Human T-Cell Leukemia Virus Type 1 Tax Protein Abrogates Interleukin-2 Dependence in a Mouse T-Cell Line

Iwanaga, Yoichi; Tsukahara, Tomonori; Ohashi, Takashi; Tanaka, Yuetsu; Arai, Masaaki; Nakamura, Masataka; Ohtani, Kiyoshi; Koya, Yoshihiro; Kannagi, Mari; Yamamoto, Naoki; Fujii, Masahiro

doi:10.1128/jvi.73.2.1271-1277.1999

Cited by 77 publications

(44 citation statements)

References 42 publications

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“…pHbPr-1-neo-Tax1, pHbPr-1-neo-TaxM22, and pHbPr-1-neo-Tax703 were expression plasmids encoding Tax1, TaxM22, and Tax703, respectively. (19,22) CS-EF-Tax1 is a lentiviral vector expressing Tax1. (23) To construct the expression vectors for Tax1 mutant genes, the TaxM22 and Tax703 cDNA fragments were amplified by PCR from the pHbPr-1-neo-TaxM22 and pHbPr-1-neo-Tax703 plasmids, respectively, and the fragments were inserted into the Gateway entry vector pENTR ⁄ D-TOPO (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

“…CTLL-2 cells (2.5 · 10 6 ) were transfected with pHbPr-1-neo-Tax1, pHbPr-1-neo-Tax703, or pHbPr-1neo-TaxM22, together with jB-Luc or WT-Luc (CRE-Luc), and pGK ⁄ b-gal by using the DEAE dextran method as described previously. (19) At 48 h after transfection, the cell lysates were prepared, and the luciferase and b-galactosidase activities in the lysates were measured using the Luciferase Assay System (Promega, Fitchburg, WI, USA) and Galacto-Light System (Applied Biosystems, Foster City, CA, USA), respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The cell lines used in this study have all been described previously. (19,20) SLB-1, MT-4, and HUT102 are HTLV-1-infected human T-cell lines. HUT78 and Jurkat are HTLV-1-negative human T-cell lines.…”

mentioning

confidence: 99%

“…ILT-Koy and ILT-Oot are IL-2-dependent HTLV-1-infected human T-cell lines, and they were cultured in RPMI ⁄ 20%FBS ⁄ IL-2. (19) CTLL-2 is a mouse T-cell line that grows in an IL-2-dependent manner, and the cells were cultured in RPMI ⁄ 10%FBS ⁄ IL-2 supplemented with 55 lM 2-mercaptoethanol (2-ME) (RPMI ⁄ 10%FBS ⁄ IL-2 ⁄ 2-ME). CTLL-2 cells stably expressing Tax1 were cultured in RPMI ⁄ 10%FBS ⁄ IL-2 ⁄ 2-ME containing 2 lg ⁄ mL puromycin.…”

mentioning

confidence: 99%

“…pHbPr-1-neo-Tax1, pHbPr-1-neo-TaxM22, and pHbPr-1-neo-Tax703 were expression plasmids encoding Tax1, TaxM22, and Tax703, respectively. (19,22)…”

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Activation of mTOR by human T‐cell leukemia virus type 1 Tax is important for the transformation of mouse T cells to interleukin‐2‐independent growth

et al. 2011

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Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of adult T-cell leukemia, and it immortalizes and transforms human T cells in both an interleukin (IL)-2-dependent and -independent manner. HTLV-1 encodes Tax, which plays crucial roles in HTLV-1-mediated immortalization and transformation of human T cells. A previous study showed that Tax can transform a mouse T-cell line, CTLL-2, from having IL-2-dependent growth to IL-2-independent growth. Given that the Akt ⁄ mTOR pathway is essential for IL-2-induced cell growth in T cells, we examined whether the Akt ⁄ m-TOR pathway is involved in Tax-induced transformation to IL-2-independent growth. The stable and transient expression of Tax in CTLL-2 induced the phosphorylation of p70S6 kinase and ribosomal protein S6, downstream targets of the mTOR kinase, whereas that of Akt was only minimally induced. Studies with Tax mutants indicated that the activation of mTOR by Tax was correlated with the transformation of CTLL-2 cells to IL-2-independent growth. Rapamycin, an inhibitor of mTOR kinase, reduced the growth of Taxtransformed CTLL-2 cells. Moreover, the transduction of a constitutively active form of Akt in the CTLL-2 cells also induced IL-2-independent growth. Like CTLL-2 ⁄ Tax, constitutive phosphorylation of p70S6 kinase was detected in the absence of IL-2 in all of the HTLV-1-infected human T-cell lines. These results suggest that Tax activates the mTOR pathway in T cells, and that this activation plays a crucial role in the growth of HTLV-1-infected T cells when a limited amount of IL-2 is available. (Cancer Sci 2012; 103: 369-374) H uman T-cell leukemia virus type 1 (HTLV-1) is an etiologic agent of adult T-cell leukemia (ATL), (1)(2)(3)(4) which is characterized by monoclonal proliferation of HTLV-1-infected CD4 + T cells. HTLV-1 is mainly transmitted from a mother to an infant through breast milk, but only 3-5% of infections develop ATL, with an average latency of 40-60 years.(4) HTLV-1 immortalizes CD4 + T cells in an interleukin (IL)-2-dependent manner, although some cells acquire IL-2-independent growth properties. (5,6) Understanding how HTLV-1 immortalizes and transforms CD4 + T cells is an important step to elucidate the molecular mechanism underlying the leukemogenesis.In addition to its structural genes, HTLV-1 encodes several non-structural genes.(7) Of these, tax1 is essential for the immortalization of CD4 + T cells by HTLV-1. HTLV-2, a close relative of HTLV-1, is not associated with ATL or any other types of leukemia.(11,12) HTLV-2 also encodes a transforming protein, Tax2, which has approximately 75% amino acid similarity to Tax1, and shares many functions, such as activation of NF-jB, CREB, and AP-1. Intriguingly, Tax1 has one dominant activity over Tax2; it converts a mouse T-cell line, CTLL-2, from IL-2-dependent growth to IL-2-independent growth much more efficiently than Tax2. (13,14) These results suggest that the activity of Tax1 for inducing the IL-2-independent growth of cells is associated with the HTLV-1-specific pat...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

“…pHbPr-1-neo-Tax1, pHbPr-1-neo-TaxM22, and pHbPr-1-neo-Tax703 were expression plasmids encoding Tax1, TaxM22, and Tax703, respectively. (19,22)…”

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Activation of mTOR by human T‐cell leukemia virus type 1 Tax is important for the transformation of mouse T cells to interleukin‐2‐independent growth

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IL-2 independent transformation of a unique human T cell line, TY8-3, and its subclones by HTLV-I and -II

Yoshida¹,

Miyagawa

Yamaguchi

et al. 2000

Int. J. Cancer

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Downregulation of proapoptotic Bim augments IL‐2‐independent T‐cell transformation by human T‐cell leukemia virus type‐1 Tax

et al. 2014

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Human T-cell leukemia virus type 1 (HTLV-1), an etiological agent of adult T-cell leukemia, immortalizes and transforms primary human T cells in vitro in both an interleukin (IL)-2-dependent and IL-2-independent manner. Expression of the HTLV-1 oncoprotein Tax transforms the growth of the mouse T-cell line CTLL-2 from being IL-2-dependent to IL-2-independent. Withdrawal of IL-2 from normal activated T cells induces apoptosis, which is mediated through the inducible expression of several proapoptotic proteins, including Bim. In this study, we found that Tax protects IL-2-depleted T cells against Bim-induced apoptosis. Withdrawal of IL-2 from CTLL-2 cells induced a prominent increase in the level of Bim protein in CTLL-2 cells, but not in Tax-transformed CTLL-2 cells. This inhibition of Bim in Tax-transformed CTLL-2 cells was mediated by two mechanisms: downregulation of Bim mRNA and posttranscriptional reduction of Bim protein. Transient expression of Tax in CTLL-2 cells also inhibited IL-2 depletion–induced expression of Bim, however, this decrease in Bim protein expression was not due to downregulation of Bim mRNA, thus indicating that Bim mRNA downregulation in Tax-transformed CTLL-2 occurs only after long-term expression of Tax. Transient expression of Tax in CTLL-2 cells also induced Erk activation, however, this was not involved in the reduction of Bim protein. Knockdown of Bim expression in CTLL-2 cells augmented Tax-induced IL-2-independent transformation. HTLV-1 infection of human T cells also reduced their levels of Bim protein, and restoring Bim expression in HTLV-1-infected cells reduced their proliferation by inducing apoptosis. Taken together, these results indicate that Tax-induced downregulation of Bim in HTLV-1-infected T cells promotes their IL-2-independent growth, thereby supporting the persistence of HTLV-1 infection in vivo.

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Human T-Cell Leukemia Virus Type 1 Tax Protein Abrogates Interleukin-2 Dependence in a Mouse T-Cell Line

Cited by 77 publications

References 42 publications

Activation of mTOR by human T‐cell leukemia virus type 1 Tax is important for the transformation of mouse T cells to interleukin‐2‐independent growth

Activation of mTOR by human T‐cell leukemia virus type 1 Tax is important for the transformation of mouse T cells to interleukin‐2‐independent growth

IL-2 independent transformation of a unique human T cell line, TY8-3, and its subclones by HTLV-I and -II

Downregulation of proapoptotic Bim augments IL‐2‐independent T‐cell transformation by human T‐cell leukemia virus type‐1 Tax

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