Persistent Link:
http://hdl.handle.net/10150/289937
Title:
Role of a chair-type G-quadruplex in c-mycregulation
Author:
Grand, Cory Lyle
Issue Date:
2003
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:
As the importance of developing anticancer agents specific to tumor cells grows, a need has arisen for new and better targets. It has been determined that, in addition to tumorigenic proteins and enzymes, DNA itself can be used to direct antitumor therapeutic agents. In recent years, the G-quadruplex DNA secondary structure has become of interest in terms of its use as a promising target in tumors. G-quadruplex DNA structures have been proposed to form in the promoter regions of a number of genes involved in cellular proliferation and tumorigenesis, including the proto-oncogene c-myc and many others. In this dissertation, the roles of a chair-type G-quadruplex structure in c-myc regulation and dysregulation, and its use as a target for antitumor agents, are investigated. It was found that such a structure very likely plays the part of a repressor of c-myc transcription, as its absence results in significant upregulation of this gene. Similarly, stabilization of this G-quadruplex with small molecules results in a reduction in c-myc expression, an activity lost when this structure can no longer form. It appears that this structure acts as a barrier to transcription factor binding, and Sp1 or an Sp1-like protein(s) may be the critical factor that is not permitted to bind when the quadruplex is present. Disruption of the G-quadruplex in the c-myc promoter, and subsequent upregulation of the gene, may play a role in the development of human tumors, possibly in the later stages of tumorigenesis, as mutations which abrogate quadruplex formation are found in patient tumor specimens and cultured tumor cells. Finally, a means of stabilizing the c-myc quadruplex with small molecules is developed using rational structure-based drug design, in order to take advantage of this repressor structure in a therapeutic context. Thus, there is elucidated a novel means of gene regulation heretofore unexplored, one that also represents a new frontier in anticancer drug design.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Biology, Molecular.; Health Sciences, Oncology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Cancer Biology
Degree Grantor:
University of Arizona
Advisor:
Hurley, Laurence H.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleRole of a chair-type G-quadruplex in c-mycregulationen_US
dc.creatorGrand, Cory Lyleen_US
dc.contributor.authorGrand, Cory Lyleen_US
dc.date.issued2003en_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.abstractAs the importance of developing anticancer agents specific to tumor cells grows, a need has arisen for new and better targets. It has been determined that, in addition to tumorigenic proteins and enzymes, DNA itself can be used to direct antitumor therapeutic agents. In recent years, the G-quadruplex DNA secondary structure has become of interest in terms of its use as a promising target in tumors. G-quadruplex DNA structures have been proposed to form in the promoter regions of a number of genes involved in cellular proliferation and tumorigenesis, including the proto-oncogene c-myc and many others. In this dissertation, the roles of a chair-type G-quadruplex structure in c-myc regulation and dysregulation, and its use as a target for antitumor agents, are investigated. It was found that such a structure very likely plays the part of a repressor of c-myc transcription, as its absence results in significant upregulation of this gene. Similarly, stabilization of this G-quadruplex with small molecules results in a reduction in c-myc expression, an activity lost when this structure can no longer form. It appears that this structure acts as a barrier to transcription factor binding, and Sp1 or an Sp1-like protein(s) may be the critical factor that is not permitted to bind when the quadruplex is present. Disruption of the G-quadruplex in the c-myc promoter, and subsequent upregulation of the gene, may play a role in the development of human tumors, possibly in the later stages of tumorigenesis, as mutations which abrogate quadruplex formation are found in patient tumor specimens and cultured tumor cells. Finally, a means of stabilizing the c-myc quadruplex with small molecules is developed using rational structure-based drug design, in order to take advantage of this repressor structure in a therapeutic context. Thus, there is elucidated a novel means of gene regulation heretofore unexplored, one that also represents a new frontier in anticancer drug design.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectBiology, Molecular.en_US
dc.subjectHealth Sciences, Oncology.en_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.advisorHurley, Laurence H.en_US
dc.identifier.proquest3106992en_US
dc.identifier.bibrecord.b44660418en_US
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