Persistent Link:
http://hdl.handle.net/10150/195775
Title:
A Novel Mechanism for UDCA-Induced Growth Suppression
Author:
Feldman, Rebecca A
Issue Date:
2008
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:
Bile acids have been studied for many years for their role in either promoting (Deoxycholic Acid) or suppressing (Ursodeoxycholic Acid) colon tumor development in animal models. However, the molecular mechanisms of both DCA's and UDCA's biological effects in colon tumorigenesis is still unclear. The cholesterol-like composition of bile acids and evidence of deregulating signal transduction pathways, such as the p42/44 MAP kinase cascade, led us to identify the plasma membrane as a target for bile acid-mediated effects. Specifically, plasma membrane microdomains such as lipid rafts and caveolae are particularly capable of altering mitogenic signaling due to have their role as platforms to concentrate receptors and assemble signal transduction machinery. In this study I tested the hypothesis that the growth suppressive effects of UDCA are mediated by stimulating membrane microdomains to activate protein degradation machinery to facilitate the down-regulation of receptor tyrosine kinase activity. We found that UDCA suppresses EGF-induced ERK activation, promotes interactions between EGFR and Caveolin-1 membrane fractions, whereas DCA causes redistribution. EGFR proteins that are localized to membrane fractions in the UDCA treated cells are extensively ubiquitinylated and we present evidence that this yields recruitment of the ubiquitin ligase c-Cbl to membrane fractions. UDCA increases the rate of EGFR degradation, whereas DCA sustains its' stability. I present evidence that UDCA's growth inhibitory effects on colon cancer cells may be mediated by recruitment of protein degradation machinery to membrane domains that are enriched with signaling receptors, a mechanism which has not been previously described. Importantly, I demonstrate for the first time a novel mechanism by which UDCA promotes growth inhibition, through increasing the rates of degradation of EGFR, thereby down-regulating mitogenic signaling in the cell. These experiments show exciting insights into the mechanism of bile acids and represent potential mechanisms for other chemopreventive agents.
Type:
text; Electronic Dissertation
Keywords:
bile acids; UDCA; Colon Cancer; Chemoprevention
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Cancer Biology; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
Martinez, Jesse D.

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleA Novel Mechanism for UDCA-Induced Growth Suppressionen_US
dc.creatorFeldman, Rebecca Aen_US
dc.contributor.authorFeldman, Rebecca Aen_US
dc.date.issued2008en_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.abstractBile acids have been studied for many years for their role in either promoting (Deoxycholic Acid) or suppressing (Ursodeoxycholic Acid) colon tumor development in animal models. However, the molecular mechanisms of both DCA's and UDCA's biological effects in colon tumorigenesis is still unclear. The cholesterol-like composition of bile acids and evidence of deregulating signal transduction pathways, such as the p42/44 MAP kinase cascade, led us to identify the plasma membrane as a target for bile acid-mediated effects. Specifically, plasma membrane microdomains such as lipid rafts and caveolae are particularly capable of altering mitogenic signaling due to have their role as platforms to concentrate receptors and assemble signal transduction machinery. In this study I tested the hypothesis that the growth suppressive effects of UDCA are mediated by stimulating membrane microdomains to activate protein degradation machinery to facilitate the down-regulation of receptor tyrosine kinase activity. We found that UDCA suppresses EGF-induced ERK activation, promotes interactions between EGFR and Caveolin-1 membrane fractions, whereas DCA causes redistribution. EGFR proteins that are localized to membrane fractions in the UDCA treated cells are extensively ubiquitinylated and we present evidence that this yields recruitment of the ubiquitin ligase c-Cbl to membrane fractions. UDCA increases the rate of EGFR degradation, whereas DCA sustains its' stability. I present evidence that UDCA's growth inhibitory effects on colon cancer cells may be mediated by recruitment of protein degradation machinery to membrane domains that are enriched with signaling receptors, a mechanism which has not been previously described. Importantly, I demonstrate for the first time a novel mechanism by which UDCA promotes growth inhibition, through increasing the rates of degradation of EGFR, thereby down-regulating mitogenic signaling in the cell. These experiments show exciting insights into the mechanism of bile acids and represent potential mechanisms for other chemopreventive agents.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectbile acidsen_US
dc.subjectUDCAen_US
dc.subjectColon Canceren_US
dc.subjectChemopreventionen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineCancer Biologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.chairMartinez, Jesse D.en_US
dc.contributor.committeememberMartinez, Jesse D.en_US
dc.contributor.committeememberBriehl, Margaret M.en_US
dc.contributor.committeememberBernstein, Harrisen_US
dc.contributor.committeememberBowden, George T.en_US
dc.contributor.committeememberMeuillet, Emmanuelle J.en_US
dc.identifier.proquest2857en_US
dc.identifier.oclc659749921en_US
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