title: Ultraviolet-irradiation-induced apoptosis is mediated via ligand independent activation of tumor necrosis factor receptor 1.
abstract: Ultraviolet (UV)-irradiation has been shown to induce jun N-terminal kinase activity via aggregation-mediated activation of tumor necrosis factor receptor 1 (TNFR1) but the role of TNFR1 in mediating UV-induced apoptosis has not been explored. Using p53-null cells, we demonstrate that UV-stimulated ligand independent activation of TNFR1 plays a major role in mediating the apoptotic effects of UV-irradiation. UV-irradiation and TNF alpha acted in a synergistic manner to induce apoptosis. UV-irradiation stimulated the aggregation-mediated activation of TNFR1 which was coupled with activation of caspase 8, the most proximal caspase in TNF alpha signaling pathway. CrmA and the dominant negative versions of FADD, caspase 8 and caspase 10, that block the apoptotic axis of TNFR1 at different levels, also independently inhibited the UV-induced apoptosis. The engagement of the membrane initiated events was specific for UV-irradiation since neither CrmA nor the dominant negative FADD, caspase 8 or caspase 10 blocked the ionizing radiation-induced apoptosis. Cisplatin and melphalan, the UV-mimetic agents known to elicit UV-type DNA damage, also induced apoptosis but differed from UV in that both of the former agents engaged the caspase cascade at a level distal to FADD. Consistent with these findings cisplatin also did not stimulate TNFR1 aggregation. Together these results indicate that DNA damage per se was not sufficient to activate the membrane TNFR1. Based on our results we propose that the plasma membrane initiated events play a predominant role in mediating UV-irradiation-induced apoptosis and that UV-irradiation appears to engage the apoptotic axis of TNFR1 and perhaps those of other membrane death receptors to transduce its apoptotic signals.
authors.affiliation: Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Sheikh
authors.forename: M J
authors.initials: MJ
authors.lastname: Antinore
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.forename: A J
authors.initials: AJ
authors.lastname: Fornace
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D001943:Breast Neoplasms / Q000473:pathology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000502:physiology; D002462:Cell Membrane / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein; D006367:HeLa Cells / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008175:Lung Neoplasms / Q000473:pathology; D008558:Melphalan / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases; D009363:Neoplasm Proteins / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D047888:Receptors, Tumor Necrosis Factor, Type I; D015843:Serpins / Q000235:genetics / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency; D014466:Ultraviolet Rays; D014764:Viral Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004273:DNA, Neoplasm; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; C506438:CASP10 protein, human; D002945:Cisplatin; D008558:Melphalan