Erk 1/2 differentially regulates the expression from the 1G/2G single nucleotide polymorphism in the MMP-1 promoter in melanoma cells

Abstract

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.

The collagenase-1 (MMP-1) gene promoter polymorphism - 1607/2G is associated with favourable prognosis in patients with colorectal cancer

“…The discovery of polymorphisms in MMP promoters that alter gene expression has revealed strong associations between these genetic variants and increased susceptibility to the development of malignancies and other diseases (Henney et al, 2000;Ye, 2000). The most extensively studied MMP SNP in relation to cancer is the À1607 bp insertion/deletion in the MMP-1 promoter (Rutter et al, 1998;Nishioka et al, 2000;Ghilardi et al, 2001;Zhu et al, 2001;Hinoda et al, 2002;Tower et al, 2002;Wyatt et al, 2002;Zinzindohoue et al, 2005;Elander et al, 2006). Similar studies have been conducted for the MMP-2 (Miao et al, 2003) and MMP-3 (Ghilardi et al, 2002;Hinoda et al, 2002) gene promoter polymorphism in relation to disease susceptibility and metastatic behaviour.…”

“…These studies confirmed that cells containing a 2G allele displayed enhanced transcriptional activity compared to cells harbouring the 1G allele. It was also noted that if MMP-1 transcriptional activity was not altered as a consequence of the MMP-1 polymorphism, then expression of this enzyme was likely to be differentially induced in response to cytokines and growth factors (Rutter et al, 1998;Tower et al, 2002;Wyatt et al, 2002). Investigations are currently underway in our laboratory to address this issue and to determine whether our observations are tumourspecific, or applicable to other adenocarcinomas such as breast and prostate.…”

“…A promoter containing this SNP (giving rise to the 2G genotype) displays significantly 'higher' transcriptional activity in normal and malignant cells compared to cells possessing a 1G allele (Rutter et al, 1998;Wyatt et al, 2002) with 'lower' transcriptional activity. Several studies have identified strong linkage between this polymorphism and several common malignancies, including colorectal (Ghilardi et al, 2001;Hinoda et al, 2002;Zinzindohoue et al, 2005;Elander et al, 2006), endometrial (Nishioka et al, 2000), lung (Zhu et al, 2001), and ovarian (Kanamori et al, 1999) cancers and melanoma (Rutter et al, 1998;Tower et al, 2002). Polymorphisms in the promoter of MMP-2 (Miao et al, 2003), MMP-3 (Ghilardi et al, 2002), and MMP-7 (Zhang et al, 2005) have also been associated with increased susceptibility to the development of cancer, and to poorer prognosis, but these associations have not been found in all studies (Lei et al, 2002;Wenham et al, 2003;Fong et al, 2004;Krippl et al, 2004;Zinzindohoue et al, 2005).…”

Epidermal Growth Factor Receptor Signaling Is Partially Responsible for the Increased Matrix Metalloproteinase-1 Expression in Ocular Epithelial Cells after UVB Radiation

“…38 AP-1 is a protein dimer that consists of c-jun and c-fos. Increased c-fos gene expression correlated with induced AP-1 activation in UVB-exposed keratinocytes and is directed by specific MAPK pathways.…”

“…Increased c-fos gene expression correlated with induced AP-1 activation in UVB-exposed keratinocytes and is directed by specific MAPK pathways. 38 Given this background, PECs were irradiated with 20 mJ/cm 2 UVB, RNA was harvested, and analyzed by RT-PCR (Figure 4; A to D). Note the intermediate-early induction (2 to 6 hours) of both c-fos and c-jun transcripts after UVB (Figure 4, B and C, respectively).…”