title: Sorsby fundus dystrophy-related mutation in tissue inhibitor of metalloproteinases-3 impairs regulation of its expression in mouse fibroblasts.
abstract: Mutations in the C-terminal domain of tissue inhibitor of metalloproteinases-3 (TIMP-3) are linked with Sorsby fundus dystrophy (autosomal dominant retinal dystrophy). Experiments on timp-3 gene knock-out and knock-in mice, carriers of dystrophy-linked Timp-3S156C mutation, showed that expression of mutant Timp-3S156C, in contrast to the normal one, is not regulated by phorbol-myristate-12-acetate and is retained at a high level in a medium without FCS. The mutant protein is not transported into the nucleus, while fibroblasts expressing it survive without FCS and other growth factors. It is hypothesized that normal Timp-3 is involved in the regulation of expression of its own timp-3 gene and, probably, other genes associated with growth and proliferation. The absence of this characteristic in mutant Timp-3S156C is presumably responsible for its accumulation in the extracellular matrix.
authors.affiliation: Research Center of Obstetrics, Gynecology, and Perinatology, Russian Academy of Medical Sciences, Moscow.
authors.forename: G T
authors.initials: GT
authors.lastname: Sukhikh
authors.forename: G M
authors.initials: GM
authors.lastname: Soboleva
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000201:enzymology; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005654:Fundus Oculi; D008268:Macular Degeneration / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D008934:Mitogens / Q000494:pharmacology; D009154:Mutation; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D008934:Mitogens; D019717:Tissue Inhibitor of Metalloproteinase-3; D003907:Dexamethasone; D013755:Tetradecanoylphorbol Acetate