Fra-1 targets the AP-1 site/2G single nucleotide polymorphism (ETS site) in the MMP-1 promoter
Fra-1 targets the AP-1 site/2G single nucleotide polymorphism (ETS site) in the MMP-1 promoter
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DOI：
10.1046/j.1432-1033.2003.03821.x
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发表时间：
2003-10-01
期刊：
影响因子：
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通讯作者：
Brinckerhoff, CE
中科院分区：
文献类型：
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作者：
Tower, GB;Coon, CI;Brinckerhoff, CE
基质金属蛋白酶(MMPs)家族降解细胞外基质。该家族的成员之一，基质金属蛋白酶-1，启动间质胶原蛋白的分解。基质金属蛋白酶-1的表达受丝裂原活化蛋白激酶(MAPK)途径(S)调控，激活蛋白-1(AP-1)和多瘤增强活性-3/E26病毒(PEA3/ETS)转录因子的活性通过启动子中存在的共同结合位点来调节。在MMP1启动子的另一个Ets位点是通过单核苷酸多态(SNP)在-1607处创建的，SNP包含两个鸟嘌呤(5‘-GGAT-3’；‘2G SNP’)，而不是一个鸟嘌呤(5‘-GAT-3’；‘1G SNP’)，与AP-1结合位点相邻，位于-1602bp。2G SNP表现出比1G SNP更强的转录活性，AP-1和ETS转录因子家族协同作用增加转录。2G SNP与几种癌症的发生和发展有关，也与非肿瘤性疾病有关；尽管其潜在机制(S)尚未阐明。在这项研究中，我们证明了Fos样区抗原(Fra-1)的表达是A2058黑色素瘤细胞中MMP1转录所必需的。Fos样区抗原是AP-1转录因子的一个组成部分，也与肿瘤疾病密切相关。与含有1G SNP的DNA相比，抑制Fra-1的表达优先下调含有2G SNP的MMP-1启动子DNA的转录。本研究提供的证据表明，AP-1家族成员Fra-1与2G DNA多态性协同作用，促进了黑色素瘤细胞中基质金属蛋白酶-1的高结构性表达。
The matrix metalloproteinase (MMP) family degrades the extracellular matrix. One member of this family, MMP-1, initiates the breakdown of interstitial collagens. The expression of MMP-1 is controlled by the mitogen activated protein kinase (MAPK) pathway(s) via the activity of activator protein-1 (AP-1) and polyoma enhancing activity-3/E26 virus (PEA3/ETS) transcription factors through consensus binding sites present in the promoter. Another ETS site in the MMP-1 promoter is created at -1607 by by a single nucleotide polymorphism (SNP), which contains two guanines (5'-GGAT-3'; '2G SNP'), rather one guanine (5'-GAT-3'; '1G SNP'), adjacent to an AP-1 binding site at -1602 bp. The 2G SNP displays greater transcriptional activity than the 1G SNP, and AP-1 and Ets families of transcription factors cooperate to increase transcription. The 2G SNP has been linked to the incidence and the progression of several cancers and is also associated with non-neoplastic diseases; although the underlying mechanism(s) has yet to be elucidated. In this study we demonstrate that the expression of Fos-like region antigen (Fra-1), an AP-1 transcription factor component that also correlates strongly with neoplastic disease, is necessary for MMP-1 transcription in A2058 melanoma cells. The inhibition of Fra-1 expression preferentially downregulates transcription from the MMP-1 promoter DNA containing the 2G SNP, compared to DNA containing the 1G SNP. This study provides evidence that, in cooperation with the 2G DNA polymorphism, the AP-1 family member, Fra-1, contributes to the high constitutive expression of MMP-1 in melanoma cells.