Co-operative interactions between NFAT (nuclear factor of activated T cells) c1 and the zinc finger transcription factors Spl/Sp3 and Egr-1 regulate MT1-MMP (membrane type 1 matrix metalloproteinase) transcription by glomerular mesangial cells
Co-operative interactions between NFAT (nuclear factor of activated T cells) c1 and the zinc finger transcription factors Spl/Sp3 and Egr-1 regulate MT1-MMP (membrane type 1 matrix metalloproteinase) transcription by glomerular mesangial cells
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DOI：
10.1042/bj20031281
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发表时间：
2004-06-15
影响因子：
4.1
通讯作者：
Lovett, DH
中科院分区：
文献类型：
--
作者：
Alfonso-Jaume, MA;Mahimkar, R;Lovett, DH
正常静止的肾小球MC（系膜细胞）向具有肌成纤维细胞特征的高度增殖表型的转变是在影响肾小球的炎性疾病中常见的过程，其最终结果是肾小球硬化。通过膜相关的I型膜（NIT 1）-MMP产生蛋白水解活性MMP（基质金属蛋白酶）-2负责肾小球系膜细胞向肌成纤维细胞表型的转变[Turck，Pollock，Lee，Marti和Lovett（1996）J.Biol.Chem.271，15074 - 15083]。在本研究中，我们发现在MCs中NIT I-MMP的表达是由三个独立的顺式作用元件介导的：一个邻近的非典型的Sp1位点，它优先结合Sp1;以及在MC核提取物中存在的结合NFAT c I同种型的NFAT（活化T细胞的核因子）的更远端结合位点。用NFAT c I表达质粒转染，或用钙离子载体激活钙调磷酸酶，产生了NFAT c 1核DNA结合活性、NIT I-MMP转录和蛋白质合成的显著增加，这与近端Sp1和重叠Sp1/Egr-1位点提供的较低水平的反式激活是相加的。通过染色质免疫沉淀研究证实NFAT cl与MT1-MMP启动子的特异性结合，而用钙调磷酸酶抑制剂环孢菌素A处理抑制MT1-MMP表达。这些研究首次证明了特定的NFAT同种型增强MMP（NITI-MMP）的转录，所述MMP在蛋白水解事件中起主要作用，所述蛋白水解事件是急性肾小球炎症的主要特征。常用钙调磷酸酶抑制剂对MT 1-MMP的抑制可能在肾移植后肾纤维化的发生中发挥作用。
The transition of normally quiescent glomerular MCs (mesangial cells) to a highly proliferative phenotype with characteristics of myofibroblasts is a process commonly observed in inflammatory diseases affecting the renal glomerulus, the ultimate result of which is glomerulosclerosis. Generation of proteolytically active MMP (matrix metalloproteinase)-2 by the membrane-associated membrane type I (NIT 1)-MMP is responsible for the transition of mesangial cells to the myofibroblast phenotype [Turck, Pollock, Lee, Marti and Lovett (1996) J. Biol. Chem. 271, 15074-15083]. In the present study, we show that the expression of NIT I -MMP within the context of MCs is mediated by three discrete cis-acting elements: a proximal non-canonical Sp1 site that preferentially binds Sp1; an overlapping Sp1/Egr-1-binding site that preferentially binds Egr-1; and a more distal binding site for the NFAT (nuclear factor of activated T cells) that binds the NFAT c I isoform, present in MC nuclear extracts. Transfection with an NFAT c I expression plasmid, or activation of calcineurin with a calcium ionophore, yielded major increases in NFAT c1 nuclear DNA-binding activity, NIT I -MMP transcription and protein synthesis, which were additive with the lower levels of transactivation provided by the proximal Sp1 and the overlapping Sp1/Egr-1 sites. Specific binding of NFAT cl to the MT1-MMP promoter was confirmed by chromatin immunoprecipitation studies, while MT1-MMP expression was suppressed by treatment with the calcineurin inhibitor, cyclosporin A. These studies are the first demonstration that a specific NFAT isoform enhances transcription of an MMP (NIT I -MMP) that plays a major role in the proteolytic events that are a dominant feature of acute glomerular inflammation. Suppression of MT1-MMP by commonly used calcineurin inhibitors may play a role in the development of renal fibrosis following renal transplantation.