An enhancer sequence instability that diversifies the cell repertoire for expression of a murine leukemia virus.
An enhancer sequence instability that diversifies the cell repertoire for expression of a murine leukemia virus.
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增强子序列不稳定性使鼠白血病病毒表达的细胞库多样化。
DOI：
10.1016/0042-6822(88)90548-x
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发表时间：
1988
期刊：
影响因子：
3.7
通讯作者：
Kabat,D
中科院分区：
文献类型：
--
作者：
Spiro,C;Li,JP;Bestwick,RK;Kabat,D
对引起胸腺或红系白血病的鼠白血病病毒（MuLV）之间的重组体的研究表明，长末端重复序列（LTR）中的增强子序列可以决定致病的靶组织。已经推断，增强子可以特异性地将病毒表达靶向到细胞中，然后变成肿瘤。然而，这些研究中的肿瘤是在laviral之后形成的，并且含有与注射病毒在增强子序列和包膜（env）基因上不同的最终病毒（称为MCFs）。来自这些近端和最终病毒的LTR的转录活性尚未在不同的造血谱系中进行彻底分析。我们目前的证据表明，朋友脾病灶形成病毒（SFFV），一个最终的erythroleukemogenic逆转录病毒的增强子，包含一个不稳定的42个核苷酸的直接重复。其他终极红白血病MuLV（朋友MCF）包含一个增强子几乎相同的SFFV在其序列和其特定的不稳定性。不稳定性发生在含有反向重复的序列中，我们认为它是通过一个简单的逆转录酶跳跃机制发生的。我们构建了含有两种形式的SFFV LTR连接到细菌氯霉素乙酰转移酶（CAT）基因的质粒，并在瞬时转染试验中与从Friend和Moloney MuLV构建的LTR-CAT质粒进行了比较。该试验采用红白血病细胞、胸腺淋巴瘤细胞和成纤维细胞。表达的向性仅与发病机制的组织特异性弱相关，并且每个LTR在所有细胞中都是活跃的。SFFV 42-核苷酸重复减少了在红系细胞中的表达，增加了在成纤维细胞中的表达。我们的结论是，逆转录病毒增强子不严格指导基因表达到特定的细胞谱系，但相反，它们是泄漏的，并含有复制不稳定性，也表达到特定的细胞谱系，但相反，它们是泄漏的，并含有复制不稳定性，也可能促进病毒在整个主机的战壕。这些结果对于理解小鼠逆转录病毒的进化和白血病发生的多步骤过程具有重要意义。
Studies of recombinants between murine leukemia viruses (MuLVs) that cause thymic or erythroid leukemias have shown that enhancer sequences in the long-terminal repeats (LTRs) can determine the target tissues for pathogenesis. It has been inferred that the enhancers may specifically target viral expression into the cells that then become neoplastic. However, the neoplasms in those studies formed after latencies and contained ultimate viruses (called MCFs) that differed from the injected viruses in their enhancer sequences and envelope (env) genes. Transcriptional activities of LTRs from these proximal and ultimate viruses have not been thoroughly analyzed in different hematopoietic lineages. We present evidence that the enhancer of Friend spleen focus-forming virus (SFFV), an ultimate erythroleukemogenic retrovirus, contains an unstable 42-nucleotide direct repeat. Other ultimate erythroleukemogenic MuLVs (Friend MCFs) contain an enhancer nearly identical to that of SFFV both in its sequence and in its specific instability. The instability occurs in sequences that contain inverted repeats and we propose that it occurs by a simple reverse transcriptase hop mechanism. We constructed plasmids that contain the two forms of the SFFV LTR linked to the bacterial chloramphenicol acetyltransferase (CAT) gene, and we compared these in transient transfection assays with LTR-CAT plasmids constructed from Friend and Moloney MuLVs. The assays employed erythroleukemia cells, thymic lymphoma cells, and fibroblasts. The tropisms of expression correlated only weakly with tissue specificities of pathogenesis and each LTR was active in all cells. The SFFV 42-nucleotide duplication reduced expression in erythroid cells and increased expression in fibroblasts. We conclude that retroviral enhancers do not stringently direct gene expression into specific cell lineages, but on the contrary they are leaky and contain replicative instabilities that also expression into specific cell lineages, but on the contrary they are leaky and contain replicative instabilities that also may facilitate viral entrenchment throughout the host. These results have important implications for understanding murine retroviral evolution and the multi-step process of leukemogenesis.