Modulation of glutathione synthetic enzymes by acidic fibroblast growth factor.
Increasing evidence suggests that glutathione (GSH) synthesis is a regulated process. Documented increases in gamma-glutamylcysteine synthetase (GCS) occur in response to oxidants, in tumors, on plating cells at a low cell density, and with nerve growth factor stimulation, suggesting that GSH synthesis may be related to the cell growth and transformation. Previously, extracellular acidic fibroblast growth factor (FGF-1) has been demonstrated to cause transformation and aggressive cell growth in murine embryonic fibroblasts. In the present investigation, we sought to determine whether FGF-1, with its growth inducing properties, resulted in the modulation of GSH biosynthetic enzymes, GCS and GSH synthetase. Murine fibroblasts transduced with (hst/KS)FGF-1, a chimeric human FGF-1 gene containing a signal peptide sequence for secretion, displayed elevated gene expression of both heavy and light subunits of GCS. Activity of GSH synthetase was also elevated in these cells compared with control cells. Nonetheless, GSH was decreased in the FGF-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, which induces intrinsic FGF-1 secretion, resulted in similar changes in GCS, GS, and GSH. The results suggest that although increases in the enzymes of GSH synthesis are a common response to growth factors, an increase in GSH content per se is not required for altered cell growth.
Choi
J
J
Department of Molecular Pharmacology, University of Southern California School of Pharmacy, Los Angeles, California, 90033, USA.
Opalenik
S R
SR
Wu
W
W
Thompson
J A
JA
Forman
H J
HJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D005786:Gene Expression Regulation / Q000187:drug effects; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D005981:Glutathione Synthase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007424:Intracellular Fluid / Q000201:enzymology; D051379:Mice; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection
D015696:Gene Products, tat; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D009243:NAD; D016220:Fibroblast Growth Factor 1; D000255:Adenosine Triphosphate; D005721:Glutamate-Cysteine Ligase; D005981:Glutathione Synthase; D005978:Glutathione