Marcellus R C, Teodoro J G, Wu T, Brough D E, Ketner G, Shore G C, Branton P E
Department of Biochemistry McGill University, Montréal, Quebec, Canada.
J Virol. 1996 Sep;70(9):6207-15. doi: 10.1128/JVI.70.9.6207-6215.1996.
In the absence of E1B, the 289- and 243-residue E1A products of human adenovirus type 5 induce p53-dependent apoptosis. However, our group has shown recently that the 289-residue E1A protein is also able to induce apoptosis by a p53-independent mechanism (J. G. Teodoro, G. C. Shore, and P. E. Branton, Oncogene 11:467-474, 1995). Preliminary results suggested that p53-independent cell death required expression of one or more additional adenovirus early gene products. Here we show that both the E1B 19-kDa protein and cellular Bcl-2 inhibit or significantly delay p53-independent apoptosis. Neither early region E2 or E3 appeared to be necessary for such cell death. Analysis of a series of E1A mutants indicated that mutations in the transactivation domain and other regions of E1A correlated with E1A-mediated transactivation of E4 gene expression. Furthermore, p53-deficient human SAOS-2 cells infected with a mutant which expresses E1B but none of the E4 gene products remained viable for considerably longer times than those infected with wild-type adenovirus type 5. In addition, an adenovirus vector lacking both E1 and E4 was unable to induce DNA degradation and cell killing in E1A-expressing cell lines. These data showed that an E4 product is essential for E1A-induced p53-independent apoptosis.
在缺乏E1B的情况下，人5型腺病毒的289个和243个氨基酸残基的E1A产物可诱导p53依赖性凋亡。然而，我们小组最近发现，289个氨基酸残基的E1A蛋白也能够通过一种不依赖p53的机制诱导凋亡（J.G. 特奥多罗、G.C. 肖尔和P.E. 布兰顿，《癌基因》11:467 - 474，1995年）。初步结果表明，不依赖p53的细胞死亡需要一种或多种额外腺病毒早期基因产物的表达。在此我们表明，E1B 19 kDa蛋白和细胞Bcl - 2都能抑制或显著延迟不依赖p53的凋亡。早期区域E2或E3似乎都不是这种细胞死亡所必需的。对一系列E1A突变体的分析表明，E1A反式激活结构域和其他区域的突变与E1A介导的E4基因表达的反式激活相关。此外，用表达E1B但不表达任何E4基因产物的突变体感染的p53缺陷型人SAOS - 2细胞比用野生型5型腺病毒感染的细胞存活时间长得多。另外，一种同时缺失E1和E4的腺病毒载体在表达E1A的细胞系中无法诱导DNA降解和细胞杀伤。这些数据表明，一种E4产物对于E1A诱导的不依赖p53的凋亡至关重要。
