Molecular Mechanisms of Polyamine Metabolism Affecting Oncogenic Signaling

Persistent Link:
http://hdl.handle.net/10150/299021
Title:
Molecular Mechanisms of Polyamine Metabolism Affecting Oncogenic Signaling
Author:
Paz, Edwin Alfredo
Issue Date:
2013
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:
Eukaryotic cells tightly regulate metabolism in order to sustain normal processes. Dysregulation of cellular metabolism is associated with multiple diseases including cancer. Polyamine metabolism is a tightly regulated process that is co-opted by multiple cancers for selective growth advantages. Polyamines are small organic molecules with two or more amino groups attached, whose biosynthesis is initiated by ornithine decarboxylase (ODC). Although much is known regarding the effects of polyamine metabolism and ODC on cellular processes, little is known regarding the intracellular signaling events that are regulated by polyamines. Clinical studies demonstrated that the ODC inhibitor difluromethylornithine (DFMO) was an effective chemopreventative strategy causing a reduction of colon adenomas in patients with prior colon polyps. However, the molecular mechanisms leading to this reduction are unknown. This dissertation provides mechanistic insight into the biological roles of the polyamines and show that these amines are regulators of multiple non-coding RNAs involved in cellular responses including effects on the let-7 microRNA family. Moreover, the polyamine modified translation factor eIF5A is demonstrated to regulate the oncofetal factor LIN28. This work also indicates that polyamines regulate the mTOR pathway and suggests alternative signaling nodes for polyamine-mediated regulation of cellular processes. Overall, these findings support the notion that polyamines are oncometabolites that are targetable and serve as a promising approach to manipulate oncogenic signaling for cancer therapy.
Type:
text; Electronic Dissertation
Keywords:
DFMO; eIF5A; let-7; oncometabolite; polyamines; LIN28; Cancer Biology
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Cancer Biology
Degree Grantor:
University of Arizona
Advisor:
Gerner, Eugene; Thompson, Patricia

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleMolecular Mechanisms of Polyamine Metabolism Affecting Oncogenic Signalingen_US
dc.creatorPaz, Edwin Alfredoen_US
dc.contributor.authorPaz, Edwin Alfredoen_US
dc.date.issued2013-
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.abstractEukaryotic cells tightly regulate metabolism in order to sustain normal processes. Dysregulation of cellular metabolism is associated with multiple diseases including cancer. Polyamine metabolism is a tightly regulated process that is co-opted by multiple cancers for selective growth advantages. Polyamines are small organic molecules with two or more amino groups attached, whose biosynthesis is initiated by ornithine decarboxylase (ODC). Although much is known regarding the effects of polyamine metabolism and ODC on cellular processes, little is known regarding the intracellular signaling events that are regulated by polyamines. Clinical studies demonstrated that the ODC inhibitor difluromethylornithine (DFMO) was an effective chemopreventative strategy causing a reduction of colon adenomas in patients with prior colon polyps. However, the molecular mechanisms leading to this reduction are unknown. This dissertation provides mechanistic insight into the biological roles of the polyamines and show that these amines are regulators of multiple non-coding RNAs involved in cellular responses including effects on the let-7 microRNA family. Moreover, the polyamine modified translation factor eIF5A is demonstrated to regulate the oncofetal factor LIN28. This work also indicates that polyamines regulate the mTOR pathway and suggests alternative signaling nodes for polyamine-mediated regulation of cellular processes. Overall, these findings support the notion that polyamines are oncometabolites that are targetable and serve as a promising approach to manipulate oncogenic signaling for cancer therapy.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectDFMOen_US
dc.subjecteIF5Aen_US
dc.subjectlet-7en_US
dc.subjectoncometaboliteen_US
dc.subjectpolyaminesen_US
dc.subjectLIN28en_US
dc.subjectCancer Biologyen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineCancer Biologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorGerner, Eugeneen_US
dc.contributor.advisorThompson, Patriciaen_US
dc.contributor.committeememberDoetschman, Tomen_US
dc.contributor.committeememberMartinez, Jesse D.en_US
dc.contributor.committeememberGerner, Eugene W.en_US
dc.contributor.committeememberThompson, Patriciaen_US
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