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首页> 外文期刊>Biochimica et biophysica acta. Molecular basis of disease: BBA >Erk 1/2 differentially regulates the expression from the 1G/2G single nucleotide polymorphism in the MMP-1 promoter in melanoma cells
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Erk 1/2 differentially regulates the expression from the 1G/2G single nucleotide polymorphism in the MMP-1 promoter in melanoma cells

机译：Erk 1/2差异调节黑素瘤细胞MMP-1启动子中1G / 2G单核苷酸多态性的表达

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摘要

Matrix metalloproteinase-1 (MMP-1) breaks down interstitial collagens, a major component of stromal tissue and a barrier for invading tumor cells. The degradation of collagen by MMP-1 may, therefore, provide one mechanism for facilitating tumor invasion and metastasis. Because of the potential for excessive matrix degradation, the expression of MMP-1 is tightly regulated, often by the mitogen-activated protein kinase (MAPK) pathway. The MAK signal cascade consists of three separate pathways, the extracellular response kinase (ERK), p38 and Jun N-terminal kinase, which target proteins of the AP-1 and ETS families transcription of the gene. The MMP-1 promoter contains a single nucleotide polymorphism (SNP) at -1607 bp, which creates an ETS binding site by the addition of a guanine (5'-GGAT-3' or '2G SNP') compared to the 1G SNP (5'-GAT-3'), and enhances MMP-1 transcription. A2058 melanoma cells represent one tumor cell line that is homozygous for the 2G allele and that produces consititutively high levels of MMP-1. Thus, we used these cells to define the mechanism(s) responsible for this high level of expression. We show that inhibition of ERK 1/2 leads to the repression of MMP-1 transcription, and that both the 2G polymorphism and the adjacent AP-1 site at -1602 bp are necessary for high levels of MMP-1 transcription and for the inhibition of MMP-1 expression by PD098059, a specific ERK inhibitor. Furthermore, restoration of MMP-1 levels after ERK 1/2 inhibition requires de novo protein synthesis of a factor necessary for MMP-1 expression. Thus, this study suggests that the ERK 1/2 pathway targets the 2G polymorphism, and that the continuous synthesis of a protein(s) is necessary for the constitutive expression of MMP-1.
机译：基质金属蛋白酶-1（MMP-1）分解间质胶原蛋白，这是基质组织的主要组成部分，是侵入肿瘤细胞的屏障。因此，MMP-1对胶原蛋白的降解可提供促进肿瘤侵袭和转移的一种机制。由于潜在的过度基质降解，MMP-1的表达通常通过有丝分裂原激活的蛋白激酶（MAPK）途径受到严格调节。 MAK信号级联由三个单独的途径组成，即细胞外应答激酶（ERK），p38和Jun N末端激酶，它们靶向该基因的AP-1和ETS家族转录蛋白。 MMP-1启动子在-1607 bp处含有一个单核苷酸多态性（SNP），与1G SNP相比，它通过添加鸟嘌呤（5'-GGAT-3'或'2G SNP'）来创建ETS结合位点。 5'-GAT-3'），并增强MMP-1转录。 A2058黑色素瘤细胞代表一种肿瘤细胞系，该细胞系对2G等位基因是纯合的，并且能产生高水平的MMP-1。因此，我们使用这些细胞来定义负责这种高水平表达的机制。我们表明，ERK 1/2的抑制导致MMP-1转录的抑制，并且2G多态性和-1602 bp处的相邻AP-1位点对于高水平的MMP-1转录和抑制都是必需的特异性ERK抑制剂PD098059对MMP-1表达的影响此外，ERK 1/2抑制后恢复MMP-1水平需要从头合成蛋白质，这是MMP-1表达所必需的。因此，该研究表明ERK 1/2途径靶向2G多态性，并且蛋白质的连续合成对于MMP-1的组成型表达是必需的。

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