Abstract
To study the relationship between insulin-like growth factor-II (IGF-II) and 12-lipoxygenase (12-LOX) that are upregulated in psoriasis, we monitored 12-lipoxygenase expression in the insulin-like growth factor-II treated human keratinocytes and explored the signaling pathways of 12-lipoxygenase expression. Insulin-like growth factor-II induced 12-lipoxygenase mRNA and protein levels in human keratinocytes through two major signal transduction pathways, namely, the extracellular signaling-regulated kinase (ERK)-mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. The IGF-II-induced upregulation of 12-lipoxygenase was attenuated by pretreating the cells with selective inhibitors or by overexpressing dominant-negative MEK. In addition, treatment of HaCaT cells with the 12-lipoxygenase metabolite 12 (S)-hydroxyeicosatetraenoic acid (12(S)-HETE) directly stimulated DNA synthesis and mitogenesis, and injection of insulin-like growth factor-II into the skin of hairless mice induced epidermal hyperplasia. These results suggest that insulin-like growth factor-II is involved in the pathogenesis of psoriasis as a paracrine inducer of 12-lipoxygenase.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / pharmacology
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Animals
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Arachidonate 12-Lipoxygenase / genetics
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Arachidonate 12-Lipoxygenase / metabolism*
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Blotting, Northern
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Blotting, Western
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Cell Line
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Cell Line, Transformed
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Cell Proliferation / drug effects*
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Cell Survival / drug effects
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Chromones / pharmacology
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Dose-Response Relationship, Drug
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Flavonoids / pharmacology
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Gene Expression / drug effects
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Humans
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Insulin-Like Growth Factor II / pharmacology*
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Keratinocytes / cytology
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Keratinocytes / drug effects*
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Keratinocytes / metabolism
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Mice
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Mice, Hairless
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Morpholines / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
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Skin / drug effects
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Skin / metabolism
Substances
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Chromones
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Flavonoids
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-fos
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
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Insulin-Like Growth Factor II
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Arachidonate 12-Lipoxygenase
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Extracellular Signal-Regulated MAP Kinases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one