Conditional liver-specific expression of simian virus 40 T antigen leads to regulatable development of hepatic neoplasm in transgenic mice
Conditional liver-specific expression of simian virus 40 T antigen leads to regulatable development of hepatic neoplasm in transgenic mice
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DOI：
10.1074/jbc.m009770200
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发表时间：
2001-04-27
影响因子：
4.8
通讯作者：
Liang, TJ
中科院分区：
文献类型：
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作者：
Manickan, E;Satoi, JJ;Liang, TJ
在小鼠中，适应性表观遗传变化和毒性通常伴随着转基因的组成表达或内源性基因的敲除。这些考虑可能会限制转基因技术在研究基因体内功能方面的有用性。使用条件基因表达技术，有可能超越这些限制，实现体内基因表达的时间和组织特异性操作。在四环素调控系统的基础上，我们建立了一个通过四环素在肝脏中严格调控SV40 T抗原（TAg）和lacZ两个转基因基因条件表达的二元转基因模型。利用小鼠白蛋白或小鼠主要尿蛋白启动子在一组转基因小鼠中实现了四环素应答转录激活子（tTA）的肝脏特异性表达。这些小鼠与携带TAg或lacZ的转基因小鼠在ta调控启动子的控制下杂交。对tTA和TAg（或lacZ）转基因小鼠的分析表明，转基因基因的肝脏特异性表达可以被抑制到不可检测的水平，并以四环素给药和停药的可逆方式进行调节。tTA和TAg转基因小鼠发生肝细胞腺瘤和肝细胞增生，连续给药四环素可预防。我们的报告证明了这种二元转基因模型在肝脏特异性研究任何潜在基因的生理功能方面的价值。
Adaptive epigenetic changes and toxicity often accompany constitutive expression of a transgene or knockout of an endogenous gene in mice. These considerations potentially limit the usefulness of transgenic technology in studying the in vivo functions of a gene. Using conditional gene expression technology, it is possible to override such restrictions to achieve temporal and tissue-specific manipulation of gene expression in vivo. Based on the tetracycline regulatory system, we established a binary transgenic model in which the conditional expression of two transgenes, SV40 T antigen (TAg) and lacZ, can be tightly regulated in the liver by administration of tetracycline. The mouse albumin or mouse major urinary protein promoter was used to achieve liver-specific expression of the tetracycline-responsive transcriptional activator (tTA) in one set of transgenic mice. These mice were crossed with transgenic mice carrying either TAg or lacZ under the control of the tTA-regulated promoter. Analyses of mice transgenic for both tTA and TAg (or lacZ) revealed that the liver-specific expression of the transgenes could be suppressed to undetectable levels and regulated in a reversible fashion by tetracycline administration and withdrawal. Mice with tTA and TAg transgenes developed hepatocellular adenomas and hyperplasia that could be prevented by continuous tetracycline administration. Our report demonstrates the value of this binary transgenic model in studying the physiological functions of any potential genes of interest in a liver-specific manner.