Molecular mechanisms of ultraviolet-B induced activator protein 1 activation in human keratinocytes

Persistent Link:
http://hdl.handle.net/10150/284003
Title:
Molecular mechanisms of ultraviolet-B induced activator protein 1 activation in human keratinocytes
Author:
Chen, Weixing
Issue Date:
1999
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:
Ultraviolet-B (UVB) irradiation is a major cause of human non-melanoma skin cancer. Transcription factor activator protein-1 (AP-1) plays an important role in tumor promotion. The mechanism of UVB induced tumor promotion may be through AP-1 activation. In this dissertation, the molecular mechanisms of UVB induced AP-1 activation were pursued in a human keratinocyte cell line, HaCaT. UVB induced AP-1 activation was observed by gel shift assays and transactivation assays. c-Fos and Jun D were the main components of the bound AP-1 complexes. Inhibition of RNA and protein synthesis significantly abrogated UVB induced AP-1 DNA binding. Further investigation revealed a correlation between increased AP-1 activity and c-fos gene expression after UVB. These results suggested that increased c-fos expression may play an important role in UVB induced AP-1 activation. To further examine the mechanism of UVB induced c-fos expression, the UVB signaling pathways were studied. Two members of mitogen-activated protein kinase (MAPK) family, p38 and extracellular signal-regulated protein kinase (ERK), were activated after UVB. Blocking p38 significantly abrogated UVB induced c-fos expression. Inhibiting ERK partially abrogated UVB induced c-fos expression. These data suggested that both p38 and ERK were required in UVB induced c-fos expression in human keratinocytes. Furthermore, p38 appeared to play a more important role than ERK in this process. Since c-fos expression may play an important role in UVB induced AP-1 activation, and AP-1 activation is known to play a role in tumor promotion, both p38 and ERK could be potential targets for chemoprevention of skin cancer. (-)-Epigallocatechin gallate (EGCG), the major polyphenol isolated from green tea, has been shown to inhibit UVB induced tumorigenesis. However, the mechanisms that underline the inhibitory effects of EGCG are not well understood. In this study, EGCG was found to inhibit UVB induced AP-1 transactivation and c-fos expression. Furthermore, EGCG inhibited UVB induced p38 activation. Thus, suppression of p38 signaling cascade was the mechanism of EGCG's inhibitory effect on UVB induced c-fos expression, which may further explain its inhibitory effect on UVB induced AP-1 activation.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Biology, Molecular.; Health Sciences, Radiology.; Health Sciences, Oncology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Cancer Biology
Degree Grantor:
University of Arizona
Advisor:
Bowden, G. Tim

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleMolecular mechanisms of ultraviolet-B induced activator protein 1 activation in human keratinocytesen_US
dc.creatorChen, Weixingen_US
dc.contributor.authorChen, Weixingen_US
dc.date.issued1999en_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.abstractUltraviolet-B (UVB) irradiation is a major cause of human non-melanoma skin cancer. Transcription factor activator protein-1 (AP-1) plays an important role in tumor promotion. The mechanism of UVB induced tumor promotion may be through AP-1 activation. In this dissertation, the molecular mechanisms of UVB induced AP-1 activation were pursued in a human keratinocyte cell line, HaCaT. UVB induced AP-1 activation was observed by gel shift assays and transactivation assays. c-Fos and Jun D were the main components of the bound AP-1 complexes. Inhibition of RNA and protein synthesis significantly abrogated UVB induced AP-1 DNA binding. Further investigation revealed a correlation between increased AP-1 activity and c-fos gene expression after UVB. These results suggested that increased c-fos expression may play an important role in UVB induced AP-1 activation. To further examine the mechanism of UVB induced c-fos expression, the UVB signaling pathways were studied. Two members of mitogen-activated protein kinase (MAPK) family, p38 and extracellular signal-regulated protein kinase (ERK), were activated after UVB. Blocking p38 significantly abrogated UVB induced c-fos expression. Inhibiting ERK partially abrogated UVB induced c-fos expression. These data suggested that both p38 and ERK were required in UVB induced c-fos expression in human keratinocytes. Furthermore, p38 appeared to play a more important role than ERK in this process. Since c-fos expression may play an important role in UVB induced AP-1 activation, and AP-1 activation is known to play a role in tumor promotion, both p38 and ERK could be potential targets for chemoprevention of skin cancer. (-)-Epigallocatechin gallate (EGCG), the major polyphenol isolated from green tea, has been shown to inhibit UVB induced tumorigenesis. However, the mechanisms that underline the inhibitory effects of EGCG are not well understood. In this study, EGCG was found to inhibit UVB induced AP-1 transactivation and c-fos expression. Furthermore, EGCG inhibited UVB induced p38 activation. Thus, suppression of p38 signaling cascade was the mechanism of EGCG's inhibitory effect on UVB induced c-fos expression, which may further explain its inhibitory effect on UVB induced AP-1 activation.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectBiology, Molecular.en_US
dc.subjectHealth Sciences, Radiology.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.advisorBowden, G. Timen_US
dc.identifier.proquest9957944en_US
dc.identifier.bibrecord.b40137557en_US
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