ULTRAVIOLET-IRRADIATION-INDUCED APOPTOSIS IS MEDIATED VIA LIGAND-INDEPENDENT ACTIVATION OF TUMOR-NECROSIS-FACTOR-RECEPTOR-1

Ultraviolet (UV)-irradiation has been shown to induce jun N-terminal k inase activity via aggregation-mediated activation of tumor necrosis f actor receptor 1 (TNFR1) but the role of TNFR1 in mediating UV-induced apoptosis has not been explored. Using p53-null cells, me demonstrate that UV-stimulated ligand independent activation of TNFR1 plays a maj or role in mediating the apoptotic effects of UV-irradiation. UV-irrad iation and TNF alpha acted in a synergistic manner to induce apoptosis , UV-irradiation stimulated the aggregation-mediated activation of TNF R1 which was coupled with activation of caspase 8, the most proximal c aspase in TNF alpha signaling pathway, CrmA and the dominant negative versions of FADD, caspase 8 and caspase 10, that block the apoptotic a xis 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 negat ive FADD, caspase 8 or caspase 10 blocked the ionizing radiation-induc ed 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 le vel distal to FADD. Consistent with these findings cisplatin also did not stimulate TNFR1 aggregation. Together these results indicate that DNA damage pel se was not sufficient to activate the membrane TNFR1. B ased on our results we propose that the plasma membrane initiated even ts play a predominant role in mediating UV-irradiation-induced apoptos is and that UV-irradiation appears to engage the apoptotic axis of TNF R1 and perhaps those of other membrane death receptors to transduce it s apoptotic signals.