REGULATION OF EXPRESSION OF MHC CLASS I GENES

MHC I 类基因表达的调节

• 批准号: 3774396
• 负责人: D SINGER
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 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/3774396
• 关键词: DNA binding protein; MHC class I antigen; cell transformation; cell type; gene deletion mutation; gene expression; genetic enhancer element; genetic regulation; genetic regulatory element; genetically modified animals; laboratory mouse; protooncogene; transcription factor

MHC class I genes encoding transplantation antigens are ubiquitously expressed, although their level of expression varies among tissues. Analysis of the 5' flanking DNA sequence of a swine class I gene has demonstrated that this region contains a series of negative and positive regulatory elements. One of these elements, consisting of overlapping negative and positive regulatory elements, is a regulatory domain responsible for establishing tissue-specific levels of MHC class I gene expression. Introduction into transgenic mice of a series of nested deletion mutants which differ in the extent of the regulatory domain, reveals that the enhancer activity predominates in lymphoid tissues. The tissue-specific domain forms distinct enhancer and silencer associated complexes with cellular trans acting factors. Enhancer binding activity is present in extracts from various cell types, independent of levels of class I expression. In contrast, the level of silencer binding is inversely proportional to the level of class I gene expression. Thus, class I genes are found to be negatively regulated. Biochemical characterization of the regulatory factors has demonstrated that each factor consists of at least two distinct components, one of which appears to be common to both factors. Both the silencer and enhancer factors are redox-sensitive. The enhancer factor complex is approximately 3OkD. The enhancer unique subunit is also glycosylated. The silencer factor complex is approximately 95kD. An additional negative regulatory element has been identified which the proto-oncogene, c-jun, binds as a homo or heterodimer, and acts as a specific negative regulator. These observations. suggest that class I expression is actively regulated during cell activation, and also suggest a mechanism whereby cells transformed by oncogenic variants of c-jun could decrease class I expression.

编码移植抗原的MHC I类基因是普遍存在的， 表达，尽管它们的表达水平在组织中不同。 猪I类基因5'侧翼DNA序列的分析 表明这个区域包含一系列消极和积极的 监管要素。这些元素之一，由重叠的 负调控元件和正调控元件，是一个调控域 负责建立MHC I类基因的组织特异性水平 表情向转基因小鼠中引入一系列巢式 在调节结构域的范围上不同的缺失突变体， 表明增强子活性在淋巴组织中占主导地位。的 组织特异性结构域形成不同的增强子和沉默子 与细胞反式作用因子的复合物。 增强子结合活性 存在于来自各种细胞类型的提取物中，不依赖于 I类表达。相比之下，沉默者结合的水平是 与I类基因表达水平成反比。因此，在本发明中， 发现I类基因是负调控的。生化 对调节因子的表征表明， 因子至少由两个不同的组成部分组成，其中一个出现在 这两个因素是共同的。沉默因子和增强因子都是 氧化还原敏感的。增强子因子复合物约为30 kD。的 增强子独特亚基也被糖基化。沉默因子复合体 约为95 kD。 已经鉴定了另外的负调节元件， 原癌基因c-jun以同源或异源二聚体的形式结合， 特定负调节器。 这些观察。表明I类 表达在细胞活化过程中受到积极调节，也表明 c-jun致癌变异体转化细胞的机制 减少I类表达。