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首页> 外文期刊>Molecular and Cellular Biology >A truncated herpes simplex virus thymidine kinase phosphorylates thymidine and nucleoside analogs and does not cause sterility in transgenic mice.
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A truncated herpes simplex virus thymidine kinase phosphorylates thymidine and nucleoside analogs and does not cause sterility in transgenic mice.

机译：截短的单纯疱疹病毒胸苷激酶使胸苷和核苷类似物磷酸化，不会在转基因小鼠中引起不育。

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摘要

Dividing eukaryotic cells expressing the herpes simplex virus type 1 thymidine kinase (TK) gene are sensitive to the cytotoxic effect of nucleoside analogs such as acyclovir or ganciclovir (GCV). Transgenic mice with cell-targeted expression of this conditional toxin have been used to create animals with temporally controlled cell-specific ablation. In these animal models, which allow the study of the physiological importance of a cell type, males are sterile. In this study, we showed that this phenomenon is due to testis-specific high-level expression of short TK transcripts initiated mainly upstream of the second internal ATG of the TK gene. This expression is DNA methylation independent. To obtain a suicide gene that does not cause male infertility, we generated and analyzed the properties of a truncated TK (delta TK) lacking the sequences upstream of the second ATG. We showed that when expressed at sufficient levels, the functional properties of delta TK are similar to those of TK in terms of thymidine or GCV phosphorylation. This translated into a similar GCV-dependent toxicity for delta TK- or TK-expressing cells, both in vitro and in transgenic mice. However, delta TK behaved differently from TK in two ways. First, it did not cause sterility in delta TK transgenic males. Second, low-level delta TK RNA expression did not confer sensitivity to GCV. The uses of delta TK in cell-specific ablation in transgenic mice and in gene therapy are discussed.
机译：表达单纯疱疹病毒1型胸苷激酶（TK）基因的真核细胞对诸如阿昔洛韦或更昔洛韦（GCV）等核苷类似物的细胞毒性作用敏感。具有这种条件毒素的细胞靶向表达的转基因小鼠已被用于创建具有时间控制的细胞特异性消融的动物。在这些允许研究细胞类型的生理重要性的动物模型中，雄性是不育的。在这项研究中，我们表明，这种现象是由于短TK转录物的睾丸特异性高水平表达引起的，该转录物主要在TK基因的第二个内部ATG上游启动。该表达是DNA甲基化无关的。为了获得不会引起男性不育的自杀基因，我们生成并分析了缺少第二个ATG上游序列的截短TK（δTK）的特性。我们表明，当以足够的水平表达时，就胸苷或GCV磷酸化而言，δTK的功能特性与TK相似。在体外和转基因小鼠中，这转化为对表达δTK或TK的细胞的类似的GCV依赖性毒性。但是，增量传统知识在两个方面与传统知识有所不同。首先，它没有在TK TK转基因男性中引起不育。其次，低水平的Delta TK RNA表达不赋予对GCV的敏感性。讨论了δTK在转基因小鼠的细胞特异性消融和基因治疗中的用途。

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