REGULATORY ELEMENT IN THE MMTV LTR

描述：小鼠乳腺肿瘤病毒（MMTV）导致小鼠乳腺癌 通过将其基因组的拷贝整合到宿主染色体中， 改变细胞基因的表达，这些基因现在受到 病毒信号 病毒和邻近宿主基因的表达， 组织特异性和对类固醇激素敏感。 对类固醇的反应 激素是通过激素受体与识别 前病毒的长末端重复序列（LTR）区域内的序列 基因组 与激素受体结合位点相邻的18 bp序列具有 被确定为激素反应所需的额外物质， 能够以组织特异性方式结合宿主细胞蛋白。 的 18 bp序列在MMTV毒株之间是可变的，并且在一个毒株中缺失 分离自肾癌。 拟议研究的假设 18 bp的序列部分决定了MMTV对 乳腺中的复制和肿瘤发生。 序列介导 这种作用是通过结合转录调节因子实现的。 具体 目的是：1）测试报告基因在乳腺和肾细胞中的活性 与MMTV LTR连锁的基因，该区域缺失或改变; 2） 检测重组质粒的组织嗜性和相对致瘤性 仅在18 bp区域不同的病毒; 3）获得并确定 编码能够表达蛋白质的cDNA的分子克隆的核苷酸序列 特异性结合18 bp序列; 4）测试组织 编码18 bp结合蛋白的转录物的分布。 是 预期由此鉴定的小鼠蛋白质将在以下方面发挥作用： 介导正常宿主对类固醇激素的反应， 可以鉴定功能相似的同系物。 的说明， 18 bp元件在类固醇激素反应中的作用及其鉴定 实现这种效应的因素可能会建议阻止这种效应的策略。 治疗反应。

DESCRIPTION: Mouse mammary tumor virus (MMTV) causes breast cancer in mice by integrating a copy of its genome into the host chromosome, thereby altering the expression of cellular genes which now come under control of viral signals. The expression of the virus, and adjacent host genes, is tissue-specific and sensitive to steroid hormones. The response to steroid hormones is mediated by binding of the hormone receptor to a recognition sequence within the long terminal repeat (LTR) region of the proviral genome. An 18 bp sequence adjacent to the hormone receptor binding site has been identified as additionally required for the hormone response and is capable of binding host cellular proteins in a tissue-specific fashion. The 18 bp sequence is variable among MMTV strains and is missing from a strain isolated from a kidney carcinoma. The hypothesis for the proposed studies is that the 18 bp sequence partially determines the specificity of MMTV for replication and tumorigenesis in the mammary gland. The sequence mediates this effect by binding transcriptional regulatory factors. The specific aims are: 1) to test the activity in mammary and kidney cells of a reporter gene linked to the MMTV LTR with deletions or alterations of this region; 2) to test the tissue tropism and relative tumorigenicity of recombinant viruses differing only in the 18bp region; 3) to obtain and determine the nucleotide sequence of molecular clones of cDNAs encoding proteins capable of specifically binding the 18 bp sequence; 4) to test the tissue distribution of transcript encoding the 18 bp binding protein. It is expected that the mouse proteins thus identified will play a role in mediating the normal host response to steroid hormones, and that human homologs may be identified that function similarly. The elucidation of the 18 bp element's role in the steroid response and the identification of factors that carry out the effect may suggest strategies to block such responses therapeutically.