Protein kinase C inhibits singlet oxygen-induced apoptosis by decreasing caspase-8 activation.
Although activation of protein kinase C (PKC) inhibits apoptosis induced by a variety of stimuli including singlet oxygen, the step at which PKC activation interferes with apoptotic signaling is not well defined. We have shown previously that caspase-8 and p38 mediate singlet oxygen-induced apoptosis in HL-60 cells. In this study, we investigated the influence of PKC on regulation of the caspase and p38 pathways initiated by singlet oxygen. Singlet oxygen induced Fas clustering and subsequent recruitment of FADD and caspase-8. Treatment of cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), a PKC activator, did not affect the binding of caspase-8 to the aggregated Fas. Surprisingly, under the same conditions PKC activation was still able to prevent singlet oxygen-induced activation of caspase-8 and block its downstream signaling events including cleavage of Bid and caspase-3, decrease in mitochondrial transmembrane potential and release of cytochrome c from mitochondria. Inhibition of PKC by GF109203 or H7 counteracted the TPA-mediated effects on the cleavage of caspases -3 and -8. However, neither activation nor inhibition of PKC affected p38 phosphorylation. These data indicate that PKC inhibits singlet oxygen-induced apoptosis by blocking activation of caspase-8.
Zhuang
S
S
Wellman Laboratories of Photomedicine, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114, USA.
Demirs
J T
JT
Kochevar
I E
IE
D017209:Apoptosis; D029681:Arabidopsis Proteins; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044943:Fatty Acid Desaturases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System; D008564:Membrane Potentials; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D019014:fas Receptor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D029681:Arabidopsis Proteins; D002352:Carrier Proteins; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D005419:Flavonoids; D008024:Ligands; D020033:Protein Isoforms; D019014:fas Receptor; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D013755:Tetradecanoylphorbol Acetate; D010100:Oxygen; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one