Activation of PKC is required for arsenite-induced signal transduction.
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.
Chen
N Y
NY
The Hormel Institute, University of Minnesota, Austin 55912, USA.
Ma
W Y
WY
Huang
C
C
Ding
M
M
Dong
Z
Z
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D018053:Arsenites / Q000037:antagonists & inhibitors / Q000633:toxicity*; D001578:Benzopyrans / Q000494:pharmacology; D002273:Carcinogens / Q000633:toxicity*; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000378:metabolism; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D000098:Acetophenones; D018053:Arsenites; D001578:Benzopyrans; D002273:Carcinogens; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D018808:Transcription Factor AP-1; C085746:rottlerin; C497259:Prkcd protein, mouse; C497256:Prkce protein, mouse; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C015001:arsenite; D013110:Sphingosine; C005682:safingol