Adenovirus E1A oncogene expression in tumor cells enhances killing by TNF-related apoptosis-inducing ligand (TRAIL)
Adenovirus E1A oncogene expression in tumor cells enhances killing by TNF-related apoptosis-inducing ligand (TRAIL)
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DOI：
10.4049/jimmunol.165.8.4522
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发表时间：
2000-10-15
影响因子：
4.4
通讯作者：
Cook, JL
中科院分区：
文献类型：
--
作者：
Routes, JM;Ryan, S;Cook, JL
腺病毒血清型 5 (Ad5) EIA 致癌基因的表达使细胞对 TNF-α 和 Fas 配体的凋亡敏感。由于 TNF 相关凋亡诱导配体 (TRAIL) 以与 TNF-α 和 Fas 配体类似的方式杀死细胞，我们想知道 E1A 表达是否可能使细胞对 TRAIL 的裂解敏感。为了检验这一假设，我们检查了 TRAIL 诱导的对表达 E1A 的人黑色素瘤 (A2058) 或纤维肉瘤 (H4) 细胞的杀伤，这些细胞在感染 Ad5 或用 Ad5-E1A 稳定转染后，E1A 转染的 A2058 (A2058-E1A) 或 H4 (H4-E1A) 细胞对 TRAIL 诱导的杀伤高度敏感，但是 表达同样高水平的 E1A 蛋白的 Ad5 感染细胞仍然对 TRAIL 具有抗性，用 Ad5 感染 A2058-E1A 细胞降低了它们对 TRAIL 依赖性杀伤的敏感性，因此，感染 Ad5 后表达的病毒基因产物抑制了对 TRAIL 诱导杀伤的敏感性，而转染 E1A、E1B 和 E3 基因产物已显示出抑制 TNF-α- 和Fas依赖性杀伤。通过使用不表达E3(H5d1327)或E1B-19K(H5d1250)编码区的Ad5突变体检查这些基因产物对TRAIL依赖性杀伤的影响。感染H5d1327的A2058细胞对TRAIL依赖性杀伤敏感。此外，H5d1327感染不会抑制A2058-E1A细胞的TRAIL依赖性杀伤。 H5dl250感染使A2058细胞对TRAIL诱导的杀伤敏感，但远低于H5dl327感染。总之，Ad5-E1A基因产物的表达使细胞对TRAIL依赖性杀伤敏感，而E3基因产物以及较小程度的E1B-19K抑制这种作用。
Expression of the adenovirus serotype 5 (Ad5) EIA oncogene sensitizes cells to apoptosis by TNF-alpha and Fas-ligand, Because TNF-related apoptosis-inducing ligand (TRAIL) kills cells in a similar manner as TNF-alpha and Fas ligand, we asked whether E1A expression might sensitize cells to lysis by TRAIL. To test this hypothesis, we examined TRAIL-induced killing of human melanoma (A2058) or fibrosarcoma (H4) cells that expressed E1A following either infection,vith Ad5 or stable transfection with Ad5-E1A, E1A-transfected A2058 (A2058-E1A) or H4 (H4-E1A) cells were highly sensitive to TRAIL-induced killing, but Ad5-infected cells expressing equally high levels of E1A protein remained resistant to TRAIL, Infection of A2058-E1A cells with Ad5 reduced their sensitivity to TRAIL dependent killing, Therefore, viral gene products expressed following infection with Ad5 inhibited the sensitivity to TRAIL-induced killing conferred by transfection with E1A, E1B and E3 gene products have been shown to inhibit TNF-alpha- and Fas-dependent killing. The effect of these gene products on TRAIL-dependent killing was examined by using Ad5-mutants that did not express either the E3 (H5dl327) or E1B-19K (H5dl250) coding regions. A2058 cells infected with H5dl327 were susceptible to TRAIL-dependent killing. Furthermore, TRAIL-dependent killing of A2058-E1A cells was not inhibited by infection with H5dl327. Infection with H5dl250 sensitized A2058 cells to TRAIL-induced killing, but considerably less than H5dl327-infection, In summary, expression of Ad5-E1A gene products sensitizes cells to TRAIL-dependent killing whereas E3 gene products, and to a lesser extent E1B-19K, inhibit this effect.