Mutation of the core or adjacent LVb elements of the Moloney murine leukemia virus enhancer alters disease specificity.
Mutation of the core or adjacent LVb elements of the Moloney murine leukemia virus enhancer alters disease specificity.
复制标题
莫洛尼鼠白血病病毒增强子的核心或相邻 LVb 元件的突变会改变疾病特异性。
DOI：
10.1101/gad.4.2.233
复制
发表时间：
1990
影响因子：
10.5
通讯作者：
Hopkins,N
中科院分区：
文献类型：
--
作者：
Speck,NA;Renjifo,B;Golemis,E;Fredrickson,TN;Hartley,JW;Hopkins,N
复制能力的小鼠C型逆转录病毒的转录增强子是不同病毒分离株的不同疾病诱导表型的有效决定因素，并且还可以强烈影响疾病诱导的发生率和潜伏期。为了研究单个蛋白质结合位点对病毒致病性的贡献，我们将突变引入Moloney小鼠白血病病毒增强子区域中的每个已知核因子结合位点，并将具有这些突变的病毒注射到新生NFS小鼠中。所有病毒都会诱发疾病。在白血病病毒因子a（LVa）位点、白血病病毒因子c（LVc）位点或仅在糖皮质激素反应元件（GRE）的启动子近端拷贝中具有突变的病毒具有与野生型莫洛尼病毒难以区分的疾病发作和疾病特异性的潜伏期。在两个或三个GRE中、在白血病病毒因子B（LV B）位点的两个拷贝中、在四个核因子1（NF 1）共有基序中的两个中或在保守的病毒核心元件的两个拷贝中具有突变的病毒显示出疾病诱导的潜伏期的显著延迟。引人注目的是，核心元件突变的病毒主要诱导红白血病，LVb位点突变也导致红白血病的显著发病率。这些和其他遗传和生物化学研究提出了小鼠C型逆转录病毒增强子高度保守结构的微妙变化如何对疾病特异性产生显着影响的模型。
Transcriptional enhancers of replication-competent mouse C-type retroviruses are potent determinants of the distinct disease-inducing phenotypes of different viral isolates and can also strongly influence the incidence and latent period of disease induction. To study the contribution of individual protein-binding sites to viral pathogenicity, we introduced mutations into each of the known nuclear factor-binding sites in the enhancer region of the Moloney murine leukemia virus and injected viruses with these mutations into newborn NFS mice. All viruses induced disease. Viruses with mutations in both copies of the leukemia virus factor a (LVa) site, leukemia virus factor c (LVc) site, or in just the promoter proximal copy of the glucocorticoid response element (GRE) had a latent period of disease onset and disease specificity indistinguishable from that of the wild-type Moloney virus. Viruses with mutations in two or three of the GREs, in both copies of the leukemia virus factor b (LVb) site, in two of the four nuclear factor 1 (NF1) consensus motifs, or in both copies of the conserved viral core element showed a significant delay in latent period of disease induction. Strikingly, viruses with mutations in the core element induced primarily erythroleukemias, and mutations in the LVb site also resulted in a significant incidence of erythroleukemias. These and other genetic and biochemical studies suggest models for how subtle alterations in the highly conserved structure of mouse C-type retrovirus enhancers can produce a dramatic effect on disease specificity.