title: HTLV-1 bZIP factor protein targets the Rb/E2F-1 pathway to promote proliferation and apoptosis of primary CD4(+) T cells.
abstract: Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that induces a fatal T-cell malignancy, adult T-cell leukemia (ATL). Among several regulatory/accessory genes in HTLV-1, HTLV-1 bZIP factor (HBZ) is the only viral gene constitutively expressed in infected cells. Our previous study showed that HBZ functions in two different molecular forms, HBZ protein and HBZ RNA. In this study, we show that HBZ protein targets retinoblastoma protein (Rb), which is a critical tumor suppressor in many types of cancers. HBZ protein interacts with the Rb/E2F-1 complex and activates the transcription of E2F-target genes associated with cell cycle progression and apoptosis. Mouse primary CD4(+) T cells transduced with HBZ show accelerated G1/S transition and apoptosis, and importantly, T cells from HBZ transgenic (HBZ-Tg) mice also demonstrate enhanced cell proliferation and apoptosis. To evaluate the functions of HBZ protein alone in vivo, we generated a new transgenic mouse strain that expresses HBZ mRNA altered by silent mutations but encoding intact protein. In these mice, the numbers of effector/memory and Foxp3(+) T cells were increased, and genes associated with proliferation and apoptosis were upregulated. This study shows that HBZ protein promotes cell proliferation and apoptosis in primary CD4(+) T cells through activation of the Rb/E2F pathway, and that HBZ protein also confers onto CD4(+) T-cell immunophenotype similar to those of ATL cells, suggesting that HBZ protein has important roles in dysregulation of CD4(+) T cells infected with HTLV-1.
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kawatsuki
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: J-I
authors.initials: JI
authors.lastname: Yasunaga
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Mitobe
authors.affiliation: Center for Retrovirus Research and Departments of Veterinary Biosciences and Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Green
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: M
authors.identifier: 0000-0002-0473-754X
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D000818:Animals; D017209:Apoptosis; D050976:Basic-Leucine Zipper Transcription Factors / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology* / Q000821:virology; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D050687:E2F1 Transcription Factor / Q000502:physiology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016160:Retinoblastoma Protein / Q000502:physiology*; D012191:Retroviridae Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D000099186:Histone Deacetylase 3
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D050687:E2F1 Transcription Factor; D006655:Histone Deacetylases; D016160:Retinoblastoma Protein; D012191:Retroviridae Proteins; D016159:Tumor Suppressor Protein p53; D000099186:Histone Deacetylase 3; C493753:E2F1 protein, human; C479751:HBZ protein, human T-cell leukemia virus type I