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 e ects of UV-irradiation. UV-irradiation and TNFa 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 TNFa signaling pathway. CrmA and the dominant negative versions of FADD, caspase 8 and caspase 10, that block the apoptotic axis of TNFR1 at di erent levels, also independently inhibited the UV-induced apoptosis. The engagement of the membrane initiated events was speci®c 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 UVtype DNA damage, also induced apoptosis but di ered from UV in that both of the former agents engaged the caspase cascade at a level distal to FADD. Consistent with these ®ndings cisplatin also did not stimulate TNFR1 aggregation. Together these results indicate that DNA damage per se was not su cient 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.

Lack of functional pRb results in attenuated recovery of mRNA synthesis and increased apoptosis following UV radiation in human breast cancer cells

“…Even though UV has been shown to be capable of activating membrane death receptors (Kulms et al, 1999;Rehemtulla et al, 1997;Sheikh et al, 1998), we did not ®nd a correlation between UV sensitivity and sensitivity to death receptor signaling. However, it is possible that UV radiation is signaling through another, as yet undetermined, death receptor.…”

“…It has been shown that UV radiation can activate membrane death receptors and initiate a death signal (Kulms et al, 1999;Rehemtulla et al, 1997;Sheikh et al, 1998). Thus, it was possible that alterations in a death receptor signaling pathway in MDA-MB-468 cells may be responsible for the hypersensitivity of these cells to low doses of UV radiation.…”

“…UV radiation in¯uences both the cell membrane and the nucleus. At the cell membrane, UV radiation has been shown to activate transmembrane receptors, such as the EGF receptor as well as membrane death receptors such as Fas and TNFR (Rehemtulla et al, 1997;Sachsenmaier et al, 1994;Sheikh et al, 1998). Death receptors are normally activated by ligand-induced clustering; however, UV radiation has been shown to induce clustering and activation of these death receptors in the absence of ligand.…”

DNA damage, death receptor activation and reactive oxygen species contribute to ultraviolet radiation-induced apoptosis in an essential and independent way

“…There is convincing evidence that UVB directly activates death receptors including CD95 and the TNF receptor 1 (Aragane et al, 1998;Rehemtulla et al, 1997;Sheikh et al, 1998). Inhibition of death receptor activation by exposing cells at a low temperature (4 -108C) to UVB is associated with a partial reduction in UVB-induced apoptosis.…”

UVB-induced activation and internalization of keratinocyte growth factor receptor

“…Exposure to UV radiation causes a complex cellular response, which includes the regulation of gene expression, DNA damage, lipid peroxidation and induction of apoptosis (Schwarz et al, 1995;Rosette and Karin, 1996;Sheikh et al, 1998;Glenn McGregor, 1999;Wikonkal and Brash, 1999). UV radiation, causing DNA damage by either direct interactions or by indirect pathways, may play a pivotal role in the process of carcinogenesis (for a recent review, see de Gruijl, 2000).…”