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Matrix metalloproteinase-2 (MMP-2) is an enzyme with proteolytic activity against matrix and nonmatrix 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 remodeling. We scanned a 2-kilobase pair promoter region and all 13 exons of the human MMP-2 gene, from a panel of 32 individuals, and we identified the position, nature, and relative allele frequencies of 15 variant loci as follows: 6 in the promoter, 1 in the 5'-untranslated region, 6 in the coding region, 1 in intronic sequence, and 1 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 characterized 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 tumor invasion and metastasis.

Original publication

DOI

10.1074/jbc.M010242200

Type

Journal article

Journal

J Biol Chem

Publication Date

09/03/2001

Volume

276

Pages

7549 - 7558

Keywords

3' Untranslated Regions, 5' Untranslated Regions, Alleles, Animals, Cell Line, Cell Nucleus, Chromatography, High Pressure Liquid, Databases, Factual, Exons, Genes, Reporter, Genetic Variation, Humans, Introns, Matrix Metalloproteinase 2, Mice, Models, Genetic, Molecular Sequence Data, Polymorphism, Genetic, Promoter Regions, Genetic, Sp1 Transcription Factor, Transcription, Genetic, Transfection