Gene regulation of the serine proteinase inhibitors α1-antitrypsin and α1-antichymotrypsin
Gene regulation of the serine proteinase inhibitors α1-antitrypsin and α1-antichymotrypsin
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DOI：
10.1042/bst0300093
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发表时间：
2002-04-01
影响因子：
3.9
通讯作者：
Morgan, K
中科院分区：
文献类型：
--
作者：
Kalsheker, N;Morley, S;Morgan, K
丝氨酸蛋白酶抑制剂（sereproteinase inhibitors，Serpin）是一个具有多种功能的蛋白质超家族，包括控制血液凝固、补体激活、程序性细胞死亡和发育。人血浆中最丰富的丝氨酸蛋白酶抑制剂是α（1）-抗胰蛋白酶（AAT）和α（1）-抗胰凝乳蛋白酶（ACT）。在炎症期间，前者的循环水平可增加高达3倍，后者可增加4-5倍。增加合成的主要部位是肝脏。其他组织，如肺，也能够合成AAT和ACT，并且表达可以通过细胞因子增加高达100倍。存在用于肝脏的组织特异性启动子和用于表达AAT的其它组织的替代启动子。基础AAT表达受组织特异性转录因子肝细胞核因子1 α和4的协同作用调节。一个增强器定位接近。1.2在3'侧翼序列中，距离最后一个外显子末端1.2kb调节白细胞介素-6和制瘤素M诱导的白细胞介素表达。微细胞杂交转染研究表明，含有15 kb 5'侧翼序列的序列足以允许AAT以位置非依赖性方式稳定表达。ACT可能只有一个发起人。抑瘤素M-诱导元件已经在5'侧翼序列中鉴定出约100个。100 bp上游的转录起始位点，和进一步的白细胞介素-1响应增强子已被确定约。上游13 kb。体液反应的途径正在以高分辨率绘制。
The serine proteinase inhibitors (serpins) are a superfamily of proteins with a diverse set of functions, including the control of blood coagulation, complement activation, programmed cell death and development. The most abundant serpins in human plasma are alpha(1)-antitrypsin (AAT) and alpha(1)-antichymotrypsin (ACT). During inflammation, circulating levels can increase by up to 3-fold for the former and by 4-5-fold for the latter. The major site for increased synthesis is the liver. Other tissues, such as the lung, are also capable of synthesizing AAT and ACT, and expression can be increased by up to 100-fold by cytokines. There is a tissue-specific promoter for the liver, and alternative promoters for other tissues that express AAT. Basal AAT expression is regulated by the synergistic action of the tissue-specific transcription factors hepatocyte nuclear factors 1alpha and 4. An enhancer positioned approx. 1.2 kb from the end of the last exon in the 3' flanking sequence modulates cytokine-induced expression by interleukin-6 and oncostatin M. Microcell hybrid transfection studies have shown that a sequence containing 15 kb of 5' flanking sequence is sufficient to allow stable expression of AAT in a position-independent manner. There is probably a single promoter for ACT. Oncostatin M-inducible elements have been identified in the 5' flanking sequence approx. 100 bp upstream from the transcription initiation site, and a further interleukin-1-responsive enhancer has been identified approx. 13 kb upstream. The pathways for a humoral response are being mapped at high resolution.