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PMID:10848577

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Citation

Wang, Y, Wu, TR, Cai, S, Welte, T and Chin, YE (2000) Stat1 as a component of tumor necrosis factor alpha receptor 1-TRADD signaling complex to inhibit NF-kappaB activation. Mol. Cell. Biol. 20:4505-12

Abstract

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.

Links

PubMed PMC85828

Keywords

Adaptor Proteins, Signal Transducing; Antigens, CD/genetics; Antigens, CD/immunology; Antigens, CD/metabolism; Apoptosis/physiology; Biological Transport; Carrier Proteins/immunology; Carrier Proteins/metabolism; Cell Line/drug effects; Cell Nucleus/metabolism; DNA-Binding Proteins/metabolism; Fas-Associated Death Domain Protein; Humans; Immunochemistry/methods; NF-kappa B/drug effects; NF-kappa B/genetics; NF-kappa B/metabolism; Proteins/genetics; Proteins/immunology; Proteins/metabolism; Receptor-Interacting Protein Serine-Threonine Kinases; Receptors, Tumor Necrosis Factor/genetics; Receptors, Tumor Necrosis Factor/immunology; Receptors, Tumor Necrosis Factor/metabolism; Receptors, Tumor Necrosis Factor, Type I; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; STAT1 Transcription Factor; Signal Transduction; TNF Receptor-Associated Factor 1; TNF Receptor-Associated Factor 2; Trans-Activators/metabolism; Transcriptional Activation/drug effects; Tumor Necrosis Factor-alpha/pharmacology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TNR1A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P42224

F

Seeded From UniProt

complete

HUMAN:TNR1B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P42224

F

Seeded From UniProt

complete

HUMAN:STAT1

involved_in

GO:0033209: tumor necrosis factor-mediated signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:STAT1

involved_in

GO:0043124: negative regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:STAT1

enables

GO:0005164: tumor necrosis factor receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P19438

F

Seeded From UniProt

complete

HUMAN:STAT1

enables

GO:0005164: tumor necrosis factor receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P20333

F

Seeded From UniProt

complete

HUMAN:STAT1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15628

F

Seeded From UniProt

complete

HUMAN:TRADD

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P42224

F

Seeded From UniProt

complete


See also

References

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