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

Eur J Biochem. 2003 Oct;270(20):4216-25. doi: 10.1046/j.1432-1033.2003.03821.x.

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'; '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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • DNA Mutational Analysis
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Humans
  • Matrix Metalloproteinase 1 / genetics*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic*
  • Proto-Oncogene Proteins c-fos / drug effects
  • Proto-Oncogene Proteins c-fos / metabolism*

Substances

  • Enzyme Inhibitors
  • Flavonoids
  • Proto-Oncogene Proteins c-fos
  • fos-related antigen 1
  • Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 1
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one