Erk 1/2 differentially regulates the expression from the 1G/2G single nucleotide polymorphism in the MMP-1 promoter in melanoma cells.
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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DOI：
10.1016/s0925-4439(01)00105-3
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发表时间：
2002-04
期刊：
影响因子：
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通讯作者：
Grant B. Tower;Charles C Coon;U. Benbow;M. Vincenti;C. Brinckerhoff
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文献类型：
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作者：
Grant B. Tower;Charles C Coon;U. Benbow;M. Vincenti;C. Brinckerhoff
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 MAPK 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 constitutively 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.
