PMID- 10385526 OWN - NLM STAT- MEDLINE DCOM- 19990802 LR - 20231213 IS - 0021-9525 (Print) IS - 1540-8140 (Electronic) IS - 0021-9525 (Linking) VI - 145 IP - 7 DP - 1999 Jun 28 TI - The zinc finger protein A20 inhibits TNF-induced NF-kappaB-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-kappaB-inhibiting protein ABIN. PG - 1471-82 AB - The zinc finger protein A20 is a tumor necrosis factor (TNF)- and interleukin 1 (IL-1)-inducible protein that negatively regulates nuclear factor-kappa B (NF-kappaB)-dependent gene expression. However, the molecular mechanism by which A20 exerts this effect is still unclear. We show that A20 does not inhibit TNF- induced nuclear translocation and DNA binding of NF-kappaB, although it completely prevents the TNF- induced activation of an NF-kappaB-dependent reporter gene, as well as TNF-induced IL-6 and granulocyte macrophage-colony stimulating factor gene expression. Moreover, NF-kappaB activation induced by overexpression of the TNF receptor-associated proteins TNF receptor-associated death domain protein (TRADD), receptor interacting protein (RIP), and TNF recep- tor-associated factor 2 (TRAF2) was also inhibited by expression of A20, whereas NF-kappaB activation induced by overexpression of NF-kappaB-inducing kinase (NIK) or the human T cell leukemia virus type 1 (HTLV-1) Tax was unaffected. These results demonstrate that A20 inhibits NF-kappaB-dependent gene expression by interfering with a novel TNF-induced and RIP- or TRAF2-mediated pathway that is different from the NIK-IkappaB kinase pathway and that is specifically involved in the transactivation of NF-kappaB. Via yeast two-hybrid screening, we found that A20 binds to a novel protein, ABIN, which mimics the NF-kappaB inhibiting effects of A20 upon overexpression, suggesting that the effect of A20 is mediated by its interaction with this NF-kappaB inhibiting protein, ABIN. FAU - Heyninck, K AU - Heyninck K AD - Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, B-9000 Ghent, Belgium. FAU - De Valck, D AU - De Valck D FAU - Vanden Berghe, W AU - Vanden Berghe W FAU - Van Criekinge, W AU - Van Criekinge W FAU - Contreras, R AU - Contreras R FAU - Fiers, W AU - Fiers W FAU - Haegeman, G AU - Haegeman G FAU - Beyaert, R AU - Beyaert R LA - eng SI - GENBANK/AJ242777 SI - GENBANK/AJ242778 PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Cell Biol JT - The Journal of cell biology JID - 0375356 RN - 0 (Carrier Proteins) RN - 0 (DNA-Binding Proteins) RN - 0 (Gene Products, tax) RN - 0 (Interleukin-6) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (NF-kappa B) RN - 0 (Nuclear Proteins) RN - 0 (Proteins) RN - 0 (TNF Receptor-Associated Death Domain Protein) RN - 0 (TNF Receptor-Associated Factor 1) RN - 0 (TNF Receptor-Associated Factor 2) RN - 0 (Tradd protein, mouse) RN - 0 (Trans-Activators) RN - 0 (Tumor Necrosis Factor Receptor-Associated Peptides and Proteins) RN - 0 (Tumor Necrosis Factor-alpha) RN - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor) RN - 9007-49-2 (DNA) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (RIPK1 protein, human) RN - EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Ripk1 protein, mouse) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 3.4.19.12 (TNFAIP3 protein, human) RN - EC 3.4.19.12 (Tumor Necrosis Factor alpha-Induced Protein 3) RN - EC 3.4.22.- (Cysteine Endopeptidases) RN - EC 3.4.22.- (Tnfaip3 protein, mouse) SB - IM MH - Animals MH - Calcium-Calmodulin-Dependent Protein Kinases/metabolism MH - Carrier Proteins/genetics/*metabolism MH - Cell Line MH - Cell Nucleus/drug effects/metabolism MH - Cysteine Endopeptidases MH - DNA/genetics/metabolism MH - DNA-Binding Proteins MH - Enzyme Activation/drug effects MH - Gene Products, tax/genetics/metabolism MH - Granulocyte-Macrophage Colony-Stimulating Factor/genetics MH - Humans MH - Interleukin-6/genetics MH - Intracellular Signaling Peptides and Proteins MH - Mice MH - *Mitogen-Activated Protein Kinases MH - Molecular Sequence Data MH - NF-kappa B/antagonists & inhibitors/*metabolism MH - Nuclear Proteins/genetics/physiology MH - Protein Binding/drug effects MH - Protein Serine-Threonine Kinases/genetics/metabolism MH - Proteins/chemistry/genetics/*metabolism MH - Receptor-Interacting Protein Serine-Threonine Kinases MH - Signal Transduction/drug effects MH - TNF Receptor-Associated Death Domain Protein MH - TNF Receptor-Associated Factor 1 MH - TNF Receptor-Associated Factor 2 MH - Trans-Activators/genetics/physiology MH - *Transcriptional Activation/drug effects MH - *Tumor Necrosis Factor Receptor-Associated Peptides and Proteins MH - Tumor Necrosis Factor alpha-Induced Protein 3 MH - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/pharmacology MH - Yeasts/genetics MH - Zinc Fingers MH - p38 Mitogen-Activated Protein Kinases MH - NF-kappaB-Inducing Kinase PMC - PMC2133159 EDAT- 1999/06/29 00:00 MHDA- 1999/06/29 00:01 PMCR- 1999/12/28 CRDT- 1999/06/29 00:00 PHST- 1999/06/29 00:00 [pubmed] PHST- 1999/06/29 00:01 [medline] PHST- 1999/06/29 00:00 [entrez] PHST- 1999/12/28 00:00 [pmc-release] AID - 10.1083/jcb.145.7.1471 [doi] PST - ppublish SO - J Cell Biol. 1999 Jun 28;145(7):1471-82. doi: 10.1083/jcb.145.7.1471.