Abstract
The role of the PI 3-kinase signaling pathway in UVB-induced c-fos gene expression was investigated in a human keratinocyte cell line, HaCaT. The enzymatic activity of PI 3-kinase was increased threefold by 250 J/m(2) UVB. Inhibition of PI 3-kinase activity, via expression of a mutant p85 subunit or treatment with wortmannin, resulted in decreased levels of c-fos promoter activity and c-fos protein. Two members of the PI 3-kinase signaling pathway, Akt and GSK-3beta, were also found to affect c-fos transactivation. Expression of dominant negative Akt or wild-type GSK-3beta significantly inhibited UVB-induced c-fos promoter activity. In addition, when GSK-3beta activity was inhibited by lithium chloride, both c-fos promoter activity and protein levels increased. These results demonstrate that both Akt activation and GSK-3beta inactivation are required in the UVB-induction of c-fos. Our results demonstrate for the first time that UVB induction of c-fos is in part mediated by the PI 3-kinase signaling pathway in the HaCaT cell line. By identifying the multiple signaling pathways that are induced by UVB and contribute to the induction of c-fos expression, more drug targets may be identified to aid attempts to prevent and treat skin cancer.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Androstadienes / pharmacology
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Anti-Inflammatory Agents / pharmacology
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Blotting, Western
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cell Line
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DNA Primers / chemistry
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Electrophoretic Mobility Shift Assay
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Glycogen Synthase Kinase 3
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Humans
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Keratinocytes / metabolism
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Keratinocytes / radiation effects*
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Lithium Chloride / pharmacology
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Phosphatidylinositol 3-Kinases / physiology*
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Phosphoinositide-3 Kinase Inhibitors
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-fos / antagonists & inhibitors
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Proto-Oncogene Proteins c-fos / metabolism*
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Signal Transduction / physiology
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Transfection
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Ultraviolet Rays
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Wortmannin
Substances
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Androstadienes
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Anti-Inflammatory Agents
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DNA Primers
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-fos
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Calcium-Calmodulin-Dependent Protein Kinases
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Glycogen Synthase Kinase 3
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Lithium Chloride
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Wortmannin