Glutathione depletion associated with the HIV-1 TAT protein mediates the extracellular appearance of acidic fibroblast growth factor.
Primary murine embryonic fibroblasts transfected with HIV-1 TAT demonstrated decreased levels of high energy phosphates (ATP, GTP, UTP/CTP), adenine nucleotides (ATP, ADP, AMP), and both NAD+/NADH redox pairs, resulting in a substantial loss of redox poise. A greater than 50% decrease in intracellular reduced glutathione (GSH) concentration was accompanied by the extracellular appearance of acidic fibroblast growth factor (FGF-1). Addition of either N-acetyl-L-cysteine or glutathione ester (GSE), but not L-2-oxothiazolidine 4-carboxylate, partially restored intracellular GSH levels and resulted in loss of extracellular FGF-1. Treatment of FGF-1-transduced cells with buthionine sulfoximine (BSO) resulted in a time- and dose-dependent decrease in total cellular GSH concentration that was accompanied by the extracellular appearance of FGF-1. Inclusion of GSE during BSO treatment eliminated the extracellular appearance of FGF-1. BSO treatment of cells transfected with a mutant form of FGF-1, in which all three cysteine residues were replaced with serines, also decreased total cellular GSH concentration but failed to induce the extracellular appearance of FGF-1. Collectively, these results suggest that HIV-1 TAT induces a condition of oxidative stress, which mediates cellular secretion of FGF-1, an observation relevant to the pathophysiologic development and progression of AIDS-associated Kaposi's sarcoma.
Opalenik
S R
SR
Department of Surgery, School of Medicine, University of Alabama at Birmingham 35294, USA.
Ding
Q
Q
Mallery
S R
SR
Thompson
J A
JA
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D015696:Gene Products, tat / Q000235:genetics / Q000502:physiology*; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1; D051379:Mice; D016296:Mutagenesis; D010084:Oxidation-Reduction; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus
D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D015696:Gene Products, tat; D054322:tat Gene Products, Human Immunodeficiency Virus; D016220:Fibroblast Growth Factor 1; D019328:Buthionine Sulfoximine; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D000111:Acetylcysteine