title: BCL3 acts as a negative regulator of transcription from the human T-cell leukemia virus type 1 long terminal repeat through interactions with TORC3.
abstract: 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.
authors.affiliation: 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.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hishiki
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Shido, Sanuki City, Kagawa 769-2193, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ohshima
authors.affiliation: Department of Viral Oncology, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ego
authors.affiliation: 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. Electronic address: kshimoto@virus.kyoto-u.ac.jp.
authors.forename: Kunitada
authors.initials: K
authors.lastname: Shimotohno
mesh_terms: D000081242:B-Cell Lymphoma 3 Protein; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016356:Gene Products, tax / Q000378:metabolism; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism*; D020079:Terminal Repeat Sequences / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology
chemical_list: D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; C115163:CREB1 protein, human; C495791:CRTC3 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D016356:Gene Products, tax; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C012589:trichostatin A