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

Arch Biochem Biophys. 2000 Feb 15;374(2):313-24. doi: 10.1006/abbi.1999.1625.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkyl and Aryl Transferases / metabolism*
  • Bridged-Ring Compounds / pharmacology
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Line
  • Cycloheximide / pharmacology
  • Fibroblasts / metabolism
  • Fibronectins / genetics*
  • Fibronectins / metabolism*
  • Genistein / pharmacology
  • Humans
  • Isoenzymes / metabolism*
  • Kinetics
  • Lung / metabolism*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphodiesterase Inhibitors / pharmacology
  • Protein Kinase C / metabolism*
  • Protein Kinase C-delta
  • Protein Prenylation
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Thiones / pharmacology
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology*
  • Transforming Growth Factor beta / pharmacology*
  • Type C Phospholipases / metabolism*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Bridged-Ring Compounds
  • Fibronectins
  • Isoenzymes
  • Phosphodiesterase Inhibitors
  • RNA, Messenger
  • Thiones
  • Transforming Growth Factor beta
  • tricyclodecane-9-yl-xanthogenate
  • Cycloheximide
  • Genistein
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I
  • PRKCD protein, human
  • Protein Kinase C
  • Protein Kinase C-delta
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Type C Phospholipases
  • phosphatidylcholine-specific phospholipase C