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    Identification of molecular targets for the chemoprevention of non-melanoma skin cancer

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    Author
    Bachelor, Michael A.
    Issue Date
    2004
    Keywords
    Biology, Molecular.
    Health Sciences, Oncology.
    Advisor
    Bowden, G. Timothy
    
    Metadata
    Show full item record
    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 ultraviolet (UV) component of sunlight has been identified as a major etiological factor in the development of non-melanoma skin cancer (NMSC). Upregulation of Activator Protein-1 (AP-1) and Cyclooxygenase-2 (COX-2) have clearly demonstrated a functional role in skin tumor promotion. The goal of this work was to contribute to the growing knowledge of UVA and UVB induced signaling events leading to increases in AP-1 and COX-2. We show that UVA induces COX-2 expression in the human keratinocyte cell line, HaCaT through a post-transcriptional mechanism involving the 3 ' untranslated region (3'UTR). Use of a pharmacological inhibitor of p38 MAPK, SB202190, decreased UVA-induced COX-2 steady-state mRNA and protein levels. The stability of COX-2 mRNA is increased in UVA-irradiated cells and dependent upon p38 MAPK activity. We further explored the role of UVA-induced p38 MAPK activity in apoptosis in both HaCaT cells and primary keratinocytes. Dramatic increases in apoptosis were observed in UVA-irradiated cells treated with SB202190 or through the use of a dominant-negative construct. UVA induced expression of Bcl-X L with abrogation of expression using SB202190. Overexpression of Bcl-X L prevented PARP (Poly ADP-ribose Polymerase) cleavage induced by the combination of UVA and p38 MAPK inhibition. We further demonstrated that UVA enhanced the stability of Bcl-XL mRNA through increases in p38 MAPK activity mediated through the 3' UTR. p38 MAPK and Bcl-XL expression play critical roles in the survival of UVA-irradiated keratinocytes. Previous investigations from the laboratory identified p38 MAPK and PI3-Kinase as the major mediators of UVB-induced AP-1 and COX-2 in the HaCaT cell line. To further validate p38 MAPK and PI3-Kinase as potential molecular targets we investigated whether an acute UVB dose activated the p38 MAPK and PI3-Kinase pathways in vivo. We observed rapid increases in both p38 MAPK and PI3-Kinase signaling in mouse epidermis. Activation of these pathways resulted in the phosphorylation of cyclic AMP response element binding protein (CREB). Topical treatment with SB202190 or LY294002 (a specific inhibitor of PI3-Kinase) significantly decreased UVB-induced COX-2 expression and AP-1 activation in vivo. Our data suggest that p38 MAPK and PI3-Kinase may serve as significant molecular targets for the chemoprevention of UVB-induced NMSC.
    Type
    text
    Dissertation-Reproduction (electronic)
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Cancer Biology
    Degree Grantor
    University of Arizona
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