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Papers In Press, published online ahead of print December 12, 2000
Department of Cardiovascular Medicine, University of Oxford, Oxford, OXON OX3 9DU
Corresponding Author: pricey{at}well.ox.ac.uk
Matrix metalloproteinase-2 (MMP-2) is an enzyme with proteolytic activity against matrix and non-matrix proteins, particularly basement membrane constituents. Thus, any naturally occurring genetic variants that directly affect gene expression and/or protein function would be expected to impact on progression of pathological processes involving tissue remodelling. We scanned a 2Kb promoter region and all 13 exons of the human MMP-2 gene, from a panel of 32 individuals, and identified the position, nature and relative allele frequencies of fifteen variant loci: six in the promoter, one in the 5´untranslated region, six in the coding region, one in intronic sequence and one in the 3´untranslated region. The majority of coding region polymorphisms resulted in synonymous substitutions whereas three promoter variants (at -1306, -790 and +220) mapped onto cis-acting elements. We functionally characterised all promoter variants by transient transfection experiments with 293, RAW264.7 and A10 cells. The common C/T transition at -1306 (allele frequency 0.26), which disrupts an Sp1-type promoter site (CCACC box), displayed a strikingly lower promoter activity with the T allele. Electrophoretic mobility shift assays confirmed that these differences in allelic expression were attributable to abolition of Sp1 binding. These data suggest that this common functional genetic variant influences MMP-2 gene transcription in an allele-specific manner and is therefore an important candidate to test for association in a wide spectrum of pathologies for which a role for MMP-2 is implicated, including atherogenesis and tumour invasion and metastasis.
J. Biol. Chem, 10.1074/jbc.M010242200
Submitted on November 9, 2000
Revised on December 12, 2000
Accepted on December 12, 2000
Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene: role of Sp1 in allele-specific transcriptional regulation
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