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

被引:18
作者
Yoshita, Manami [1 ]
Higuchi, Masaya [1 ]
Takahashi, Masahiko [1 ]
Oie, Masayasu [1 ]
Tanaka, Yuetsu [2 ,3 ]
Fujii, Masahiro [1 ]
机构
[1] Niigata Univ, Div Virol, Grad Sch Med & Dent Sci, Niigata, Japan
[2] Univ Ryukyus, Fac Med, Nishihara, Okinawa 90301, Japan
[3] Univ Ryukyus, Grad Sch, Dept Immunol, Nishihara, Okinawa 90301, Japan
关键词
DOMAIN-BINDING MOTIF; HTLV-1; TAX1; LYMPHOCYTES; MUTANTS; LINE; IMMORTALIZATION; PROLIFERATION; ONCOPROTEIN; ANTIBODIES; PARTICLES;
D O I
10.1111/j.1349-7006.2011.02123.x
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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)
引用
收藏
页码:369 / 374
页数:6
相关论文
共 35 条
[1]   Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase [J].
Ahmed, NN ;
Grimes, HL ;
Bellacosa, A ;
Chan, TO ;
Tsichlis, PN .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (08) :3627-3632
[2]   Characterization of peripheral blood T-lymphocytes transduced with HTLV-I Tax mutants with different trans-activating phenotypes [J].
Akagi, T ;
Ono, H ;
Nyunoya, H ;
Shimotohno, K .
ONCOGENE, 1997, 14 (17) :2071-2078
[3]   PROLIFERATIVE RESPONSE OF TAX1-TRANSDUCED PRIMARY HUMAN T-CELLS TO ANTI-CD3 ANTIBODY STIMULATION BY AN INTERLEUKIN-2-INDEPENDENT PATHWAY [J].
AKAGI, T ;
SHIMOTOHNO, K .
JOURNAL OF VIROLOGY, 1993, 67 (03) :1211-1217
[4]   A MAMMALIAN PROTEIN TARGETED BY G1-ARRESTING RAPAMYCIN-RECEPTOR COMPLEX [J].
BROWN, EJ ;
ALBERS, MW ;
SHIN, TB ;
ICHIKAWA, K ;
KEITH, CT ;
LANE, WS ;
SCHREIBER, SL .
NATURE, 1994, 369 (6483) :756-758
[5]   Human T-cell leukemia virus type 2 (HTLV-2) Tax protein transforms a rat fibroblast cell line but less efficiently than HTLV-1 Tax [J].
Endo, K ;
Hirata, A ;
Iwai, K ;
Sakurai, M ;
Fukushi, M ;
Oie, M ;
Higuchi, M ;
Hall, WW ;
Gejyo, F ;
Fujii, M .
JOURNAL OF VIROLOGY, 2002, 76 (06) :2648-2653
[6]   RETRACTED: Human T-cell Leukemia Virus Type I Tax Down-regulates the Expression of Phosphatidylinositol 3,4,5-Trisphosphate Inositol Phosphatases via the NF-κB Pathway (Retracted Article) [J].
Fukuda, Ryu-ich ;
Tsuchiya, Kiyohito ;
Suzuki, Koji ;
Itoh, Katsuhiko ;
Fujita, Jun ;
Utsunomiya, Atae ;
Tsuji, Takashi .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (05) :2680-2689
[7]   ROLE OF HUMAN T-CELL LEUKEMIA-VIRUS TYPE-1 X-REGION PROTEINS IN IMMORTALIZATION OF PRIMARY HUMAN-LYMPHOCYTES IN CULTURE [J].
GRASSMANN, R ;
BERCHTOLD, S ;
RADANT, I ;
ALT, M ;
FLECKENSTEIN, B ;
SODROSKI, JG ;
HASELTINE, WA ;
RAMSTEDT, U .
JOURNAL OF VIROLOGY, 1992, 66 (07) :4570-4575
[8]   Deregulation of cell-signaling pathways in HTLV-1 infection [J].
Hall, WW ;
Fujii, M .
ONCOGENE, 2005, 24 (39) :5965-5975
[9]   Cooperation of NF-κB2/p100 activation and the PDZ domain binding motif signal in human T-cell leukemia virus type 1 (HTLV-1) Tax1 but not HTLV-2 Tax2 is crucial for interleukin-2-independent growth transformation of a T-cell line [J].
Higuchi, Masaya ;
Tsubata, Chikako ;
Kondo, Rie ;
Yoshida, Sakiko ;
Takahashi, Masahiko ;
Oie, Masayasu ;
Tanaka, Yuetsu ;
Mahieux, Renaud ;
Matsuoka, Masao ;
Fujii, Masahiro .
JOURNAL OF VIROLOGY, 2007, 81 (21) :11900-11907
[10]   Distinct functions of HTLV-1 Tax1 from HTLV-2 Tax2 contribute key roles to viral pathogenesis [J].
Higuchi, Masaya ;
Fujii, Masahiro .
RETROVIROLOGY, 2009, 6