Fra‐1 targets the AP‐1 site/2G single nucleotide polymorphism (ETS site) in the MMP‐1 promoter

Abstract

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 bp by a single nucleotide polymorphism (SNP), which contains two guanines (5¢-GGAT-3¢; Ô2G SNPÕ), rather one guanine (5¢-GAT-3¢; Ô1G SNPÕ), 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.

Haplotype Effects on Matrix Metalloproteinase-1 Gene Promoter Activity in Cancer Cells

“…In A2058 melanoma cells, all haplotypes containing the À1607GG allele had significantly higher promoter activity than the haplotypes with the À1607G allele, which is in concordance with results from previous studies on the functional effect of the À1607GG>G polymorphism, whereas the other MMP1 gene promoter polymorphisms had not been taken into account (9,19). Furthermore, an important finding of our study is that in A2058 melanoma cells, there were significant differences among the six haplotypes that contain the À1607GG allele, such that the GG-…”

Interaction of matrix metalloproteinases with pulmonary pollutants: Table 1–

“…Furthermore, data from the literature suggest that fra-1 can modulate the expression of other MMPs after air pollutant exposure. Indeed, fra-1 has been shown to upregulate MMP-12 gene expression in the U937 human monocytic cell line [65], and to play a critical role in maintaining a high-level constitutive MMP-1 gene expression in melanoma cells [66]. Consistent with the study by ZHANG et al [63], MATSUZAKI et al [67] showed an increase in MMP-9 protein release from human neutrophils after incubation for 2 h with DEP extracts prepared on methanol.…”

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

“…A limitation of our study was that we did not confirm whether this polymorphism was indeed functional. There is, however, ample supportive evidence establishing the functionality of this polymorphism in both normal stromal cells (Wyatt et al, 2002) and tumour cells, including melanoma (Tower et al, 2003a) and breast cancer cells (Tower et al, 2003b). These studies confirmed that cells containing a 2G allele displayed enhanced transcriptional activity compared to cells harbouring the 1G allele.…”