Membrane Perturbation By Bile Acids and Their Potential Role in Signaling

Persistent Link:
http://hdl.handle.net/10150/193551
Title:
Membrane Perturbation By Bile Acids and Their Potential Role in Signaling
Author:
Jean-Louis, Samira
Issue Date:
2005
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:
Secondary bile acids have long been postulated to be tumor promoters in the colon but their mechanism of action are yet to be delineated. Though most bile acids are chemically similar, they have been found to exert contrasting signaling effects in the colonic epithelium. Particularly, hydrophobic bile acids such as deoxycholic acid (DCA) are found to be tumor promoters while their hydrophilic counterparts such as ursodeoxycholic acid (UDCA) are chemopreventive. Given the fact that colon cells do not possess bile acid transporters, the question that arises is how do bile acids activate intracellular signaling? In our studies, we examined the actions of bile acids at the cell membrane and found that hydrophobic bile acids can perturb membrane structure. This membrane perturbation was found to be characterized by a change in membrane fluidity and by cholesterol aggregation. Additionally, several membrane associated proteins were found to be deregulated in response to DCA further supporting the above conclusion regarding membrane perturbation. Moreover, caveolin, a negative regulator of membrane microdomains was seen to be dephosphorylated and disassociated from the membrane microdomains, implicating membrane microdomains as a possible target of the effects of DCA on the membrane. Consistent with this, we found that DCA was able to cause rapid and sustained activation of the receptor tyrosine kinase, EGFR and that this activation was ligand-independent. Using fluorescent-tagged bile acids we showed increased aggregation and clustering in the membranes treated with FITC-DCA in a manner that was reminiscent of receptor activation in immune cells. Collectively, these data suggest that bile-acid induced signaling is likely to be initiated through alterations of the plasma membrane structure in colon cancer cells.
Type:
text; Electronic Dissertation
Keywords:
Bile Acid; DCA; Membrane Perturbation; Cholesterol; EGFR; Signaling
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Cancer Biology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Martinez, Jesse D.
Committee Chair:
Martinez, Jesse D.

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleMembrane Perturbation By Bile Acids and Their Potential Role in Signalingen_US
dc.creatorJean-Louis, Samiraen_US
dc.contributor.authorJean-Louis, Samiraen_US
dc.date.issued2005en_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.abstractSecondary bile acids have long been postulated to be tumor promoters in the colon but their mechanism of action are yet to be delineated. Though most bile acids are chemically similar, they have been found to exert contrasting signaling effects in the colonic epithelium. Particularly, hydrophobic bile acids such as deoxycholic acid (DCA) are found to be tumor promoters while their hydrophilic counterparts such as ursodeoxycholic acid (UDCA) are chemopreventive. Given the fact that colon cells do not possess bile acid transporters, the question that arises is how do bile acids activate intracellular signaling? In our studies, we examined the actions of bile acids at the cell membrane and found that hydrophobic bile acids can perturb membrane structure. This membrane perturbation was found to be characterized by a change in membrane fluidity and by cholesterol aggregation. Additionally, several membrane associated proteins were found to be deregulated in response to DCA further supporting the above conclusion regarding membrane perturbation. Moreover, caveolin, a negative regulator of membrane microdomains was seen to be dephosphorylated and disassociated from the membrane microdomains, implicating membrane microdomains as a possible target of the effects of DCA on the membrane. Consistent with this, we found that DCA was able to cause rapid and sustained activation of the receptor tyrosine kinase, EGFR and that this activation was ligand-independent. Using fluorescent-tagged bile acids we showed increased aggregation and clustering in the membranes treated with FITC-DCA in a manner that was reminiscent of receptor activation in immune cells. Collectively, these data suggest that bile-acid induced signaling is likely to be initiated through alterations of the plasma membrane structure in colon cancer cells.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectBile Aciden_US
dc.subjectDCAen_US
dc.subjectMembrane Perturbationen_US
dc.subjectCholesterolen_US
dc.subjectEGFRen_US
dc.subjectSignalingen_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.advisorMartinez, Jesse D.en_US
dc.contributor.chairMartinez, Jesse D.en_US
dc.contributor.committeememberWilson, Jeanen_US
dc.contributor.committeememberNelson, Marken_US
dc.contributor.committeememberPayne, Claireen_US
dc.contributor.committeememberMeuillet, Emmanuelleen_US
dc.contributor.committeememberErickson, Roberten_US
dc.identifier.proquest1471en_US
dc.identifier.oclc137356920en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.