A20 and A20-binding proteins as cellular inhibitors of nuclear factor-kappa B-dependent gene expression and apoptosis

Proper gene expression and cell growth are critical for the survival of all organisms. Nuclear factor-kappaB (NF-kappa B)-dependent gene expression an d apoptosis play crucial roles in numerous cellular processes, and defects in their regulation may contribute to a variety of diseases including infla mmation and cancer. Although there has recently been tremendous progress in our understanding of the signaling pathways that lead to NF-kappa B activa tion and apoptosis, signaling mechanisms that negatively regulate these pro cesses are only partially understood. This review deals with the zinc finge r protein A20, which has been characterized as a dual inhibitor of NF-kappa B activation and apoptosis. Its inducible expression by a wide variety of stimuli, including cytokines such as turner necrosis factor, interleukin-1, and CD40, as well as bacterial and viral products such as lipopolysacchari de, Epstein-Barr virus latent membrane protein 1, and human T-cell leukemia virus type I Tax, suggests that it is involved in the negative feedback re gulation of signaling. We will discuss the possible underlying mechanisms, placing emphasis on the role of several A20-binding proteins that have rece ntly been described. Moreover, evidence is presented that A20 and A20-bindi ng proteins are potential novel therapeutic tools in the treatment of a var iety of diseases. BIOCHEM PHARMACOL 60;8:1143-1151, 2000. (C) 2000 Elsevier Science Inc.