REQUIREMENT FOR GERANYLGERANYL TRANSFERASE-I AND ACYL TRANSFERASE IN THE TGF-BETA-STIMULATED PATHWAY LEADING TO ELASTIN MESSENGER-RNA STABILIZATION

The TGF-beta s are multipotent in their biological activity, modulatin g cell growth and differentiation as well as extracellular matrix depo sition and degradation. Most of these activities involve modulation of gene transcription. However, TGF-beta 1 has been shown previously to substantially increase the expression of elastin by stabilization of t ropoelastin mRNA through a signaling pathway which involves a phosphat idylcholine-specific phospholipase and a protein kinase C. The present results, through the use of specific inhibitors of geranylgeranyl tra nsferase I, farnesyl transferase, and acyl transferase, demonstrate th at geranylgeranylated and acylated, but not farnesyslated protein(s) i s required for this TGF-beta 1 effect. In addition, the general tyrosi ne kinase inhibitor genistein completely blocked this TGF-beta 1 effec t. The results suggest that the TGF-beta 1signaling pathway requires n ot only receptor ser/thr kinase activity, but also tyrosine kinase and small GTPase activities. (C) 1998 Acaemic Press.