Abstract
Transforming growth factors (TGFs)-beta are multipotent in their biologic activity, regulating cell growth and differentiation as well as extracellular matrix deposition and degradation. Most of these activities involve modulation of gene transcription, but TGF-beta1 has been shown previously to substantially increase the expression of elastin by stabilization of tropoelastin mRNA through a signaling pathway that likely involves a phosphatidylcholine-specific phospholipase C, a protein kinase C, prenylated and acylated protein(s), and one or more tyrosine kinases. However, there is a 4- to 6-h lag period after the addition of TGF-beta1 before significant stimulation of elastin expression is observed and the question of whether the Smads are involved has not been addressed. In the present work, using cultured human fetal lung fibroblasts, we show through the use of specific inhibitors and transfection of a Smad 7 construct that in addition to de novo protein synthesis and active Smads, the extended activity of protein kinase C (PKC)-delta and the stress-activated protein kinase, p38, is required for TGF-beta1 to achieve elastin mRNA stabilization.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetophenones / pharmacology
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Benzopyrans / pharmacology
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Carbazoles / pharmacology
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Cells, Cultured
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Cycloheximide / pharmacology
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DNA-Binding Proteins / metabolism
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Elastin / genetics*
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Elastin / metabolism
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Enzyme Inhibitors / pharmacology
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Fibroblasts / drug effects
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Fibroblasts / physiology
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Gene Expression Regulation / physiology
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Genes, Reporter
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Humans
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Indoles / pharmacology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism*
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / metabolism*
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Protein Kinase C-delta
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Protein Synthesis Inhibitors / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / physiology
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Smad7 Protein
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Time Factors
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Trans-Activators / metabolism
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Transforming Growth Factor beta / metabolism*
Substances
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Acetophenones
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Benzopyrans
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Carbazoles
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DNA-Binding Proteins
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Enzyme Inhibitors
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Indoles
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Isoenzymes
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Protein Synthesis Inhibitors
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RNA, Messenger
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Recombinant Fusion Proteins
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SMAD7 protein, human
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Smad7 Protein
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Trans-Activators
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Transforming Growth Factor beta
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Go 6976
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Elastin
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Cycloheximide
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rottlerin
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PRKCD protein, human
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Protein Kinase C
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Protein Kinase C-delta
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Mitogen-Activated Protein Kinases