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J. Biol. Chem., Vol. 282, Issue 39, 28335-28343, September 28, 2007

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BCL3 Acts as a Negative Regulator of Transcription from the Human T-cell Leukemia Virus Type 1 Long Terminal Repeat through Interactions with TORC3^*

Takayuki Hishiki¹, Takayuki Ohshima^¶, Takeshi Ego, and Kunitada Shimotohno²

From the Department of Viral Oncology, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, and ^¶Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Shido, Sanuki City, Kagawa 769-2193, Japan

By associating with cyclic AMP-responsive element-binding protein (CREB), the human T-cell leukemia virus type 1 (HTLV-1) Tax protein activates transcription from the HTLV-1 long terminal repeat (LTR), which contains multiple cyclic AMP-responsive elements. The transducers of regulated CREB activity (TORCs) were a recently identified family of CREB co-activators that bind to CREB to enhance CRE-mediated transcription. TORC3, a TORC family protein, dramatically enhances Tax-mediated transcription from the LTR. In this study, we performed a yeast two-hybrid screen using the N-terminal region of TORC3 as bait and identified B-cell chronic lymphatic leukemia protein 3 (BCL3) as a protein interacting with TORC3. This interaction was confirmed by glutathione S-transferase pulldown assays and co-immunoprecipitation experiments with detection by Western blotting. The ankyrin repeat domain of BCL3 interacted with TORC3. By using a luciferase assay, we determined that BCL3 inhibited transcription from the HTLV-1 LTR in a manner dependent on TORC3. Knockdown of endogenous BCL3 using RNA interference enhanced transcriptional activation of CRE. Treatment with trichostatin A, a potent inhibitor of the transcriptional co-repressor HDAC, partially reversed the inhibitory effect of BCL3. These results suggest that BCL3 functions as a repressor of HTLV-1 LTR-mediated transcription through interactions with TORC3. In addition to stimulating transcription from the HTLV-1 LTR, Tax also enhances BCL3 expression; thus, transcription from the LTR is regulated by both positive and negative feedback mechanisms.

Received for publication, March 28, 2007 , and in revised form, June 26, 2007.

^* This work was supported in part by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Takeda Science Foundation, and the Suzuken Memorial Foundation. 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 Supported by the 21st Century COE Program of the Ministry of Education, Culture, Sports, Science and Technology of Japan at Kyoto University.

² To whom correspondence should be addressed: Laboratory of Human Tumor Viruses, Dept. of Viral Oncology, Institute for Virus Research, Kyoto University, 53 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: 81-75-751-4000; Fax: 81-75-751-3998; E-mail: kshimoto{at}virus.kyoto-u.ac.jp.

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