dc.subject | Induced | |
dc.subject | Mapk | |
dc.subject | Pancreatic Acinar Cells | |
dc.subject | Role | |
dc.subject | Vitro | |
dc.subject | Vivo | |
dc.title | The role of c-jun/AP-1 in cholecystokinin induced pancreatic acinar cell growth in vivo and in vitro. | |
dc.type | Thesis | |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Animal Physiology | |
dc.description.thesisdegreediscipline | Biological Sciences | |
dc.description.thesisdegreediscipline | Cellular biology | |
dc.description.thesisdegreediscipline | Molecular biology | |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/127015/2/3304973.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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