OVEREXPRESSION OF THE TYPE II TRANSFORMING GROWTH FACTOR-β RECEPTOR INHIBITS FIBROBLAST PROLIFERATION AND ACTIVATES EXTRACELLULAR SIGNAL REGULATED KINASE AND C-JUN N-TERMINAL KINASE

Transforming growth factor-β (TGF-β) is a bimodal regulator of cellular growth. The cellular effects of TGF-β depend on the intensity of signals emanating from TGF-β receptors. Low levels of receptor activity are sufficient to stimulate cell proliferation, while higher degrees of receptor activation are associated with growth inhibition. To study the mechanisms of these effects, a tetracycline-inducible expression system was used to overexpress type II TGF-β receptors in NIH 3T3 fibroblasts. Overexpressed type II TGF-β receptors suppressed fibroblast proliferation elicited by TGF-β1, fibroblast growth factor (FGF) or platelet-derived growth factor (PDGF). Accompanying these anti-proliferative effects, increases in extracellular-signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activity were detected. Furthermore, PDGF α-, but not PDGF β-receptor protein levels were reduced by type II TGF-β receptor overexpression. In conclusion, our system is an excellent tool to study the molecular mechanisms of growth inhibition by TGF-β in fibroblasts. Activation of JNK and ERK, or modulation of PDGF receptor expression may be involved in this process.