Abstract
Connective tissue growth factor (CTGF) is a 38-kDa cysteine-rich peptide, whose synthesis and secretion are selectively induced by transforming growth factor beta (TGF-beta) in connective tissue cells. Previous studies have demonstrated that CTGF functions as a downstream mediator of TGF-beta mitogenic activity, where it controls cell cycle progression through late G1 and S-phase entry of NRK fibroblast suspension cultures. Here we report that CTGF induces this S-phase entry by upregulating cyclin A levels. The molecular mechanism for cyclin A induction appears to be via reduction of p27(Kip1) levels, which results in hyperphosphorylation of pRb and release of E2F, a known modulator of cyclin A gene transcription. These data indicate that CTGF acts as a mediator of TGF-beta-induced fibroblast proliferation in suspension cultures by regulating cdk activities.
Copyright 2000 Wiley-Liss, Inc.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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8-Bromo Cyclic Adenosine Monophosphate / antagonists & inhibitors
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8-Bromo Cyclic Adenosine Monophosphate / pharmacology
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Animals
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Cell Cycle / drug effects*
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Cell Cycle Proteins*
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Cell Line
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Cell Transformation, Neoplastic / drug effects
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Connective Tissue Growth Factor
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Cyclic AMP / analogs & derivatives
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Cyclic AMP / antagonists & inhibitors
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Cyclic AMP / pharmacology*
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Cyclin A / biosynthesis
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Cyclin A / genetics
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Cyclin A / physiology
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Cyclin-Dependent Kinases / metabolism
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Fibroblasts / cytology*
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Growth Substances / pharmacology*
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Immediate-Early Proteins*
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Intercellular Signaling Peptides and Proteins*
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Kidney / cytology
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Microtubule-Associated Proteins / metabolism
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Mitogens / pharmacology*
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Phosphorylation / drug effects
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Promoter Regions, Genetic / genetics
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Rats
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Retinoblastoma Protein / metabolism
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / pharmacology
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Tumor Suppressor Proteins*
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Up-Regulation / drug effects
Substances
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CCN2 protein, rat
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Cdkn1b protein, rat
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Cell Cycle Proteins
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Cyclin A
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Growth Substances
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Immediate-Early Proteins
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Intercellular Signaling Peptides and Proteins
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Microtubule-Associated Proteins
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Mitogens
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Retinoblastoma Protein
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Transforming Growth Factor beta
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Tumor Suppressor Proteins
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Connective Tissue Growth Factor
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Cyclin-Dependent Kinase Inhibitor p27
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8-Bromo Cyclic Adenosine Monophosphate
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Cyclic AMP
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Cyclin-Dependent Kinases