Stat1 as a component of tumor necrosis factor alpha receptor 1-TRADD signaling complex to inhibit NF-kappaB activation.
Activated tumor necrosis factor alpha (TNF-alpha) receptor 1 (TNFR1) recruits TNFR1-associated death domain protein (TRADD), which in turn triggers two opposite signaling pathways leading to caspase activation for apoptosis induction and NF-kappaB activation for antiapoptosis gene upregulation. Here we show that Stat1 is involved in the TNFR1-TRADD signaling complex, as ... determined by employing a novel antibody array screening method. In HeLa cells, Stat1 was associated with TNFR1 and this association was increased with TNF-alpha treatment. TNFR1 signaling factors TRADD and Fas-associated death domain protein (FADD) were also found to interact with Stat1 in a TNF-alpha-dependent process. Our in vitro recombinant protein-protein interaction studies demonstrated that Stat1 could directly interact with TNFR1 and TRADD but not with FADD. Interaction between Stat1 and receptor-interacting protein (RIP) or TNFR-associated factor 2 (TRAF2) was not detected. Examination of Stat1-deficient cells showed an apparent increase in TNF-alpha-induced TRADD-RIP and TRADD-TRAF2 complex formation, while interaction between TRADD and FADD was unaffected. As a consequence, TNF-alpha-mediated I-kappaB degradation and NF-kappaB activation were markedly enhanced in Stat1-deficient cells, whereas overexpression of Stat1 in 293T cells blocked NF-kappaB activation by TNF-alpha. Thus, Stat1 acts as a TNFR1-signaling molecule to suppress NF-kappaB activation.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Antigens, CD, Apoptosis, Biological Transport, Carrier Proteins, Cell Line, Cell Nucleus, DNA-Binding Proteins, Fas-Associated Death Domain Protein, Humans, Immunochemistry, NF-kappa B, Proteins, Receptor-Interacting Protein Serine-Threonine Kinases, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Recombinant Fusion Proteins, STAT1 Transcription Factor, Signal Transduction, TNF Receptor-Associated Factor 1, TNF Receptor-Associated Factor 2, Trans-Activators, Transcriptional Activation, Tumor Necrosis Factor-alpha
Adaptor Proteins, Signal Transducing, Antigens, CD, Apoptosis, Biological Transport, Carrier Proteins, Cell Line, Cell Nucleus, DNA-Binding Proteins, Fas-Associated Death Domain Protein, Humans, Immunochemistry, NF-kappa B, Proteins, Receptor-Interacting Protein Serine-Threonine Kinases, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Recombinant Fusion Proteins, STAT1 Transcription Factor, Signal Transduction, TNF Receptor-Associated Factor 1, TNF Receptor-Associated Factor 2, Trans-Activators, Transcriptional Activation, Tumor Necrosis Factor-alpha
Mol. Cell. Biol.
Date: Jul. 01, 2000
PubMed ID: 10848577
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