Abstract
Trivalent arsenic (arsenite) is a human carcinogen. However, the molecular mechanism of arsenite-induced carcinogenesis is still not well understood. In this study, we found that arsenite induced translocation of PKCepsilon, PKCdelta, and PKCalpha from cytosol to membranes. Rottlerin, a selective inhibitor for PKCdelta, and safingol, a specific inhibitor for PKCalpha, both markedly inhibited arsenite-induced AP-1 activity. These inhibitory effects by rottlerin and safingol appeared to be dose dependent. Arsenite-induced phosphorylation of Erks was inhibited by rottlerin, while safingol inhibited arsenite-induced phosphorylation of JNKs and p38 kinases. Dominant negative mutant transfectant of PKCepsilon markedly blocked arsenite-induced AP-1 activity and the phosphorylation of Erks, JNKs, and p38 kinases. These data demonstrate that PKCdelta, PKCepsilon, and PKCalpha mediate arsenite-induced AP-1 activation in JB6 cells through different MAP kinase (Erks, JNKs, and p38 kinases) pathways.
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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Acetophenones / pharmacology
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Animals
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Arsenites / antagonists & inhibitors
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Arsenites / toxicity*
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Benzopyrans / pharmacology
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Carcinogens / toxicity*
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Cell Membrane / enzymology
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Cells, Cultured
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Cytosol / enzymology
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Enzyme Activation
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Enzyme Activators / toxicity*
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Enzyme Inhibitors / pharmacology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / genetics
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Isoenzymes / metabolism
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Signaling System / drug effects*
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MAP Kinase Signaling System / physiology
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Mice
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Mutation
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / genetics
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Protein Kinase C / metabolism*
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Protein Kinase C-alpha
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Protein Kinase C-delta
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Protein Kinase C-epsilon
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Skin / cytology
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Skin / drug effects
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Skin / metabolism
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Sphingosine / analogs & derivatives
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Sphingosine / pharmacology
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Transcription Factor AP-1 / biosynthesis
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Transcription Factor AP-1 / metabolism
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Transfection
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p38 Mitogen-Activated Protein Kinases
Substances
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Acetophenones
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Arsenites
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Benzopyrans
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Carcinogens
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Enzyme Activators
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Enzyme Inhibitors
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Isoenzymes
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Transcription Factor AP-1
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rottlerin
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Prkcd protein, mouse
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Prkce protein, mouse
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Prkca protein, mouse
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Protein Kinase C
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Protein Kinase C-alpha
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Protein Kinase C-delta
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Protein Kinase C-epsilon
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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arsenite
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Sphingosine
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safingol