Heat stress downregulates FLIP and sensitizes cells to Fas receptor-mediated apoptosis.
The heat shock response and death receptor-mediated apoptosis are both key physiological determinants of cell survival. We found that exposure to a mild heat stress rapidly sensitized Jurkat and HeLa cells to Fas-mediated apoptosis. We further demonstrate that Hsp70 and the mitogen-activated protein kinases, critical molecules involved in both stress-associated and apoptotic responses, are not responsible for the sensitization. Instead, heat stress on its own induced downregulation of FLIP and promoted caspase-8 cleavage without triggering cell death, which might be the cause of the observed sensitization. Since caspase-9 and -3 were not cleaved after heat shock, caspase-8 seemed to be the initial caspase activated in the process. These findings could help understanding the regulation of death receptor signaling during stress, fever, or inflammation.
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000032:analysis / Q000502:physiology*; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D053418:Death Domain Receptor Signaling Adaptor Proteins; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000502:physiology*; D006358:Hot Temperature; D006801:Humans; D007075:Immunoglobulin M / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D008164:Luminescent Proteins / Q000235:genetics; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System / Q000502:physiology; D008562:Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D008859:Microscopy, Polarization; D008928:Mitochondria / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D014157:Transcription Factors; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D000590:Amino Acid Chloromethyl Ketones; D017304:Annexin A5; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D007075:Immunoglobulin M; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D016755:Proto-Oncogene Proteins c-jun; D018124:Receptors, Tumor Necrosis Factor; D014157:Transcription Factors; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; C425644:isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; D049452:Green Fluorescent Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases