Protein kinase C signal transduction in liver cell proliferation following partial hepatectomy.

Persistent Link:
http://hdl.handle.net/10150/186650
Title:
Protein kinase C signal transduction in liver cell proliferation following partial hepatectomy.
Author:
Daller, John Alfons.
Issue Date:
1994
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Following partial hepatectomy, a complex series of biochemical and molecular events culminate in hepatocyte proliferation. These events proceed through a number of signal transduction mechanisms, including protein kinase C. The hypothesis of this research project was that the mitogenic signals induced by partial hepatectomy are transduced through protein kinase C activation and that this mechanism is an integral component of the signal transduction pathways culminating in hepatocyte proliferation. After preliminary toxicologic evaluation, we employed nontoxic doses of suramin, a relatively specific protein kinase C inhibitor, to abrogate the proliferative response following partial hepatectomy. Administered as a single intraperitoneal injection fourteen days prior to operation, suramin caused a significant dose-dependent decrease in liver cell proliferation as quantitated by thymidine kinase activity, radiolabelled thymidine incorporation and mitotic indices. Furthermore, suramin inhibited protein kinase C as enzyme activation was nearly abolished in liver particulate fractions of animals which had received 160 mg/kg body weight of the drug; however, diacylglycerol generation was unaffected. This suggests that the observed inhibition was due to a direct effect on protein kinase C rather than an indirect effect mediated by blockade of growth factor ligand-receptor interaction and consequent inhibition of diacylglycerol generation. When administered two hours prior to partial hepatectomy to minimize intracellular accumulation, suramin inhibited the regenerative response in six-week-old animals by nearly 50%, while having no effect on three-week-old rats, suggesting disparate mechanisms of regulation. Interestingly, three-week-old control animals exhibited a 1.6-fold greater degree of thymidine incorporation than 6-week-old control rats. In vitro analysis using a rat brain cytosol enzyme preparation showed that suramin has a biphasic effect on protein kinase C activity; low doses (10 μM) resulted in a nearly six-fold increase in enzyme activity while suramin concentrations greater than 60 μM caused inhibition of activity. Finally, protein kinase M, the constitutively active, catalytic domain of protein kinase C, also exhibited temporal alterations following partial hepatectomy. These results suggest that protein kinase C and, perhaps protein kinase M, are central to the initiation and/or regulation of hepatocyte proliferation following partial hepatectomy.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Dissertations, Academic.; Pharmacology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmacology and Toxicology; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
Putnam, Charles W.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleProtein kinase C signal transduction in liver cell proliferation following partial hepatectomy.en_US
dc.creatorDaller, John Alfons.en_US
dc.contributor.authorDaller, John Alfons.en_US
dc.date.issued1994en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractFollowing partial hepatectomy, a complex series of biochemical and molecular events culminate in hepatocyte proliferation. These events proceed through a number of signal transduction mechanisms, including protein kinase C. The hypothesis of this research project was that the mitogenic signals induced by partial hepatectomy are transduced through protein kinase C activation and that this mechanism is an integral component of the signal transduction pathways culminating in hepatocyte proliferation. After preliminary toxicologic evaluation, we employed nontoxic doses of suramin, a relatively specific protein kinase C inhibitor, to abrogate the proliferative response following partial hepatectomy. Administered as a single intraperitoneal injection fourteen days prior to operation, suramin caused a significant dose-dependent decrease in liver cell proliferation as quantitated by thymidine kinase activity, radiolabelled thymidine incorporation and mitotic indices. Furthermore, suramin inhibited protein kinase C as enzyme activation was nearly abolished in liver particulate fractions of animals which had received 160 mg/kg body weight of the drug; however, diacylglycerol generation was unaffected. This suggests that the observed inhibition was due to a direct effect on protein kinase C rather than an indirect effect mediated by blockade of growth factor ligand-receptor interaction and consequent inhibition of diacylglycerol generation. When administered two hours prior to partial hepatectomy to minimize intracellular accumulation, suramin inhibited the regenerative response in six-week-old animals by nearly 50%, while having no effect on three-week-old rats, suggesting disparate mechanisms of regulation. Interestingly, three-week-old control animals exhibited a 1.6-fold greater degree of thymidine incorporation than 6-week-old control rats. In vitro analysis using a rat brain cytosol enzyme preparation showed that suramin has a biphasic effect on protein kinase C activity; low doses (10 μM) resulted in a nearly six-fold increase in enzyme activity while suramin concentrations greater than 60 μM caused inhibition of activity. Finally, protein kinase M, the constitutively active, catalytic domain of protein kinase C, also exhibited temporal alterations following partial hepatectomy. These results suggest that protein kinase C and, perhaps protein kinase M, are central to the initiation and/or regulation of hepatocyte proliferation following partial hepatectomy.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectDissertations, Academic.en_US
dc.subjectPharmacology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmacology and Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.chairPutnam, Charles W.en_US
dc.contributor.committeememberBrendel, Klausen_US
dc.contributor.committeememberSipes, I. Glennen_US
dc.contributor.committeememberHendrix, Mary J.C.en_US
dc.contributor.committeememberPalmer, Johnen_US
dc.identifier.proquest9424982en_US
dc.identifier.oclc722837073en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.