Aberrant Activation of the Interleukin-2 Autocrine Loop through the Nuclear Factor of Activated T Cells by Nonleukemogenic Human T-Cell Leukemia Virus Type 2 but Not by Leukemogenic Type 1 Virus

Niinuma, Akiko; Higuchi, Masakazu; Takahashi, Masahiko; Oie, Masayasu; Tanaka, Yuetsu; Gejyo, Fumitake; Tanaka, Nobuyuki; Sugamura, Kazuo; Xie, Li; Green, Patrick L.; Fujii, Masahiro

doi:10.1128/jvi.79.18.11925-11934.2005

Cited by 26 publications

(29 citation statements)

References 42 publications

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“…In contrast to Tax1⌬C, the transforming activity of Tax2B without the PBM was augmented by an active NIK. Previous studies have reported that Tax2 but not Tax1 strongly activates NFAT, and this activity is important for Tax2-mediated transformation of CTLL-2 cells (21,31). Therefore, NFAT activation may play a role in the augmentation of Tax2B's transforming activity by active NIK.…”

Section: Discussionmentioning

confidence: 98%

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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

Higuchi

Tsubata

Kondo

et al. 2007

J Virol

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112

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Human T-cell leukemia virus type 1 (HTLV-1) but not HTLV-2 is associated with adult T-cell leukemia, and the distinct pathogenicity of these two closely related viruses is thought to stem from the distinct biological functions of the respective transforming proteins, HTLV-1 Tax1 and HTLV-2 Tax2. In this study, we demonstrate that Tax1 but not Tax2 interacts with NF-B2/p100 and activates it by inducing the cleavage of p100 into the active transcription factor p52. Using RNA interference methods, we further show that NF-B2/p100 is required for the transformation induced by Tax1, as determined by the ability to convert a T-cell line (CTLL-2) from interleukin-2 (IL-2)-dependent to -independent growth. While Tax2 shows a reduced transforming activity relative to Tax1, Tax2 fused with a PDZ domain binding motif (PBM) present only in Tax1 shows transforming activity equivalent to that of Tax1 in CTLL-2 cells expressing an inducer of p52 processing. These results reveal that the activation of NF-B2/p100 plays a crucial role in the Tax1-mediated transformation of T cells and that NF-B2/p100 activation and PBM function are both responsible for the augmented transforming activity of Tax1 relative to Tax2, thus suggesting that these Tax1-specific functions play crucial roles in HTLV-1 leukemogenesis.

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Section: Discussionmentioning

confidence: 98%

“…SLB-1 and ILT-Koy are HTLV-1-positive human T-cell lines. PBL01 and PBL2 are HTLV-2-positive human T-cell lines (31). Jurkat, SLB-1, and CTLL-2/Tax1 were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) (RPMI-10% FBS).…”

Section: Methodsmentioning

confidence: 99%

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

Higuchi

Tsubata

Kondo

et al. 2007

J Virol

Self Cite

112

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“…IL-13 stimulation by an HTLV Tax-responsive NFAT site Tax, has little or no impact on NFAT activation required for the stimulation of an NFAT-dependent promoter (Niinuma et al, 2005). The low but detectable levels of NFAT1 protein in the nuclei of all HTLV-transformed cells tested in this and other studies (Niinuma et al, 2005;Sharma et al, 2002) could be due to expression of the HTLV-1 p12(I) protein, which could enhance NFAT activation by increasing cytoplasmic calcium (Yasunaga & Matsuoka, 2007). Additionally, differentiation or transformation-specific activation of the cells could contribute to NFAT activation.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of interleukin-13 expression by human T-cell leukemia virus type 1 oncoprotein Tax via a dually active promoter element responsive to NF-κB and NFAT

Silbermann

Schneider

Grassmann

2008

Journal of General Virology

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The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein transforms human lymphocytes and is critical for the pathogenesis of HTLV-1-induced adult T-cell leukaemia. In HTLVtransformed cells, Tax upregulates interleukin (IL)-13, a cytokine with proliferative and antiapoptotic functions that is linked to leukaemogenesis. Tax-stimulated IL-13 is thought to result in autocrine stimulation of HTLV-infected cells and thus may be relevant to their growth. The causal transactivation of the IL-13 promoter by Tax is predominantly dependent on a nuclear factor of activated T cells (NFAT)-binding P element. Here, it was shown that the isolated IL-13 Taxresponsive element (IL13TaxRE) was sufficient to mediate IL-13 transactivation by Tax and NFAT1. However, cyclosporin A, a specific NFAT inhibitor, revealed that Tax transactivation of IL13TaxRE or wild-type IL-13 promoter was independent of NFAT and that NFAT did not contribute to IL-13 upregulation in HTLV-transformed cells. By contrast, Tax stimulation was repressible by an efficient nuclear factor (NF)-kB inhibitor (IkBaDN), indicating the requirement for NF-kB. The capacity of NF-kB to stimulate IL13TaxRE was demonstrated by a strong response to NF-kB in reporter assays and by direct binding of NF-kB to IL13TaxRE. Thus, IL13TaxRE in the IL-13 promoter represents a dually active promoter element responsive to NF-kB and NFAT. Together, these results indicate that Tax causes IL-13 upregulation in HTLV-1-infected cells via NF-kB. INTRODUCTIONHuman T-cell leukemia virus type 1 (HTLV-1), a deltaretrovirus, is the aetiological agent of a severe malignancy of CD4 + T cells, adult T-cell leukaemia (ATL), and of a neurodegenerative, inflammatory disease of the spinal cord, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) (Gessain et al., 1985; Poiesz et al., 1980;Yoshida et al., 1984). After primary infection, HTLV establishes life-long persistence and replicates mainly as integrated provirus. Viral persistence is characterized by long-lasting HTLV-infected T-cell clones, even in non-leukaemic patients. The clonal amplification of infected T cells and the capacity of these cells to establish permanent growth in culture suggest a growth-stimulating viral function that actively supports the replication of infected cells.Besides structural proteins, the proviral HTLV-1 genome encodes the regulatory proteins Rex and Tax, which are essential for the virus life cycle. The accessory proteins p12, p13 and p30 are important for viral infectivity and replication but are dispensable for transformation. An HTLV-1-encoded minus-strand gene encoding the HBZ protein is probably relevant to the pathogenesis of ATL (Yasunaga & Matsuoka, 2007). HTLV exerts its transforming capacity mainly through the viral oncoprotein Tax. This protein capably immortalizes human T cells (Akagi et al., 1997;Schmitt et al., 1998) and is leukaemogenic in transgenic mice (Grossman et al., 1995;Hasegawa et al., 2006). Proliferation of infected cells is enhanced by Tax by stimulating the G 1 to...

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“…Moreover, several reports have shown that Tax-1 and Tax-2 have distinct biological properties (30)(31)(32)(33)(34)(35)(36)(37).…”

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confidence: 99%

Inhibition of human T cell leukemia virus type 2 replication by the suppressive action of class II transactivator and nuclear factor Y

Tosi

Pilotti

Mortara

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The master regulator of MHC-II gene transcription, class II transactivator (CIITA), acts as a potent inhibitor of human T cell leukemia virus type 2 (HTLV-2) replication by blocking the activity of the viral Tax-2 transactivator. Here, we show that this inhibitory effect takes place at the nuclear level and maps to the N-terminal 1-321 region of CIITA, where we identified a minimal domain, from positions 64 -144, that is strictly required to suppress Tax-2 function. Furthermore, we show that Tax-2 specifically cooperates with cAMP response element binding protein-binding protein (CBP) and p300, but not with p300͞CBP-associated factor, to enhance transcription from the viral promoter. This finding represents a unique difference with respect to Tax-1, which uses all three coactivators to transactivate the human T cell leukemia virus type 1 LTR. Direct sequestering of CBP or p300 is not the primary mechanism by which CIITA causes suppression of Tax-2. Interestingly, we found that the transcription factor nuclear factor Y, which interacts with CIITA to increase transcription of MHC-II genes, exerts a negative regulatory action on the Tax-2-mediated HTLV-2 LTR transactivation. Thus, CIITA may inhibit Tax-2 function, at least in part, through nuclear factor Y. These findings demonstrate the dual defensive role of CIITA against pathogens: it increases the antigen-presenting function for viral determinants and suppresses HTLV-2 replication in infected cells. Tax-2 MHC class II ͉ viral replication ͉

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Aberrant Activation of the Interleukin-2 Autocrine Loop through the Nuclear Factor of Activated T Cells by Nonleukemogenic Human T-Cell Leukemia Virus Type 2 but Not by Leukemogenic Type 1 Virus

Cited by 26 publications

References 42 publications

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

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

Stimulation of interleukin-13 expression by human T-cell leukemia virus type 1 oncoprotein Tax via a dually active promoter element responsive to NF-κB and NFAT

Inhibition of human T cell leukemia virus type 2 replication by the suppressive action of class II transactivator and nuclear factor Y

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