TRANSFORMING GROWTH-FACTOR-BETA-1 REGULATION OF SIGNAL-TRANSDUCTION IN 2 RENAL EPITHELIAL-CELL LINES

The present studies examine the effect of transforming growth factor-beta1 (TGF-beta1) on signal transduction pathways in two cultured renal epithelial cell lines. TGF-beta1 promotes basal and agonist-stimulated adenylate cyclase activity in LLC-PK1 but not MDCK cell membranes. TGF-beta1 stimulation of LLC-PK1 membrane adenylate cyclase activity occurs quickly and can be attenuated by pertussis toxin pretreatment. Both TGF-beta1 and adenosine 3',5'-cyclic monophosphate (cAMP) exert comparable effects on [H-3]thymidine uptake in LLC-PK, cells, suggesting that TGF-beta1 regulation of adenylate cyclase activity potentially plays a role in mediating biological responses to TGF-beta1. The activities of protein kinase C and phospholipase A are not affected by TGF-beta1 in either LLC-PK1 or MDCK cells. Both TGF-beta1 and epidermal growth factor (EGF) increase expression and induce the appearance of new forms of the cAMP response element binding protein (CREB) in LLC-PK1 cells. These effects of TGF-beta1 and EGF on CREB appear to be specific since neither TGF-beta1 nor EGF alters expression of an activating transcription factor in LLC-PK1 cells. The effect of TGF-beta1 and EGF to alter expression of CREB does not affect CREB binding to its regulatory element in LLC-PK1 cell lysates. These results suggest that some of the biological effects of TGF-beta1 may be attributed to stimulation of adenylate cyclase activity and cAMP formation as well as to enhanced expression and/or modification of the CREB transcription factor in LLC-PK1 cells.