Chatterjee M, Wu S
Department of Radiation Oncology, Division of Radiation and Cancer Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Mol Carcinog. 2001 Jan;30(1):47-55. doi: 10.1002/1098-2744(200101)30:1<47::aid-mc1012>3.0.co;2-3.
Fas receptor and tumor necrosis factor receptor-1 (TNFR1) mediate the activation of acid sphingomyelinase (ASMase), which catalyzes the hydrolysis of sphingomyelin to ceramide. Ceramide acts as a second messenger in mediating cell growth, differentiation, stress response, and apoptosis. Ultraviolet (UV) irradiation induces Fas receptor and TNFR1 aggregation. However, the roles of Fas receptor and TNFR1 in mediating UV-induced ASMase activation have not been explored. In this report, we demonstrate that Fas receptor, not TNFR1, mediated UV-induced activation of ASMase. Our data indicate that ASMase activity was not induced with UV irradiation but by TNFalpha in MCF-7 cells that expressed low levels of Fas receptor. In contrast, ASMase was activated by UV irradiation or TNFalpha treatment in Fas stably transfected MCF-7 cells. Immunofluorescence staining of TNFR1 on MCF-7 cells showed that TNFR1 was aggregated after treatment with UV irradiation or TNFalpha. However, UV-induced aggregation of TNFR1 did not lead to induction of ASMase activity. These results suggest that Fas receptor aggregation is solely responsible for UV-induced activation of ASMase. Further, with the use of BJAB and dominant-negative Fas-associated death domain-containing protein (FADD) stably transfected BJAB cells, we demonstrated that dominant-negative FADD partly inhibited UV-induced ASMase activation. Our results suggest that FADD is involved in UV-induced and Fas-mediated signaling pathways for activation of ASMase. Mol. Carcinog. 30:47-55, 2001.
Fas受体和肿瘤坏死因子受体-1（TNFR1）介导酸性鞘磷脂酶（ASMase）的激活，该酶催化鞘磷脂水解为神经酰胺。神经酰胺作为第二信使，介导细胞生长、分化、应激反应和细胞凋亡。紫外线（UV）照射可诱导Fas受体和TNFR1聚集。然而，Fas受体和TNFR1在介导UV诱导的ASMase激活中的作用尚未得到研究。在本报告中，我们证明是Fas受体而非TNFR1介导了UV诱导的ASMase激活。我们的数据表明，在表达低水平Fas受体的MCF-7细胞中，UV照射不会诱导ASMase活性，而是TNFα可诱导其活性。相反，在稳定转染Fas的MCF-7细胞中，UV照射或TNFα处理均可激活ASMase。对MCF-7细胞上TNFR1的免疫荧光染色显示，UV照射或TNFα处理后TNFR1会聚集。然而，UV诱导的TNFR1聚集并未导致ASMase活性的诱导。这些结果表明，Fas受体聚集是UV诱导的ASMase激活的唯一原因。此外，通过使用BJAB细胞和稳定转染显性负性含Fas相关死亡结构域蛋白（FADD）的BJAB细胞，我们证明显性负性FADD可部分抑制UV诱导的ASMase激活。我们的结果表明，FADD参与了UV诱导的以及Fas介导的ASMase激活信号通路。《分子致癌学》30:47 - 55，2001年。
