TGF-beta1 stimulation of fibronectin transcription in cultured human lung fibroblasts requires active geranylgeranyl transferase I, phosphatidylcholine-specific phospholipase C, protein kinase C-delta, and p38, but not erk1/erk2.
The cytokine transforming growth factor-beta (TGF-beta) has multiple effects on a variety of cell types, modulating cell growth and differentiation as well as extracellular matrix deposition and degradation. In the present work, we demonstrate that TGF-beta1 produces a fourfold increase in transcription of the fibronectin gene in cultured human fetal lung fibroblasts with only a small increase in mRNA stability resulting in a significant increase in fibronectin mRNA steady state level. A corresponding increase in production of fibronectin protein accompanied the increase in mRNA. Through the use of specific inhibitors, we demonstrate that geranylgeranylated, but not farnesylated or acylated protein(s), protein kinase C-delta, phosphatidylcholine-specific phospholipse C, tyrosine kinase activity, and stress-activated protein kinase p38 are required for this TGF-beta1 effect. Trimeric G proteins and mitogen-activated protein kinases erk1 and erk2 do not appear to be involved. While these results emphasize the complexities involved in the control of extracellular matrix synthesis by TGF-beta, they also identify reaction sites that may be amenable to pharmacologic modulation. Such modulation could be of great advantage in the treatment of a wide variety of undesirable fibrotic reactions.
Kucich
U
U
Department of Anatomy and Histology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania 19104, USA.
Rosenbloom
J C
JC
Shen
G
G
Abrams
W R
WR
Hamilton
A D
AD
Sebti
S M
SM
Rosenbloom
J
J
D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics* / Q000378:metabolism*; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008168:Lung / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009636:Norbornanes; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D017368:Protein Prenylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D001952:Bridged-Ring Compounds; D005353:Fibronectins; D007527:Isoenzymes; D009636:Norbornanes; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D013859:Thiocarbamates; D013871:Thiones; D016212:Transforming Growth Factor beta; C046498:tricyclodecane-9-yl-xanthogenate; D003513:Cycloheximide; D019833:Genistein; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C