tailieunhanh - Báo cáo khoa học: Fra-1 targets the AP-1 site/2G single nucleotide polymorphism (ETS site) in the MMP-1 promoter

The matrix metalloproteinase (MMP) family degrades the extracellular matrix. One member of this family, MMP-1, initiates the breakdown of interstitial collagens. The expression ofMMP-1 is controlled by themitogen activated protein kinase (MAPK) pathway(s) via the activity of acti-vator protein-1 (AP-1) and polyoma enhancing activity-3/ E26 virus (PEA3/ETS) transcription factors through con-sensus binding sites present in the promoter. | Eur. J. Biochem. 270 4216-4225 2003 FEBS 2003 doi Fra-1 targets the AP-1 site 2G single nucleotide polymorphism ETS site in the MMP-1 promoter Grant B. Tower1 Charles I. Coon2 Karine Belguise3 Dany Chalbos3 and Constance E. Brinckerhoff1 2 Department of 1 Biochemistry and 2Medicine at Dartmouth Medical School Hanover NH USA 3Institut National de la Sante et de la Recherche Medicale Endocrinologie Moleculaire et Cellulaire des Cancers Montpellier France 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 TG 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 .