MOLECULAR BASIS FOR THE PATHOGENICITY OF MURINE RETROVIRUSES

鼠逆转录病毒致病性的分子基础

• 批准号: 3774875
• 负责人: S K RUSCETTI
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3774875
• 关键词: DNA binding protein; Friend leukemia; brain cell; chimeric proteins; erythroid stem cell; erythropoietin; gene induction /repression; genetic promoter element; genome; globin; growth factor receptors; host organism interaction; laboratory mouse; molecular oncology; nervous system disorder; oncogenic virus; receptor binding; tissue /cell culture; vascular endothelium; viral leukemogenesis; virus cytopathogenic effect; virus genetics; virus protein; virus replication

Mouse model systems are utilized to study the molecular basis for the pathogenesis of certain retroviruses. The gag-myb-ets-containing ME26 virus causes a high incidence of leukemia in mice. Both in vivo and in vitro, ME26 virus infection leads to the activation in hematopoietic precursor cells of certain erythroid-specific genes, such as GATA-1, Epo receptor, and globin, but not others. Transactivation studies indicate that the ME26 viral gene product transactivates the GATA-1 gene and then cooperates with the GATA-1 protein to transactivate the Epo receptor gene. DNA-binding studies show that the ME26 viral gene product specifically binds to the GATA-1 promoter. Studies utilizing mutated viral genomes suggest that changes in both the myb and ets regions of the virus can alter its biological activity and that both the v-myb and v-ets genes must be expressed as a fusion gene product to have a biological effect. These studies indicate that ME26 virus induces leukemia in mice by a novel mechanism involving the uncoupling of proliferation and differentiation. PVC-211 murine leukemia virus (MuLV) is a neuropathogenic, weaky- leukemogenic variant of the non-neuropathogenic, highly-leukemogenic Friend MuLV. Studies utilizing chimeric viruses indicate that the 5' half of the env gene, which encodes the receptor binding region of the protein, contains the determinant(s) responsible for pathological changes in the central nervous system (CNS). When viruses were tested for their ability to replicate in cultured brain capillary endothelial cells (BCEC), the primary site of PVC-211 MuLV replication within the CNS, there was a direct correlation between the replication efficiency of the virus in BCEC in vitro and its ability to cause neurological disease in vivo. These studies indicate that the sequences in PVC-211 MuLV which render it neuropathogenic affect its replication in BCEC and suggest that efficient viral replication in BCEC is crucial for the pathological changes in the CNS that result in neurological disease.

小鼠模型系统用于研究分子基础 某些逆转录病毒的发病机制。 含有 gag-myb-ets 的 ME26 该病毒导致小鼠白血病发病率很高。 无论是体内还是体内 体外，ME26病毒感染导致造血功能激活 某些红细胞特异性基因的前体细胞，例如 GATA-1、Epo 受体和球蛋白，但不是其他。 反式激活研究表明 ME26病毒基因产物反式激活GATA-1基因，然后 与GATA-1蛋白配合反式激活Epo受体基因。 DNA 结合研究表明 ME26 病毒基因产物特异性 与 GATA-1 启动子结合。 利用突变病毒基因组的研究 表明病毒的 myb 和 ets 区域的变化可以 改变其生物活性，并且 v-myb 和 v-ets 基因都必须 表达为融合基因产物以产生生物学效应。 这些 研究表明 ME26 病毒通过一种新的机制诱发小鼠白血病 涉及增殖和分化解偶联的机制。 PVC-211 鼠白血病病毒 (MuLV) 是一种神经致病性、弱 非神经病原性、高度白血病性的白血病变体 穆尔夫朋友。 利用嵌合病毒的研究表明，5'半 env 基因，编码蛋白质的受体结合区域， 包含导致病理变化的决定因素 中枢神经系统（CNS）。 当病毒被测试其能力时 在培养的脑毛细血管内皮细胞（BCEC）中复制 PVC-211 MuLV 在 CNS 内复制的主要站点，有一个 BCEC中病毒复制效率之间存在直接相关性 体外及其在体内引起神经系统疾病的能力。 这些 研究表明 PVC-211 MuLV 中的序列使其 神经病理性影响其在 BCEC 中的复制，并表明有效 BCEC 中的病毒复制对于 BCEC 的病理变化至关重要 导致神经系统疾病的中枢神经系统。