TNF-INDUCED MITOCHONDRIAL CHANGES AND ACTIVATION OF APOPTOTIC PROTEASES ARE INHIBITED BY A20

A20 zinc finger protein is a product of a cytokine-induced primary res ponse gene. It functions as a negative regulator of the tumor necrosis factor (TNF) inhibiting both TNF-mediated apoptosis and activation of transcription factors. We demonstrated that A20 overexpression blocks early TNF-induced signaling events including the generation of free r adicals, the fall in mitochondrial transmembrane potential (Delta psi( m)), and the activation of caspase-3-like apoptotic proteases. General inhibitor of caspases, cow pox virus-derived CrraA, also inhibited TN F-induced mitochondrial changes indicating that early caspase activati on occurs upstream from mitochondrial changes. Interestingly, changes in mitochondrial function or induction of caspase-3-like activity indu ced by anti-Fas or doxorubicin were not inhibited by A20. The data sho w that A20 is a specific inhibitor of TNF signaling and acts upstream of INF-induced free radical formation, fall in mitochondrial transmemb rane potential (Delta psi(m)), and activation of caspase-3-like protea ses. (C) 1998 Elsevier Science Inc.