Genomic differences are powerful tools for identifying disease genes, the researchers note. Most such alterations, known as a polymorphisms, involve the region of genes that code the information to make proteins and enzymes. The polymorphism the DMS team documents is in the promoter or control region that turns the enzyme on and off.
Brinckerhoff and her colleagues compared versions of MMP-1 whose genetic sequence varies by a single nucleotide building block. The polymorphism entails the presence or absence of the chemical guanine (G), one of the four DNA bases for genetic blueprints. The precise order of these units is unique for each gene.
The version with the extra "G" significantly augments production of the MMP-1 gene in both normal and malignant cells, the team found. It's as if the switch for the enzyme is always in the on position. Additional analysis determined that the difference was an inherited structural variation found in the general population rather than an abnormal mutation of these cancer cells.
"It is well established that MMP-1 has a critical role in collagen degradation. Therefore, the discovery of a structural alteration in the MMP-1 gene that influences its level of expression is important to our understanding of how this enzyme modulates extracellular matrix metabolism, " said Brinckerhoff. The continuous production of the enzyme, she adds, could be a factor in tumor invasion and metastasis.
Other team members included DMS researchers Teresa Mitchell and Jennifer Meyers (biochemistry) and Joni Rutter (pharmacology and toxicology) as well as Laurie Ozelius and James Gusella of Harvard Medical School and Giovanna Buttic of the Institute de Biologie, Lille, France.
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Contact: Hali Wickner
Hali.Wickner@dartmouith.edu
603-650-1481
Dartmouth Medical School
14-Dec-1998