Molecular mechanisms that mediate UVB-inducedc-Fos expression in a human keratinocyte cell line

Persistent Link:
http://hdl.handle.net/10150/280037
Title:
Molecular mechanisms that mediate UVB-inducedc-Fos expression in a human keratinocyte cell line
Author:
Gonzales, Melissa
Issue Date:
2002
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:
The UVB portion (280--320 nm) of the ultraviolet spectrum contributes to the development of non-melanoma skin cancer (NMSC) in humans. UVB irradiation causes epigenetic alterations in target keratinocytes, including the upregulation of Activator Protein-1, a transcription factor complex that alters normal cellular gene expression. c-Fos expression is induced in a manner that correlates with the UVB-induced activation of AP-1. This suggests that c-Fos functions as a major regulatory component in the UVB-induced transactivation of AP-1. The purpose of this dissertation is to characterize UVB-induced regulation of c-Fos expression. Transcriptional regulation of c-fos is investigated by evaluating the role of each of four cis elements within the c-fos promoter. While mutation of each of these four cis elements results in significantly lower levels of UVB-induced promoter activity, the CRE and FAP1 elements mediate most of the UVB transactivation of c-fos. In addition, UVB irradiation induces homodimers of phosphorylated CREB to bind to the CRE and FAP1 elements. To identify cellular signal transduction pathways that are induced by UVB-irradiation to regulate c-Fos expression, a UVB-inducible enzyme, phosphatidylinositol 3-kinase (PI 3-kinase), is studied. Inhibition of PI 3-kinase reduces c-Fos expression in UVB-irradiated cells. Akt and GSK-3beta, constituents of the PI 3-kinase signaling pathway, are also found to be part of this UVB-induced signaling pathway. To identify potential molecular targets for the development of skin cancer chemoprevention strategies, the polyphenolic compound nordihydroguaiaretic acid is tested and found to prevent UVB-induced c-Fos expression and AP-1 transactivation by inhibiting the PI 3-kinase signal transduction pathway. Thus, phospho-CREB binding to the CRE and FAP1 cis elements and PI 3-kinase signaling are both identified as molecular mechanisms and potential molecular targets that are involved in UVB-induced c-Fos expression and AP-1 transactivation.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Biology, Molecular.; Biology, Cell.; Health Sciences, Oncology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Biochemistry and Molecular and Cellular Biology
Degree Grantor:
University of Arizona
Advisor:
Bowden, G. Tim

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleMolecular mechanisms that mediate UVB-inducedc-Fos expression in a human keratinocyte cell lineen_US
dc.creatorGonzales, Melissaen_US
dc.contributor.authorGonzales, Melissaen_US
dc.date.issued2002en_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.abstractThe UVB portion (280--320 nm) of the ultraviolet spectrum contributes to the development of non-melanoma skin cancer (NMSC) in humans. UVB irradiation causes epigenetic alterations in target keratinocytes, including the upregulation of Activator Protein-1, a transcription factor complex that alters normal cellular gene expression. c-Fos expression is induced in a manner that correlates with the UVB-induced activation of AP-1. This suggests that c-Fos functions as a major regulatory component in the UVB-induced transactivation of AP-1. The purpose of this dissertation is to characterize UVB-induced regulation of c-Fos expression. Transcriptional regulation of c-fos is investigated by evaluating the role of each of four cis elements within the c-fos promoter. While mutation of each of these four cis elements results in significantly lower levels of UVB-induced promoter activity, the CRE and FAP1 elements mediate most of the UVB transactivation of c-fos. In addition, UVB irradiation induces homodimers of phosphorylated CREB to bind to the CRE and FAP1 elements. To identify cellular signal transduction pathways that are induced by UVB-irradiation to regulate c-Fos expression, a UVB-inducible enzyme, phosphatidylinositol 3-kinase (PI 3-kinase), is studied. Inhibition of PI 3-kinase reduces c-Fos expression in UVB-irradiated cells. Akt and GSK-3beta, constituents of the PI 3-kinase signaling pathway, are also found to be part of this UVB-induced signaling pathway. To identify potential molecular targets for the development of skin cancer chemoprevention strategies, the polyphenolic compound nordihydroguaiaretic acid is tested and found to prevent UVB-induced c-Fos expression and AP-1 transactivation by inhibiting the PI 3-kinase signal transduction pathway. Thus, phospho-CREB binding to the CRE and FAP1 cis elements and PI 3-kinase signaling are both identified as molecular mechanisms and potential molecular targets that are involved in UVB-induced c-Fos expression and AP-1 transactivation.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectBiology, Molecular.en_US
dc.subjectBiology, Cell.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.disciplineBiochemistry and Molecular and Cellular Biologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorBowden, G. Timen_US
dc.identifier.proquest3053904en_US
dc.identifier.bibrecord.b42817870en_US
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