Abstract
Transforming growth factor-beta (TGF-beta) has growth-stimulating effects on mesenchymal cells and several tumor cell lines. The signaling pathway for this effect is, however, not well understood. We examined how TGF-beta stimulates proliferation of MG63 human osteosarcoma cells. Two distinct type I receptors for TGF-beta, ALK-1 and ALK-5, were expressed and functional in MG63 cells. Of these two receptors, ALK-5 appears to be responsible for the growth stimulation because expression of constitutively active ALK-5, but not ALK-1, stimulated proliferation of MG63 cells. SB-431542 (0.3 microM), a novel inhibitor of ALK4/5/7 kinase, suppressed TGF-beta-induced growth stimulation. DNA microarray analysis as well as quantitative real-time PCR analysis of RNAs from TGF-beta-treated cells demonstrated that several growth factors, including platelet-derived growth factor AA, were induced in response to TGF-beta in MG63 cells. Gleevec (1 microM) as well as AG1296 (5 microM) inhibited TGF-beta-induced growth stimulation of MG63 cells, suggesting that platelet-derived growth factor AA was mainly responsible for the growth-stimulatory effect of TGF-beta. We also examined the mechanisms of perturbation of growth-suppressing signaling in MG63 cells. We found that expression of c-Myc, which is down-regulated by TGF-beta in many other cells, was up-regulated in MG63 cells, suggesting that up-regulation of c-Myc expression may be the mechanism canceling growth-suppressing signaling of TGF-beta in MG63 cells.
MeSH terms
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Activin Receptors, Type I / biosynthesis
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Activin Receptors, Type I / physiology
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Activin Receptors, Type II
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Animals
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Antineoplastic Agents / pharmacology*
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Benzamides / pharmacology*
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Bone Neoplasms / drug therapy
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Bone Neoplasms / genetics
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Bone Neoplasms / metabolism
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Bone Neoplasms / pathology*
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Cell Division / drug effects
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Cell Division / physiology
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Cell Line, Tumor
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / biosynthesis
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Cyclins / genetics
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Dioxoles / pharmacology*
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Drug Interactions
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Imatinib Mesylate
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Mice
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NIH 3T3 Cells
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Oligonucleotide Array Sequence Analysis
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Osteosarcoma / drug therapy
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Osteosarcoma / genetics
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Osteosarcoma / metabolism
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Osteosarcoma / pathology*
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Piperazines / pharmacology*
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-myc / biosynthesis
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Proto-Oncogene Proteins c-myc / genetics
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Pyrimidines / pharmacology*
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / biosynthesis
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Receptors, Transforming Growth Factor beta / physiology
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Signal Transduction / physiology
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Transforming Growth Factor beta / antagonists & inhibitors*
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Transforming Growth Factor beta / pharmacology
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Transforming Growth Factor beta / physiology
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Up-Regulation / drug effects
Substances
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4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
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Antineoplastic Agents
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Benzamides
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Dioxoles
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Piperazines
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Proto-Oncogene Proteins c-myc
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Pyrimidines
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Receptors, Transforming Growth Factor beta
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Transforming Growth Factor beta
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Imatinib Mesylate
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Protein Serine-Threonine Kinases
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ACVRL1 protein, human
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Activin Receptors, Type I
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Activin Receptors, Type II
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Acvrl1 protein, mouse
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Receptor, Transforming Growth Factor-beta Type I
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TGFBR1 protein, human
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Tgfbr1 protein, mouse