SV40 ENHANCER AND LARGE-T ANTIGEN ARE INSTRUMENTAL IN DEVELOPMENT OF CHOROID-PLEXUS TUMORS IN TRANSGENIC MICE
SV40 ENHANCER AND LARGE-T ANTIGEN ARE INSTRUMENTAL IN DEVELOPMENT OF CHOROID-PLEXUS TUMORS IN TRANSGENIC MICE
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DOI：
10.1038/316457a0
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发表时间：
1985-01-01
期刊：
影响因子：
64.8
通讯作者：
BRINSTER, RL
中科院分区：
文献类型：
--
作者：
PALMITER, RD;CHEN, HY;BRINSTER, RL
我们最近已经表明，脉络丛肿瘤经常在转基因小鼠中发生，这些小鼠是从注射含有猿猴病毒40（SV 40）早期区域基因和金属硫蛋白（MT）融合基因的DNA分子的受精卵中发育而来的。现在已经建立了几个品系的小鼠，其中所有继承了外源DNA的后代都在3 - 5个月大时死于这些肿瘤（参考文献1和我们未发表的数据）。其他几个组织，特别是胸腺和肾脏，偶尔也会出现病理变化。SV40大T抗原蛋白和信使RNA总是存在于受影响的组织中，其浓度比未受影响的组织高得多，这表明SV40早期区域基因优先在脉络丛、胸腺和肾脏中被激活，并且这种激活经常导致脉络丛中的肿瘤发生。为了确定原始构建体的哪些区域对这种肿瘤发生是重要的，我们现在已经测试了几种衍生物，并在这里报告说，大T抗原是足够的，MT融合基因是可识别的，SV40增强子（72个碱基对的重复区域）在指导肿瘤向脉络丛转移方面具有重要作用。单独缺失SV40增强子区域通常会导致周围神经病变，以及肝脏和胰腺肿瘤，这是随附论文的主题。有证据表明，这些病理可能会导致从themt序列对大T抗原基因的增强作用，通过去除否则占主导地位的SV40增强子成为可能。
We have shown recently that choroid plexus tumours frequently develop in transgenic mice which have developed from fertilized eggs injected with DNA molecules containing both simian virus 40 (SV40) early-region genes and metallothionein (MT) fusion genes1, and several lines of mice have now been established in which all of the offspring that inherit the foreign DNA succumb to these tumours at 3–5 months of age (ref. 1 and our unpublished data). Several other tissues, notably thymus and kidney, occasionally also show pathological changes. SV40 large-T antigen protein and messenger RNA are always present in affected tissues at much greater concentrations than in unaffected tissues, suggesting that SV40 early-region genes are preferentially activated in choroid plexus, thymus and kidney and that this activation frequently leads to tumorigenesis in the choroid plexus1. To determine which regions of the original constructs are important for this tumorigenesis, we have now tested several derivatives and report here that the large-T antigen is sufficient, that the MT fusion gene is dispensable and that the SV40 enhancer (72-base-pair repeat region) has an important role in directing tumours to the choroid plexus. Deletion of the SV40 enhancer region alone commonly leads to peripheral neuropathy, as well as liver and pancreatic tumours, which are the subject of the accompanying paper. Evidence is presented that these pathologies may result from an enhancing effect of theMTsequences on large-T antigen genes, made possible by removal of the otherwise dominant SV40 enhancer.