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J. Biol. Chem., Vol. 281, Issue 2, 1215-1223, January 13, 2006

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Regulation of Transactivation Function of the Aryl Hydrocarbon Receptor by the Epstein-Barr Virus-encoded EBNA-3 Protein^*

Elena V. Kashuba, Katarina Gradin¶, Marja Isaguliants||, Laszlo Szekely, Lorenz Poellinger¶1, George Klein, and Arunas Kazlauskas**

From the Microbiology and Tumor Biology Center, Karolinska Institute, S-17177 Stockholm, Sweden, Center for Integrative Recognition in the Immune System, Karolinska Institute, S-17177 Stockholm, Sweden, the ^¶Department of Cell and Molecular Biology, Karolinska Institute, S-17177 Stockholm, Sweden, ^||Swedish Institute for Infectious Disease Control, S-17177 Stockholm, Sweden, and the ^**Department of Immunology, Institute of Biotechnology, LT-02241 Vilnius, Lithuania

EBNA-3 is one of the Epstein-Barr virus (EBV)-encoded nuclear antigens that is indispensable for immunoblastic transformation and sustained proliferation of B-lymphocytes. The molecular mechanisms responsible for the function of EBNA-3 are poorly understood. We previously found that EBNA-3 interacts with an immunophilin-like protein XAP2/ARA9/AIP, which in mammalian cells is known to interact with the latent aryl hydrocarbon receptor (AhR). AhR is a ligand-inducible transcription factor that mediates cellular responses to environmental pollutants, such as 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD). In this study, we show that EBNA-3 interacts specifically with AhR. The stability of this interaction is determined by the activation state of AhR and its association with XAP2. We and others have demonstrated that XAP2 retains the nonactivated AhR in the cell cytoplasm. However, in the presence of TCDD, the effect of XAP2 on the intracellular localization of AhR was counter-acted by EBNA-3, resulting in nuclear translocation of the AhR. In addition, EBNA-3 enhanced transactivation function by the ligand-activated AhR in cells, as assessed by reporter gene assays. Our data suggested that EBNA-3 plays a role in facilitating the ligand-dependent AhR activation process. Following activation of the AhR, we also observed that EBNA-3 counteracted the inhibitory effect of TCDD on the growth of EBV-carrying lymphoblasts. Taken together, our studies revealed a novel interaction between EBV- and AhR-dependent cellular pathways that control cell proliferation and survival.

Received for publication, August 16, 2005

^* This work was supported by the Swedish Cancer Society (Cancerfonden), by a matching grant from the Concern Foundation, Los Angeles, the Cancer Research Institute, New York, and by Swedish Society for Strategic Research and Swedish Society of Medicine. 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: Dept. of Cell and Molecular Biology, Karolinska Institute, von Eulers väg. 3, S-17177 Stockholm, Sweden. E-mail: lorenz.poellinger{at}cmb.ki.se.

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