title: Induction of Cell Death in Growing Human T-Cells and Cell Survival in Resting Cells in Response to the Human T-Cell Leukemia Virus Type 1 Tax.
abstract: Tax1 encoded by the human T-cell leukemia virus type 1 (HTLV-1) has been believed to dysregulate the expression of cellular genes involved in cell survival and mortality, leading to the development of adult T-cell leukemia (ATL). The function of Tax1 in ATL development however is still controversial, primarily because Tax1 induces cell cycle progression and apoptosis. To systemically understand cell growth phase-dependent induction of cell survival or cell death by Tax1, we established a single experimental system using an interleukin 2 (IL-2)-dependent human T-cell line Kit 225 that can be forced into resting phase by IL-2 deprivation. Introduction of Tax1 and HTLV-2 Tax (Tax2B) decreased mitochondrial activity alongside apoptosis in growing cells but not in resting cells. Cell cycle profile analysis indicated that Tax1 and Tax2B were likely to perturb the S phase in growing cells. Studies with Tax1 mutants and siRNA for NF-κB/RelA revealed that Tax1-mediated cell growth inhibition and apoptosis in growing Kit 225 cells depend on RelA. Interestingly, inactivation of the non-canonical NF-κB and p38 MAPK pathways relieved Tax1-mediated apoptosis, suggesting that the Tax1-NF-κB-p38 MAPK axis may be associated with apoptosis in growing cells. Inflammatory mediators such as CCL3 and CCL4, which are involved in oncogene-induced senescence (OIS), were induced by Tax1 and Tax2B in growing cells. In contrast, RelA silencing in resting cells reduced mitochondrial activity, indicating that NF-κB/RelA is also critical for Tax1-mediated cell survival. These findings suggest that Tax1-mediated cell survival and death depend on the cell growth phase. Both effects of Tax1 may be implicated in the long latency of HTLV-1 infection.
authors.affiliation: Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Mizuguchi
authors.affiliation: Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hara
authors.affiliation: Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Higuchi
authors.affiliation: Department of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Funato
authors.affiliation: Division of Cancer Biology and Therapeutics, Miyagi Cancer Center Research Institute, Miyagi, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujii
authors.affiliation: Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakamura
mesh_terms: D000328:Adult; D002453:Cell Cycle / Q000235:genetics; D016923:Cell Death; D049109:Cell Proliferation; D002470:Cell Survival; D018925:Chemokines / Q000378:metabolism; D005786:Gene Expression Regulation; D016356:Gene Products, tax; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D050505:Mutant Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000821:virology*; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D018925:Chemokines; D016356:Gene Products, tax; D050505:Mutant Proteins; D051996:Transcription Factor RelA
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