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Inhibition of type I collagen gene expression in normal and systemic sclerosis fibroblasts by a specific inhibitor of geranylgeranyl transferase I. 2000

J Rosenbloom, and B Saitta, and S Gaidarova, and N Sandorfi, and J C Rosenbloom, and W R Abrams, and A D Hamilton, and S M Sebti, and U Kucich, and S A Jimenez
University of Pennsylvania School of Dental Medicine, Philadelphia, USA.

OBJECTIVE To examine the effects of specific inhibition of geranylgeranyl transferase I on the expression of types I and III collagen genes in normal and systemic sclerosis (SSc) dermal fibroblasts in vitro. METHODS Fibroblasts from 2 normal subjects and 4 SSc patients were incubated with 2-10 microM of GGTI-298, a specific geranylgeranyl transferase inhibitor. Type I collagen and fibronectin production were determined by enzyme-linked immunosorbent assay. Steady-state messenger RNA (mRNA) levels for alpha1(I), alpha2(I), and alpha1(III) collagens and fibronectin were assessed by Northern hybridization, and the transcription of the alpha1(I) collagen gene was examined by transient transfections with a reporter construct containing -5.3 kb of the gene. RESULTS GGTI-298 caused a dose-dependent inhibition of type I collagen production and a reduction in the steady-state levels of alpha1(I), alpha2(I), and alpha1(III) mRNA in normal and SSc cells. A 60-70% inhibition of type I collagen production and a 70-80% reduction in the mRNA levels for alpha1(I), alpha2(I), and alpha1(III) were observed at 10 microM GGTI-298. In contrast, the expression of fibronectin, cyclooxygenase 1, and GAPDH was not affected. The effects on alpha1(I) collagen mRNA resulted from a profound reduction in transcription of the alpha1(I) collagen gene promoter. GGTI-298 did not affect cellular viability or morphology. CONCLUSIONS These results demonstrate that specific inhibition of geranylgeranyl prenylation causes a potent and selective inhibition of expression of the genes encoding types I and III collagens, without affecting cellular viability. The findings indicate that inhibition of geranylgeranyl prenylation should be further studied as a potential therapeutic approach for SSc and other fibrosing diseases.

UI MeSH Term Description Entries
D007527 Isoenzymes Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics. Alloenzyme,Allozyme,Isoenzyme,Isozyme,Isozymes,Alloenzymes,Allozymes
D008565 Membrane Proteins Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. Cell Membrane Protein,Cell Membrane Proteins,Cell Surface Protein,Cell Surface Proteins,Integral Membrane Proteins,Membrane-Associated Protein,Surface Protein,Surface Proteins,Integral Membrane Protein,Membrane Protein,Membrane-Associated Proteins,Membrane Associated Protein,Membrane Associated Proteins,Membrane Protein, Cell,Membrane Protein, Integral,Membrane Proteins, Integral,Protein, Cell Membrane,Protein, Cell Surface,Protein, Integral Membrane,Protein, Membrane,Protein, Membrane-Associated,Protein, Surface,Proteins, Cell Membrane,Proteins, Cell Surface,Proteins, Integral Membrane,Proteins, Membrane,Proteins, Membrane-Associated,Proteins, Surface,Surface Protein, Cell
D011451 Prostaglandin-Endoperoxide Synthases Enzyme complexes that catalyze the formation of PROSTAGLANDINS from the appropriate unsaturated FATTY ACIDS, molecular OXYGEN, and a reduced acceptor. Fatty Acid Cyclo-Oxygenase,PGH Synthase,Prostaglandin H Synthase,Prostaglandin Synthase,Prostaglandin-Endoperoxide Synthase,Arachidonic Acid Cyclooxygenase,Cyclo-Oxygenase,Cyclooxygenase,Cyclooxygenases,Hydroperoxide Cyclase,PGH2 Synthetase,Prostaglandin Cyclo-Oxygenase,Prostaglandin Cyclooxygenase,Prostaglandin Endoperoxide Synthetase,Prostaglandin G-H Synthase,Prostaglandin H2 Synthetase,Prostaglandin Synthetase,Cyclase, Hydroperoxide,Cyclo Oxygenase,Cyclo-Oxygenase, Fatty Acid,Cyclo-Oxygenase, Prostaglandin,Cyclooxygenase, Arachidonic Acid,Cyclooxygenase, Prostaglandin,Endoperoxide Synthetase, Prostaglandin,Fatty Acid Cyclo Oxygenase,G-H Synthase, Prostaglandin,Prostaglandin Cyclo Oxygenase,Prostaglandin Endoperoxide Synthases,Prostaglandin G H Synthase,Synthase, PGH,Synthase, Prostaglandin,Synthase, Prostaglandin G-H,Synthase, Prostaglandin H,Synthase, Prostaglandin-Endoperoxide,Synthases, Prostaglandin-Endoperoxide,Synthetase, PGH2,Synthetase, Prostaglandin,Synthetase, Prostaglandin Endoperoxide,Synthetase, Prostaglandin H2
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D002461 Cell Line, Transformed Eukaryotic cell line obtained in a quiescent or stationary phase which undergoes conversion to a state of unregulated growth in culture, resembling an in vitro tumor. It occurs spontaneously or through interaction with viruses, oncogenes, radiation, or drugs/chemicals. Transformed Cell Line,Cell Lines, Transformed,Transformed Cell Lines
D003094 Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of SKIN; CONNECTIVE TISSUE; and the organic substance of bones (BONE AND BONES) and teeth (TOOTH). Avicon,Avitene,Collagen Felt,Collagen Fleece,Collagenfleece,Collastat,Dermodress,Microfibril Collagen Hemostat,Pangen,Zyderm,alpha-Collagen,Collagen Hemostat, Microfibril,alpha Collagen
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D005347 Fibroblasts Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. Fibroblast
D005353 Fibronectins Glycoproteins found on the surfaces of cells, particularly in fibrillar structures. The proteins are lost or reduced when these cells undergo viral or chemical transformation. They are highly susceptible to proteolysis and are substrates for activated blood coagulation factor VIII. The forms present in plasma are called cold-insoluble globulins. Cold-Insoluble Globulins,LETS Proteins,Fibronectin,Opsonic Glycoprotein,Opsonic alpha(2)SB Glycoprotein,alpha 2-Surface Binding Glycoprotein,Cold Insoluble Globulins,Globulins, Cold-Insoluble,Glycoprotein, Opsonic,Proteins, LETS,alpha 2 Surface Binding Glycoprotein
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man

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