Phorbol 12-myristate 13-acetate inhibits death receptor-mediated apoptosis in Jurkat cells by disrupting recruitment of Fas-associated polypeptide with death domain.
Regulation of death receptor-mediated apoptosis is incompletely understood. Previous studies have demonstrated that phorbol 12-myristate 13-acetate (PMA), a protein kinase C activator, inhibits Fas (CD95)-mediated apoptosis in Jurkat (type II) cells but not SKW6.4 (type I) cells. In this study, we demonstrated that PMA also protects Jurkat cells from apoptosis induced by tumor necrosis factor-alpha and the tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL). Interestingly, PMA failed to protect Jurkat cells from apoptosis induced by other agents, including etoposide, camptothecin, and gamma-irradiation. Analysis of the initial events induced by agonistic anti-Fas antibodies revealed that PMA inhibited Fas binding to Fas-associated polypeptide with death domain (FADD) in Jurkat cells but not in SKW6.4 cells. Although the protein kinase inhibitor bisindoylmaleimide VIII increased apoptosis induced by agonistic anti-Fas antibody, tumor necrosis factor-alpha, and TRAIL, these effects were not observed with the protein kinase C inhibitor H7 and were not associated with increased FADD recruitment to Fas. These results indicate that PMA inhibits death signaling induced by a number of discrete receptors and suggest that the effects are mediated at the level of receptor-mediated adaptor molecule recruitment.
Meng
Xue Wei
XW
Division of Oncology Research, Department of Molecular Pharmacology, Mayo Clinic, Mayo Graduate School, Rochester, Minnesota 55905, USA.
Heldebrant
Michael P
MP
Kaufmann
Scott H
SH
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD / Q000187:drug effects / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D002166:Camptothecin / Q000633:toxicity; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D005047:Etoposide / Q000633:toxicity; D053200:Fas-Associated Death Domain Protein; D005720:Gamma Rays; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors*; D053221:TNF-Related Apoptosis-Inducing Ligand; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000187:drug effects / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D018841:HSP90 Heat-Shock Proteins; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D005047:Etoposide; D003513:Cycloheximide; D013755:Tetradecanoylphorbol Acetate; D002166:Camptothecin