Modulation of glutathione synthetic enzymes by acidic fibroblast growth factor

Increasing evidence suggests that glutathione (GSH) synthesis is a regulate d process. Documented increases in gamma-glutamylcysteine synthetase (GCS) occur in response to oxidants, in tumors, on plating cells at a low cell de nsity, and with nerve growth factor stimulation, suggesting that GSH synthe sis may be related to the cell growth and transformation. Previously, extra cellular acidic fibroblast growth factor (FGF-1) has been demonstrated to c ause transformation and aggressive cell growth in murine embryonic fibrobla sts, In the present investigation, we sought to determine whether FGF-1, wi th its growth inducing properties, resulted in the modulation of GSH biosyn thetic enzymes, GCS and GSH synthetase, Murine fibroblasts transduced with (hst/KS)FGF-1, a chimeric human FGF-1 gene containing a signal peptide sequ ence for secretion, displayed elevated gene expression of both heavy and li ght subunits of GCS. Activity of GSH synthetase was also elevated in these cells compared with control cells. Nonetheless, GSH was decreased in the FG F-1-transduced cells along with high energy phosphates, adenine nucleotides , NADH, and the redox poise. However, GSSG was not elevated in these cells, Fibroblasts stably expressing human immunodeficiency virus type 1 Tat, whi ch induces intrinsic FGF-1 secretion, resulted in similar changes in GCS, G S, and GSH, The results suggest that although increases in the enzymes of G SH synthesis are a common response to growth factors, an increase in GSH co ntent per se is not required for altered cell growth. (C) 2000 Academic Pre ss.