title: Autoamplification of apoptosis following ligation of CD95-L, TRAIL and TNF-alpha.
abstract: CD95-L, TNF-alpha and TRAIL are death-inducing ligands (DILs) which may signal apoptosis via crosslinking of their cognate receptors. The present study shows that treatment of cells with agonistic mAB alpha APO-1 (CD95), recombinant TRAIL or TNF-alpha leads to enhanced mRNA and protein expression of each DIL with concomitant death in target cells. Immunoprecipitation of CD95-L protein from supernatant as well as neutralizing antibodies suggest DIL proteins to be cooperatively acting mediators of these cytotoxic activity. Autoamplification of the death signal was blocked in cells with a defect in apoptosis signaling either due to a dysfunctional FADD molecule or to the failure to activate JNK/SAPKs. Phosphorylation and enhanced binding of cJun and ATF-2 to DIL promoters suggest JNK/SAPKs as activators of these transcription factors following death receptor triggering. In consequence, autocrine production of DILs allows the spread of death signals to sensitive target cells. Oncogene (2000) 19, 4255 - 4262
authors.affiliation: Division of Pediatric Oncology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Herr
authors.forename: C
authors.initials: C
authors.lastname: Posovszky
authors.forename: L D
authors.initials: LD
authors.lastname: Di Marzio
authors.forename: M G
authors.initials: MG
authors.lastname: Cifone
authors.forename: T
authors.initials: T
authors.lastname: Boehler
authors.forename: K M
authors.initials: KM
authors.lastname: Debatin
mesh_terms: D051698:Activating Transcription Factor 2; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D029681:Arabidopsis Proteins; D019898:Autocrine Communication / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D053222:Fas Ligand Protein; D044943:Fatty Acid Desaturases / Q000172:deficiency / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; D029681:Arabidopsis Proteins; D017362:Cyclic AMP Response Element-Binding Protein; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D016755:Proto-Oncogene Proteins c-jun; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases