TGF-beta 1 stimulation of fibronectin transcription in cultured human lungfibroblasts 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 effect s on a variety of cell types, modulating cell growth and differentiation as well as extracellular matrix deposition and degradation. In the present wo rk, we demonstrate that TGF-beta 1 produces a fourfold increase in transcri ption of the fibronectin gene in cultured human fetal lung fibroblasts with only a small increase in mRNA stability resulting in a significant increas e in fibronectin mRNA steady state level. A corresponding increase in produ ction of bronectin protein accompanied the increase in mRNA, Through the us e of specific inhibitors, we demonstrate that geranylgeranylated, but not f arnesylated or acylated protein(s), protein kinase C-delta, phosphatidylcho line-specific phospholipse C, tyrosine kinase activity, and stress-activate d protein kinase p38 are required for this TGF-beta 1 effect. Trimeric G pr oteins and mitogen-activated protein kinases erk1 and erk2 do not appear 60 be involved. While these results emphasize the complexities involved in th e control of extracellular matrix synthesis by TGF-beta, they also identify reaction sites that may be amenable to pharmacologic modulation. Such modu lation could be of great advantage in the treatment of a wide variety of un desirable fibrotic reactions. (C) 2000 Academic Press.