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Mol. Cell. Biol. 20 (13): 4505-4512

Copyright © 2000 by the American Society for Microbiology. All rights reserved.

Molecular and Cellular Biology, July 2000, p. 4505-4512, Vol. 20, No. 13
Copyright © 2000, American Society for Microbiology. All rights reserved.

Stat1 as a Component of Tumor Necrosis Factor Alpha Receptor 1-TRADD Signaling Complex To Inhibit NF-kappa B Activation

Yingjian Wang,1 Tong R. Wu,2 Shiying Cai,1 Thomas Welte,1 and Y. Eugene Chin1,*

Department of Pathology and Laboratory Medicine, Brown University School of Medicine, Providence, Rhode Island 02912,2 and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 065101

Received 14 October 1999/Returned for modification 17 November 1999/Accepted 15 March 2000

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-kappa B 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-kappa B degradation and NF-kappa B activation were markedly enhanced in Stat1-deficient cells, whereas overexpression of Stat1 in 293T cells blocked NF-kappa B activation by TNF-alpha . Thus, Stat1 acts as a TNFR1-signaling molecule to suppress NF-kappa B activation.

* Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, Brown University School of Medicine, Providence, RI 02912. Phone: (401) 863-2540. Fax: (401) 863-9008. E-mail: Y_Eugene_Chin{at}

Molecular and Cellular Biology, July 2000, p. 4505-4512, Vol. 20, No. 13
Copyright © 2000, American Society for Microbiology. All rights reserved.

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