"Hit-and-run" transformation by adenovirus oncogenes
"Hit-and-run" transformation by adenovirus oncogenes
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DOI：
10.1128/jvi.75.7.3089-3094.2001
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发表时间：
2001-04-01
影响因子：
5.4
通讯作者：
Dobner, T
中科院分区：
文献类型：
--
作者：
Nevels, M;Täuber, B;Dobner, T
根据病毒肿瘤发生的经典概念，病毒特异性癌基因的持续存在是维持转化的细胞表型所必需的，相反，“打了就跑”假说声称病毒可以通过最初的“击中”介导细胞转化，而转化状态的维持与病毒分子的丢失（“逃跑”）相容。众所周知，腺病毒E1A和E1B基因产物可以协同将人类和啮齿动物的原代细胞转化为致瘤细胞。此外，最近的研究表明，腺病毒E4区编码两种新的癌蛋白，即E4orf6和E4orf3的产物，它们与病毒EIA蛋白合作以E1B样方式转化原代大鼠细胞，然而，出乎意料的是，由E1A和E4orf6或E4orf3转化的细胞未能表达病毒E4基因产物，并且事实上，这些细胞中的大多数缺乏 E4 和 E1A 特异性 DNA 序列，这表明转化是通过“打了就跑”的机制发生的。我们提供的证据表明，腺病毒癌蛋白的不寻常转化活性可能是由于其诱变潜力，即使缺乏任何可检测到的病毒特异性分子的肿瘤也可能是病毒起源的，这可能对腺病毒载体用于基因治疗产生重大影响。
According to classical concepts of viral oncogenesis, the persistence of virus-specific oncogenes is required to maintain the transformed cellular phenotype, In contrast, the "hit-and-run" hypothesis claims that viruses can mediate cellular transformation through an initial "hit,'' while maintenance of the transformed state is compatible with the loss ("run") of viral molecules. It is well established that the adenovirus E1A and E1B gene products can cooperatively transform primary human and rodent cells to a tumorigenic phenotype and that these cells permanently express the viral oncogenes, Additionally, recent studies have shown that the adenovirus E4 region encodes two novel oncoproteins, the products of E4orf6 and E4orf3, which cooperate with the viral EIA proteins to transform primary rat cells in an E1B-like fashion. Unexpectedly, howe,er, cells transformed by E1A and either E4orf6 or E4orf3 fail to express the viral E4 gene products, and only a subset contain EIA proteins. In fact, the majority of these cells lack E4- and E1A-specific DNA sequences, indicating that transformation occurred through a hit-and-run mechanism. We provide evidence that the unusual transforming activities of the adenoviral oncoproteins may be due to their mutagenic potential. Our results strongly support the possibility that even tumors that lack any detectable virus-specific molecules can be of viral origin, which could have a significant impact on the use of adenoviral vectors for gene therapy.