title: Human T cell leukemia virus type I tax-induced IκB-ζ modulates tax-dependent and tax-independent gene expression in T cells.
abstract: Human T cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T cell leukemia (ATL) and various inflammatory disorders including HTLV-I-associated myelopathy/tropical spastic paraparesis. HTLV-I oncoprotein Tax is known to cause permanent activation of many cellular transcription factors including nuclear factor-κB (NF-κB), cyclic adenosine 3',5'-monophosphate response element-binding protein, and activator protein 1 (AP-1). Here, we show that NF-κB-binding cofactor inhibitor of NF-κB-ζ (IκB-ζ) is constitutively expressed in HTLV-I-infected T cell lines and ATL cells, and Tax transactivates the IκB-ζ gene, mainly through NF-κB. Microarray analysis of IκB-ζ-expressing uninfected T cells demonstrated that IκB-ζ induced the expression of NF-κB. and interferon-regulatory genes such as B cell CLL/lymphoma 3 (Bcl3), guanylate-binding protein 1, and signal transducer and activator of transcription 1. The transcriptional activation domain, nuclear localization signal, and NF-κB-binding domain of IκB-ζ were required for Bcl3 induction, and IκB-ζ synergistically enhanced Tax-induced Bcl3 transactivation in an NF-κB-dependent manner. Interestingly, IκB-ζ inhibited Tax-induced NF-κB, AP-1 activation, and HTLV-I transcription. Furthermore, IκB-ζ interacted with Tax in vitro and this interaction was also observed in an HTLV-I-transformed T cell line. These results suggest that IκB-ζ modulates Tax-dependent and Tax-independent gene transcription in T cells. The function of IκB-ζ may be of significance in ATL genesis and pathogenesis of HTLV-I-associated diseases.
authors.affiliation: Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan ; Transdisciplinary Research Organization for Subtropics and Island Studies, University of the Ryukyus, Nishihara, Okinawa, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Kimura
authors.forename: Masachika
authors.initials: M
authors.lastname: Senba
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Cutler
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ralph
authors.forename: Gutian
authors.initials: G
authors.lastname: Xiao
authors.forename: Naoki
authors.initials: N
authors.lastname: Mori
mesh_terms: D000081242:B-Cell Lymphoma 3 Protein; D002460:Cell Line; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000096:biosynthesis; D015973:Gene Expression Regulation, Leukemic; D016356:Gene Products, tax / Q000378:metabolism*; D057809:HEK293 Cells; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D050794:STAT1 Transcription Factor / Q000096:biosynthesis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; C490287:GBP1 protein, human; D016356:Gene Products, tax; D020672:I-kappa B Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C514970:tax protein, Human T-lymphotrophic virus 1; D019204:GTP-Binding Proteins
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