title: CD69 overexpression by human T-cell leukemia virus type 1 Tax transactivation.
abstract: Human T-cell leukemia virus type 1 (HTLV-1) infection is associated with the development of adult T-cell leukemia (ATL) and various inflammatory diseases. CD69 is a marker of early activation of lymphocytes. We investigated the effects of HTLV-1 infection on the expression of CD69. The CD69 gene was upregulated in all viral protein Tax-expressing HTLV-1-transformed T-cell lines, except MT-2 and peripheral blood mononuclear cells from patients with ATL compared with uninfected T-cell line, Tax-negative ATL-derived T-cell lines and normal peripheral blood mononuclear cells. Flow cytometric analysis and immunohistochemical analysis confirmed the enhanced expression of CD69 in HTLV-1-transformed T-cell lines and in ATL cells in lymph nodes and skin lesions, and its absence in MT-2 and peripheral blood mononuclear cells. CD69 expression was induced following infection of human T-cell line with HTLV-1, and specifically by Tax. Tax transcriptionally activated CD69 gene through both nuclear factor-κB and cyclic adenosine 3',5'-monophosphate response element-binding protein signaling pathways. Detailed analysis of the CD69 promoter indicated that the Tax-induced expression of CD69 was regulated by multiple cis-acting elements and by the interplay of transcription factors of the nuclear factor-κB, early growth response and cyclic adenosine 3',5'-monophosphate response element-binding protein families. The lack of CD69 expression in MT-2 is due to epigenetic mechanism involving deacetylation, but not methylation. We conclude that CD69 is a Tax-regulated gene, and its regulation by Tax may play a role in cellular activation and HTLV-1-induced disease pathogenesis.
authors.affiliation: Department of Microbiology and Oncology, University of the Ryukyus, Okinawa, Japan. chiezo@lab.u-ryukyu.ac.jp
authors.forename: Chie
authors.initials: C
authors.lastname: Ishikawa
authors.forename: Hirochika
authors.initials: H
authors.lastname: Kawakami
authors.forename: Jun-Nosuke
authors.initials: JN
authors.lastname: Uchihara
authors.forename: Masachika
authors.initials: M
authors.lastname: Senba
authors.forename: Naoki
authors.initials: N
authors.lastname: Mori
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D016356:Gene Products, tax / Q000235:genetics* / Q000378:metabolism; D015490:HTLV-I Infections / Q000235:genetics* / Q000473:pathology / Q000821:virology; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity; D006801:Humans; D007124:Immunoenzyme Techniques; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000473:pathology / Q000821:virology; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008156:Luciferases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016356:Gene Products, tax; D037181:Lectins, C-Type; D008156:Luciferases; D016328:NF-kappa B; D012333:RNA, Messenger; D000099192:CD69 Antigens