EVIDENCE FOR INVOLVEMENT OF PHOSPHATIDYLCHOLINE-PHOSPHOLIPASE-C AND PROTEIN-KINASE-C IN TRANSFORMING GROWTH-FACTOR-BETA SIGNALING

Transforming growth factor-beta (TGF-beta) is a multifunctional peptid e that elicits a wide variety of responses in cells. TGF-beta binds to cell surface receptors that contain cytoplasmic serine/threonine kina se domains. Here we provide evidence that both phospholipase C and pro tein kinase C (pFC) are involved in the TGF-beta activation of transcr iption and luciferase expression from the p3TP-Lux plasmid. Down-regul ation of PKC prevents TGF-beta 1 induction of luciferase expression. S taurosporin and Calphostin C, inhibitors of PKC, block the ability of TGF-beta 1 to initiate transcription of the luciferase gene. Further, D609, an inhibitor of phosphatidylcholine-phospholipase C (PC-PLC), an d secondarily PKC also blocks TGF-1-induced transcription of the trans gene in A549 cells while the phosphatidylinositol-PLC pathway inhibito r U73122 is without effect; TGF-beta elevates steady-state mRNA levels for the endogenous PAI-1 and fibronectin genes. Treatment of cells wi th calphostin C or D609 prevents the TGF-beta-induced increase in thes e mRNAs. Together, these results suggest that PC-PLC and PKC are in a TGF-beta signaling pathway that results in elevated gene expression.