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
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DOI：
10.1111/j.1349-7006.2011.02123.x
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发表时间：
2012-02-01
期刊：
影响因子：
5.7
通讯作者：
Fujii, Masahiro
中科院分区：
文献类型：
--
作者：
Yoshita, Manami;Higuchi, Masaya;Fujii, Masahiro
人类 T 细胞白血病病毒 1 型 (HTLV-1) 是成人 T 细胞白血病的病原体，它以白细胞介素 (IL)-2 依赖性和非依赖性方式永生化和转化人类 T 细胞。 HTLV-1 编码 Tax，它在 HTLV-1 介导的人类 T 细胞永生化和转化中发挥着至关重要的作用。先前的一项研究表明，Tax 可以将小鼠 T 细胞系 CTLL-2 从依赖 IL-2 的生长转变为不依赖 IL-2 的生长。鉴于 Akt/mTOR 途径对于 IL-2 诱导的 T 细胞生长至关重要，我们检查了 Akt/mTOR 途径是否参与 Tax 诱导的向 IL-2 独立生长的转化。 CTLL-2 中 Tax 的稳定和瞬时表达诱导 p70S6 激酶和核糖体蛋白 S6（mTOR 激酶的下游靶标）的磷酸化，而 Akt 的磷酸化仅受到最低程度的诱导。 Tax 突变体的研究表明，Tax 激活 mTOR 与 CTLL-2 细胞向不依赖 IL-2 的生长转变相关。雷帕霉素是一种 mTOR 激酶抑制剂，可减少 Tax 转化的 CTLL-2 细胞的生长。此外，在 CTLL-2 细胞中转导组成型活性形式的 Akt 也诱导不依赖于 IL-2 的生长。与 CTLL-2/Tax 一样，在所有 HTLV-1 感染的人 T 细胞系中，在不存在 IL-2 的情况下检测到 p70S6 激酶的组成型磷酸化。这些结果表明，Tax 激活 T 细胞中的 mTOR 通路，并且当有限量的 IL-2 可用时，这种激活在 HTLV-1 感染的 T 细胞的生长中起着至关重要的作用。 （癌症科学 2012 年；103：369374）
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/mTOR 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 Tax-transformed 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: 369374)