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ACCESSORY CELL ACTIVATION OF THE IMMUNE RESPONSE

免疫反应的辅助细胞激活

基本信息

批准号：
6752406
负责人：
PHILIP E AURON
金额：
$ 23.4万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-08-25 至 2006-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6752406
关键词：
antigen presenting cell cell differentiation cytomegalovirus gene induction /repression gene mutation genetic enhancer element genetic promoter element human T cell lymphotropic virus type 1 interleukin 1 interleukin 6 leukocyte activation /transformation lipopolysaccharides molecular cloning monocyte simian virus 40 tissue /cell culture transcription factor

项目摘要

Monocytes express at least two different classes of cell-type specific genes. One class, exemplified gy the M-CSF receptor gene, c-fms, is constitutively expressed and dependent upon the differentiated state. Another class, represented by the IL-1beta gene (il1b), is also generally monocyte-specific, but is only expressed immediately in response to a stimulation event that parallels the conversion of the resting monocyte to the activated monocyte/macrophage. Investigation of the il1b regulation mechanisms have revealed two distinct and separable regions of the gene that correspond to each of the two criteria, a cell type specific 143bp basal promoter and a signal-responsive upstream enhancer. The enhancer function depends upon the cooperative function of several broadly expressed signal-responsive transcription factors (e.g., C/EBPbeta, CREB, c-Jun, and NF- kappaB), including a novel STAT-like factor, whereas the 71 bp basal promoter appears to depend upon binding of one molecule of the mono-myeloid factor Spi-1/PU.1 (Spi-1), a factor that plays a central key role in monocyte development and cell type-specific gene expression. The functional interaction between the basal promoter and an enhancer requires a critical additional 73bp element that requires the binding of an additional Spi-1 molecule. This element is not required for enhancer-independent activity in the presence of IE2, a cytomegalovirus protein. IE2 appears to interact directly with the Spi-1 ETS domain. This region is found in all ETS proteins and mediates associations with a broad range of other proteins, modulating function in both partners. The object of this proposal is to elucidate the mechanism by which Spi-1 interacts with other proteins and integrates enhancer function into the core promoter and to attempt to clone the novel STAT-like factor that is activated in response to LPS, IL-1, and IL-6.

单核细胞表达至少两种不同类型的细胞类型特异性基因。一类，例如戈伊M-CSF受体基因c-fms，是组成型表达的，并依赖于分化状态。以IL-1 β基因（il 1b）为代表的另一类基因通常也是单核细胞特异性的，但仅在响应于刺激事件时立即表达，该刺激事件与静息单核细胞向活化单核细胞/巨噬细胞的转化平行。对il 1b调控机制的研究揭示了该基因的两个不同且可分离的区域，分别对应于两个标准：细胞类型特异性143 bp基础启动子和信号响应性上游增强子。增强子功能取决于几种广泛表达的信号响应性转录因子（例如，C/EBP β、CREB、c-Jun和NF-κ B），包括一种新的STAT样因子，而71 bp的基础启动子似乎依赖于一种单髓样因子Spi-1/PU. 1（Spi-1）分子的结合，该因子在单核细胞发育和细胞类型特异性基因表达中起关键作用。基础启动子和增强子之间的功能性相互作用需要一个关键的额外的73 bp元件，该元件需要额外的Spi-1分子的结合。在IE 2（一种巨细胞病毒蛋白）存在下，该元件不是增强子非依赖性活性所必需的。 IE 2似乎直接与Spi-1 ETS结构域相互作用。该区域存在于所有ETS蛋白中，并介导与广泛的其他蛋白质的关联，调节双方的功能。本提案的目的是阐明Spi-1与其他蛋白相互作用并将增强子功能整合到核心启动子中的机制，并试图克隆响应LPS、IL-1和IL-6而激活的新型STAT样因子。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cytomegalovirus IE2 protein stimulates interleukin 1beta gene transcription via tethering to Spi-1/PU.1.

巨细胞病毒 IE2 蛋白通过与 Spi-1/PU.1 结合刺激白细胞介素 1β 基因转录。

DOI：
10.1128/mcb.19.10.6803
发表时间：
1999
期刊：
Molecular and cellular biology
影响因子：
5.3
作者：
Wara-aswapati,N;Yang,Z;Waterman,WR;Koyama,Y;Tetradis,S;Choy,BK;Webb,AC;Auron,PE
通讯作者：
Auron,PE

Interleukin-1: a gene expression system regulated at multiple levels.