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Originally published In Press as doi:10.1074/jbc.M510891200 on February 1, 2006

J. Biol. Chem., Vol. 281, Issue 13, 8565-8572, March 31, 2006
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NF{kappa}B Signaling Is Induced by the Oncoprotein Tio through Direct Interaction with TRAF6*

Stefanie Heinemann1, Brigitte Biesinger, Bernhard Fleckenstein, and Jens-Christian Albrecht

From the Institut für Klinische und Molekulare Virologie, Friedrich-Alexander Universität Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany

The transcription factor NF{kappa}B is a major regulator of genes involved in inflammation and oncogenesis. NF{kappa}B is induced upon stimulation of cellular receptors coupled to different intracellular signaling molecules. Further downstream, TRAF6 links at least two receptor pathways to take control of I{kappa}B, the administrator of NF{kappa}B activity. Here we report on a strong NF{kappa}B activation by Tio, a unique herpesviral oncoprotein promoting transformation of human T cells in a Src-kinase-dependent manner. NF{kappa}B induction by Tio is independent of Src-kinase interaction and tyrosine phosphorylation of Tio. Mutation of a glutamic acid-rich motif at the N terminus of Tio, corresponding to a TRAF6 consensus binding motif, completely abrogated NF{kappa}B activation. Cotransfection of a dominant negative TRAF6 construct led to a decrease in NF{kappa}B activation. Furthermore, we provide evidence that TRAF6 directly binds to the Tio oncoprotein. Identification of TRAF6 as the direct target of Tio describes a novel mechanism for the constitutive activation of NF{kappa}B through an oncoprotein.


Received for publication, October 5, 2005 , and in revised form, January 12, 2006.

* This work was supported by the Deutsche Forschungsgemeinschaft (SFB 466, TP C8), the BMBF (Interdisziplinäres Zentrum für klinische Forschung Erlangen, TP B5), and the German-Israeli Foundation (674/2000). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom correspondence should be addressed: Institut für Klinische und Molekulare Virologie, Friedrich-Alexander Universität Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany. Tel.: 49-9131-8526495; Fax: 49-9131-8526493; E-mail: stefanie.heinemann{at}viro.med.uni-erlangen.de.


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