2021/10/25 更新

写真a

タカハシ マサヒコ
高橋 雅彦
TAKAHASHI Masahiko
所属
教育研究院 医歯学系 医学系列 准教授
医歯学総合研究科 地域疾病制御医学専攻 国際感染医学 准教授
職名
准教授
外部リンク

学位

  • 博士(理学) ( 2004年3月   筑波大学 )

研究キーワード

  • ストレス顆粒

  • 細胞死

  • ヒトT細胞白血病ウイルス1型

  • アグリソーム

  • 神経変性疾患

研究分野

  • ライフサイエンス / 病態医化学

  • ライフサイエンス / 細胞生物学

  • ライフサイエンス / ウイルス学

経歴(researchmap)

  • 新潟大学   医歯学総合研究科 地域疾病制御医学専攻 国際感染医学   准教授

    2016年11月 - 現在

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  • 新潟大学   医歯学総合研究科 地域疾病制御医学専攻 国際感染医学   講師

    2015年4月 - 2016年10月

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  • 新潟大学   医歯学総合研究科 地域疾病制御医学専攻   助教

    2007年4月 - 2015年3月

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  • 新潟大学   医歯学総合研究科   助手

    2004年4月 - 2007年3月

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経歴

  • 新潟大学   医歯学総合研究科 地域疾病制御医学専攻 国際感染医学   准教授

    2016年11月 - 現在

  • 新潟大学   医歯学総合研究科 地域疾病制御医学専攻 国際感染医学   講師

    2015年4月 - 2016年10月

  • 新潟大学   医歯学総合研究科 地域疾病制御医学専攻   助教

    2007年4月 - 2015年3月

  • 新潟大学   医歯学総合研究科   助手

    2004年4月 - 2007年3月

所属学協会

 

論文

  • The optineurin/TIA1 pathway inhibits aberrant stress granule formation and reduces ubiquitinated TDP-43 査読

    Taichi Kakihana, Masahiko Takahashi, Yoshinori Katsuragi, Shun-Ichi Yamashita, Junya Sango, Tomotake Kanki, Osamu Onodera, Masahiro Fujii

    iScience   24 ( 7 )   102733 - 102733   2021年7月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.isci.2021.102733

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  • Antitumor Effect of Sugar-Modified Cytosine Nucleosides on Growth of Adult T-Cell Leukemia Cells in Mice 査読

    Naoyoshi Maeda, Akira Matsuda, Satoko Otsuguro, Masahiko Takahashi, Masahiro Fujii, Katsumi Maenaka

    Vaccines   8 ( 4 )   658 - 658   2020年11月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:MDPI AG  

    Adult T-cell leukemia (ATL) is a CD4+ T-cell neoplasm caused by human T-cell leukemia virus type I. As the prognosis for patients with ATL remains extremely poor due to resistance to conventional chemotherapy regimens, introduction of novel therapeutic agents is needed. Previous studies have reported that nucleosides 2′-deoxy-2′-methylidenecytidine (DMDC) and its derivative 2′-deoxy-2′-methylidene-5-fluorocytidine (FDMDC) exhibit antitumor activities in T-cell acute lymphoblastic leukemia (T-ALL) and solid tumor cell lines. Another nucleoside, 1-(2-azido-2-deoxy-β-D-arabinofuranosyl)cytosine (cytarazid), is considered a therapeutic drug with antitumor activity in human solid tumors. In this study, we investigated the effects of these nucleosides on cell growth in vitro and in vivo using relevant leukemia cell lines and NOD/Shi-scid, IL-2Rgnull (NOG) mice, respectively. The nucleosides demonstrated significant cytotoxic effects in ATL and T-ALL cell lines. Intraperitoneal administration of FDMDC and DMDC into tumor-bearing NOG mice resulted in significant suppression of tumor growth without lethal side effects. Our findings support a therapeutic application of these nucleosides against tumor progression by targeting DNA polymerase-dependent DNA synthesis in patients with ATL.

    DOI: 10.3390/vaccines8040658

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  • G3BP1 inhibits ubiquitinated protein aggregations induced by p62 and USP10 査読 国際誌

    Sergei Anisimov, Masahiko Takahashi, Taichi Kakihana, Yoshinori Katsuragi, Hiroki Kitaura, Lu Zhang, Akiyoshi Kakita, Masahiro Fujii

    Scientific Reports   9 ( 1 )   12896 - 12896   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    <title>Abstract</title>
    The aberrant accumulation of ubiquitinated protein aggregates in cells plays a critical role in the pathogenesis of several degenerative diseases, including Parkinson disease (PD) and cystic fibrosis (CF). In this study, we found that Ras GTPase-activating protein-binding protein 1 (G3BP1) inhibits ubiquitinated protein aggregations induced by p62 and USP10 in cultured cells. p62 is a ubiquitin receptor, and p62 and its binding partner USP10 have been shown to augment ubiquitinated protein aggregation. G3BP1 interacted with p62 and USP10 and inhibited p62/USP10-induced protein aggregation. The G3BP1 inhibition of protein aggregations targeted two aggregation-prone proteins, α-synuclein and CFTR-ΔF508, which are causative factors of PD and CF, respectively. G3BP1 depletion increased the amounts of ubiquitinated α-synuclein and CFTR-ΔF508 protein. A proteasome reporter indicated that G3BP1 depletion inhibits the proteasome activity. We herein present evidence that G3BP1, p62 and USP10 together control ubiquitinated protein toxicity by controlling both ubiquitination and aggregation. Taken together, these results suggest that G3BP1, p62 and USP10 could be therapeutic targets for ubiquitinated protein aggregation disorders, including PD and CF.

    DOI: 10.1038/s41598-019-46237-1

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    その他リンク: http://www.nature.com/articles/s41598-019-46237-1

  • USP10 is a critical factor for Tau-positive stress granule formation in neuronal cells 査読 国際誌

    Svetlana Piatnitskaia, Masahiko Takahashi, Hiroki Kitaura, Yoshinori Katsuragi, Taichi Kakihana, Lu Zhang, Akiyoshi Kakita, Yuriko Iwakura, Hiroyuki Nawa, Takeshi Miura, Takeshi Ikeuchi, Toshifumi Hara, Masahiro Fujii

    Scientific Reports   9 ( 1 )   10591 - 10591   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Tau aggregates in neurons of brain lesions is a hallmark pathology of tauopathies, including Alzheimer's disease (AD). Recent studies suggest that the RNA-binding protein TIA1 initiates Tau aggregation by inducing the formation of stress granules (SGs) containing Tau. SGs are stress-inducible cytoplasmic protein aggregates containing many RNA-binding proteins that has been implicated as an initial site of multiple pathogenic protein aggregates in several neurodegenerative diseases. In this study, we found that ubiquitin-specific protease 10 (USP10) is a critical factor for the formation of Tau/TIA1/USP10-positive SGs. Proteasome inhibition or TIA1-overexpression in HT22 neuronal cells induced the formation of TIA1/Tau-positive SGs, and the formations were severely attenuated by depletion of USP10. In addition, the overexpression of USP10 without stress stimuli in HT22 cells induced TIA1/Tau/USP10-positive SGs in a deubiquitinase-independent manner. In AD brain lesions, USP10 was colocalized with Tau aggregates in the cell body of neurons. The present findings suggest that USP10 plays a key role in the initiation of pathogenic Tau aggregation in AD through SG formation.

    DOI: 10.1038/s41598-019-47033-7

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    その他リンク: http://www.nature.com/articles/s41598-019-47033-7

  • USP10はアグリソームの形成を誘導し,ユビキチン化蛋白質オリゴマーの細胞毒性を抑制する

    高橋 雅彦, PIATNITSKAIA Svetlana, ANISIMOV Sergei, 藤井雅寛

    新潟医学会雑誌   133 ( 3 )   91 - 96   2019年3月

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    担当区分:筆頭著者   記述言語:日本語  

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  • USP10 Is a Driver of Ubiquitinated Protein Aggregation and Aggresome Formation to Inhibit Apoptosis 査読 国際誌

    Masahiko Takahashi, Hiroki Kitaura, Akiyoshi Kakita, Taichi Kakihana, Yoshinori Katsuragi, Masaaki Nameta, Lu Zhang, Yuriko Iwakura, Hiroyuki Nawa, Masaya Higuchi, Masaaki Komatsu, Masahiro Fujii

    iScience   9   433 - 450   2018年11月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    Accumulation of ubiquitinated proteins is cytotoxic, but cells inactivate these cytotoxicities by inducing aggresome formation. We found that ubiquitin-specific protease 10 (USP10) inhibits ubiquitinated protein-induced apoptosis by inducing aggresome formation. USP10 interacted with the ubiquitin receptor p62 and the interaction augmented p62-dependent ubiquitinated protein aggregation and aggresome formation, thereby cooperatively inhibiting apoptosis. We provide evidence that USP10/p62-induced protein aggregates inhibit proteasome activity, which increases the amount of ubiquitinated proteins and promotes aggresome formation. USP10 induced aggresomes containing α-synuclein, a pathogenic protein in Parkinson disease, in cultured cells. In Parkinson disease brains, USP10 was colocalized with α-synuclein in the disease-linked aggresome-like inclusion Lewy bodies, suggesting that USP10 inhibits α-synuclein-induced neurotoxicity by promoting Lewy body formation. Collectively, these findings suggest that USP10 is a critical factor to control protein aggregation, aggresome formation, and cytotoxicity in protein-aggregation-related diseases.

    DOI: 10.1016/j.isci.2018.11.006

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  • MAGI-1 expression is decreased in several types of human T-cell leukemia cell lines, including adult T-cell leukemia 査読

    Takashi Kozakai, Masahiko Takahashi, Masaya Higuchi, Toshifumi Hara, Kousuke Saito, Yuetsu Tanaka, Masayoshi Masuko, Jun Takizawa, Hirohito Sone, Masahiro Fujii

    International Journal of Hematology   107 ( 3 )   337 - 344   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Membrane-associated guanylate kinase with inverted orientation protein 1 (MAGI-1) is a cytoplasmic scaffold protein that interacts with various signaling molecules
    it negatively controls the cell growth of various types of cells and positively controls cell–cell interaction. In T cells, MAGI-1 has been shown to inhibit Akt activity through its interaction with PTEN and MEK1. In this study we found that MAGI-1 expression is decreased in multiple (9 out of 15) human T-cell leukemia cell lines, including adult T-cell leukemia (ATL), T-cell acute lymphoblastic leukemia and chronic T-cell lymphocytic leukemia. The overexpression of MAGI-1 protein in a MAGI-1-low ATL cell line reduced cellular growth. While the overexpression of MAGI-1 protein in a MAGI-1-low ATL cell line reduced the Akt and MEK activities, the knockdown of MAGI-1 in a MAGI-1-high ATL cell line augmented the Akt and MEK activities. Collectively, the findings of the present study suggest that the decreased expression of MAGI-1 in human T cells contributes to the development of several types of T-cell leukemia, partly through the stimulation of the Akt and MEK pathways.

    DOI: 10.1007/s12185-017-2359-1

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    その他リンク: http://link.springer.com/content/pdf/10.1007/s12185-017-2359-1.pdf

  • USP10 Is an Essential Deubiquitinase for Hematopoiesis and Inhibits Apoptosis of Long-Term Hematopoietic Stem Cells 査読

    Masaya Higuchi, Hiroki Kawamura, Hideaki Matsuki, Toshifumi Hara, Masahiko Takahashi, Suguru Saito, Kousuke Saito, Shuying Jiang, Makoto Naito, Hiroshi Kiyonari, Masahiro Fujii

    Stem Cell Reports   7 ( 6 )   1116 - 1129   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    Self-renewal, replication, and differentiation of hematopoietic stem cells (HSCs) are regulated by cytokines produced by niche cells in fetal liver and bone marrow. HSCs must overcome stresses induced by cytokine deprivation during normal development. In this study, we found that ubiquitin-specific peptidase 10 (USP10) is a crucial deubiquitinase for mouse hematopoiesis. All USP10 knockout (KO) mice died within 1 year because of bone marrow failure with pancytopenia. Bone marrow failure in these USP10-KO mice was associated with remarkable reductions of long-term HSCs (LT-HSCs) in bone marrow and fetal liver. Such USP10-KO fetal liver exhibited enhanced apoptosis of hematopoietic stem/progenitor cells (HSPCs) including LT-HSCs but not of lineage-committed progenitor cells. Transplantation of USP10-competent bone marrow cells into USP10-KO mice reconstituted multilineage hematopoiesis. These results suggest that USP10 is an essential deubiquitinase in hematopoiesis and functions by inhibiting apoptosis of HSPCs including LT-HSCs.

    DOI: 10.1016/j.stemcr.2016.11.003

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  • Human T-cell leukemia virus type 1 (HTLV-1) Tax1 oncoprotein but not HTLV-2 Tax2 induces the expression of OX40 ligand by interacting with p52/p100 and RelB 査読

    Yosuke Motai, Masahiko Takahashi, Takayuki Takachi, Masaya Higuchi, Toshifumi Hara, Mariko Mizuguchi, Yutaka Aoyagi, Shuji Terai, Yuetsu Tanaka, Masahiro Fujii

    Virus Genes   52 ( 1 )   4 - 13   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Human T-cell leukemia virus type 1 (HTLV-1) is a causative retrovirus of adult T-cell leukemia and HTLV-1-associated myelopathy. Unlike HTLV-1, the same group of retrovirus HTLV-2 has not been found to be associated with these diseases. HTLV-1 and HTLV-2 encode transforming proteins Tax1 and Tax2, and a few distinct activities of Tax1 from those of Tax2 have been proposed to contribute to the HTLV-1-specific pathogenesis of disease. One significant difference of Tax1 from Tax2 is the activation of transcription factor NF-kappa B2/p100/p52. We found that Tax1 but not Tax2 induces the expression of OX40 ligand (OX40L) in a human T-cell line. To induce the OX40L expression, Tax1 but not Tax2 was observed to interact with NF-kappa B2/p100/p52 and RelB and the distinct interaction activity was mediated by the Tax1 amino acid region of 225-232. In addition, Tax1 but not Tax2 or Tax1/225-232 interacted with p65, p50, and c-Rel; however, the interactions were much less than those noted with NF-kappa B2/p100/p52 and RelB. OX40L is a T-cell costimulatory molecule of the tumor necrosis factor family, and its signal plays a critical role in establishing adaptive immunity by inducing the polarized differentiation of T-cells to cells such as T helper type 2 and T follicular helper cells. Therefore, the present findings suggest that Tax1 might alter the immune response to HTLV-1 and/or differentiation of HTLV-1-infected T-cells via OX40L induction, thereby acting as a factor mediating the distinct phenotypes and pathogenesis of HTLV-1 from that of HTLV-2.

    DOI: 10.1007/s11262-015-1277-7

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    その他リンク: http://link.springer.com/article/10.1007/s11262-015-1277-7/fulltext.html

  • RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells 査読

    Suguru Saito, Toshihiko Kawamura, Masaya Higuchi, Takahiro Kobayashi, Manami Yoshita-Takahashi, Maya Yamazaki, Manabu Abe, Kenji Sakimura, Yasuhiro Kanda, Hiroki Kawamura, Shuying Jiang, Makoto Naito, Takumi Yoshizaki, Masahiko Takahashi, Masahiro Fujii

    European Journal of Immunology   45 ( 5 )   1512 - 1523   2015年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    Ras GTPase-activating proteins negatively regulate the Ras/Erk signaling pathway, thereby playing crucial roles in the proliferation, function, and development of various types of cells. In this study, we identified a novel Ras GTPase-activating proteins protein, RASAL3, which is predominantly expressed in cells of hematopoietic lineages, including NKT, B, and Tcells. We established systemic RASAL3-deficient mice, and the mice exhibited a severe decrease in NKT cells in the liver at 8 weeks of age. The treatment of RASAL3-deficient mice with -GalCer, a specific agonist for NKT cells, induced liver damage, but the level was less severe than that in RASAL3-competent mice, and the attenuated liver damage was accompanied by a reduced production of interleukin-4 and interferon- from NKT cells. RASAL3-deficient NKT cells treated with -GalCer in vitro presented augmented Erk phosphorylation, suggesting that there is dysregulated Ras signaling in the NKT cells of RASAL3-deficient mice. Taken together, these results suggest that RASAL3 plays an important role in the expansion and functions of NKT cells in the liver by negatively regulating Ras/Erk signaling, and might be a therapeutic target for NKT-associated diseases.

    DOI: 10.1002/eji.201444977

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  • Human T ‐cell leukemia virus type 1 T ax oncoprotein represses the expression of the BCL 11 B tumor suppressor in T ‐cells 査読

    Takayuki Takachi, Masahiko Takahashi, Manami Takahashi‐Yoshita, Masaya Higuchi, Miki Obata, Yukio Mishima, Shujiro Okuda, Yuetsu Tanaka, Masao Matsuoka, Akihiko Saitoh, Patrick L. Green, Masahiro Fujii

    Cancer Science   106 ( 4 )   461 - 465   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia (ATL), which is an aggressive form of T-cell malignancy. HTLV-1 oncoproteins, Tax and HBZ, play crucial roles in the immortalization of T-cells and/or leukemogenesis by dysregulating the cellular functions in the host. Recent studies show that HTLV-1-infected T-cells have reduced expression of the BCL11B tumor suppressor protein. In the present study, we explored whether Tax and/or HBZ play a role in downregulating BCL11B in HTLV-1-infected T-cells. Lentiviral transduction of Tax in a human T-cell line repressed the expression of BCL11B at both the protein and mRNA levels, whereas the transduction of HBZ had little effect on the expression. Tax mutants with a decreased activity for the NF-B, CREB or PDZ protein pathways still showed a reduced expression of the BCL11B protein, thereby implicating a different function of Tax in BCL11B downregulation. In addition, the HTLV-2 Tax2 protein reduced the BCL11B protein expression in T-cells. Seven HTLV-1-infected T-cell lines, including three ATL-derived cell lines, showed reduced BCL11B mRNA and protein expression relative to an uninfected T-cell line, and the greatest reductions were in the cells expressing Tax. Collectively, these results indicate that Tax is responsible for suppressing BCL11B protein expression in HTLV-1-infected T-cells; Tax-mediated repression of BCL11B is another mechanism that Tax uses to promote oncogenesis of HTLV-1-infected T-cells.

    DOI: 10.1111/cas.12618

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.12618

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

    Masaya Higuchi, Masahiko Takahashi, Yuetsu Tanaka, Masahiro Fujii

    Cancer Medicine   3 ( 6 )   1605 - 1614   2014年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    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.

    DOI: 10.1002/cam4.329

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cam4.329

  • HTLV-1 Tax oncoprotein stimulates ROS production and apoptosis in T cells by interacting with USP10 査読

    Masahiko Takahashi, Masaya Higuchi, Grace Naswa Makokha, Hideaki Matsuki, Manami Yoshita, Yuetsu Tanaka, Masahiro Fujii

    Blood   122 ( 5 )   715 - 725   2013年8月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:American Society of Hematology  

    <title>Key Points</title>
    Interaction of HTLV-1 Tax with USP10 reduces arsenic-induced stress granule formation and enhances ROS production. USP10 controls sensitivities of leukemia cell lines to arsenic-induced apoptosis.

    DOI: 10.1182/blood-2013-03-493718

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  • Human T-cell leukemia virus type 1 Tax protein interacts with and mislocalizes the PDZ domain protein MAGI-1 査読

    Grace Naswa Makokha, Masahiko Takahashi, Masaya Higuchi, Suguru Saito, Yuetsu Tanaka, Masahiro Fujii

    Cancer Science   104 ( 3 )   313 - 320   2013年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL). HTLV-1 encodes the oncoprotein Tax1, which is essential for immortalization of human T-cells and persistent HTLV-1 infection in vivo. Tax1 has a PDZ binding motif (PBM) at its C-terminus. This motif is crucial for the transforming activity of Tax1 to a T-cell line and persistent HTLV-1 infection. Tax1 through the PBM interacts with PDZ domain proteins such as Dlg1 and Scribble, but it has not been determined yet, which cellular PDZ proteins mediate the functions of Tax1 PBM. Here we demonstrate that Tax1 interacts with the PDZ domain protein MAGI-1 in a PBM-dependent manner, and the interaction mislocalizes MAGI-1 from the detergent-soluble to the detergent-insoluble cellular fraction in 293T cells and in HTLV-1-infected T-cells. In addition, Tax1-transformation of a T-cell line from interleukin (IL)-2-dependent to IL-2-independent growth selects cells with irreversibly reduced expression of MAGI-1 at mRNA level. These findings imply that Tax1, like other viral oncoproteins, targets MAGI-1 as a mechanism to suppress its anti-tumor functions in HTLV-1-infected cells to contribute to the transforming activity of T-cells and persistent HTLV-1 infection.

    DOI: 10.1111/cas.12087

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  • Stress Granules Inhibit Apoptosis by Reducing Reactive Oxygen Species Production 査読

    M. Takahashi, M. Higuchi, H. Matsuki, M. Yoshita, T. Ohsawa, M. Oie, M. Fujii

    Molecular and Cellular Biology   33 ( 4 )   815 - 829   2013年2月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:American Society for Microbiology  

    Cells can undergo two alternative fates following exposure to environmental stress: they either induce apoptosis or inhibit apoptosis and then repair the stress-induced alterations. These processes minimize cell loss and prevent the survival of cells with aberrant DNA and protein alterations. These two alternative fates are partly controlled by stress granules (SGs). While arsenite, hypoxia, and heat shock induce the formation of SGs that inhibit apoptosis, X-ray irradiation and genotoxic drugs do not induce SGs, and they are more prone to trigger apoptosis. However, it is unclear precisely how SGs control apoptosis. This study found that SGs suppress the elevation of reactive oxygen species (ROS), and this suppression is essential for inhibiting ROS-dependent apoptosis. This antioxidant activity of SGs is controlled by two SG components, GTPase-activating protein SH3 domain binding protein 1 (G3BP1) and ubiquitin-specific protease 10 (USP10). G3BP1 elevates the steady-state ROS level by inhibiting the antioxidant activity of USP10. However, following exposure to arsenite, G3BP1 and USP10 induce the formation of SGs, which uncovers the antioxidant activity of USP10. We also found that the antioxidant activity of USP10 requires the protein kinase activity of ataxia telangiectasia mutated (ATM). This work reveals that SGs are critical redox regulators that control cell fate under stress conditions. © 2013, American Society for Microbiology.

    DOI: 10.1128/mcb.00763-12

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  • Both G3BP1 and G3BP2 contribute to stress granule formation 査読

    Hideaki Matsuki, Masahiko Takahashi, Masaya Higuchi, Grace N Makokha, Masayasu Oie, Masahiro Fujii

    Genes to Cells   18 ( 2 )   135 - 146   2013年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    Upon exposure to various environmental stresses such as arsenite, hypoxia, and heat shock, cells inhibit their translation and apoptosis and then repair stress-induced alterations, such as DNA damage and the accumulation of misfolded proteins. These types of stresses induce the formation of cytoplasmic RNA granules called stress granules (SGs). SGs are storage sites for the many mRNAs released from disassembled polysomes under these stress conditions and are essential for the selective translation of stress-inducible genes. Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. Collectively, these results suggest that both G3BP1 and G3BP2 play a role in the formation of SGs in various human cells and thereby recovery from these cellular stresses.

    DOI: 10.1111/gtc.12023

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  • Human T cell leukemia virus type 2 (HTLV-2) Tax2 has a dominant activity over HTLV-1 Tax1 to immortalize human CD4+ T cells 査読

    Michitaka Imai, Masaya Higuchi, Hiroki Kawamura, Manami Yoshita, Masahiko Takahashi, Masayasu Oie, Hideaki Matsuki, Yuetsu Tanaka, Yutaka Aoyagi, Masahiro Fujii

    Virus Genes   46 ( 1 )   39 - 46   2013年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    While human T cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T cell leukemia, a close relative, HTLV-2, is not associated with any leukemia. HTLV-1 and HTLV-2 encode the Tax1 and Tax2 proteins, respectively, which are essential for the immortalization of human T cells by the respective viruses, thereby causing persistent infection. In this study, we compared Tax1 and Tax2 with respect to their immortalization activity in human T cells. Lentivirus-mediated transduction of the tax2 gene into human peripheral blood mononuclear cells stimulated with phytohemagglutinin and interleukin-2 in 96-well plates induced outgrowing T cells in most wells, but the cells infected with the control viruses died within 3 weeks. Surprisingly, the number of outgrowing cells induced by Tax2 was much higher than that induced by Tax1, and the appearance of outgrowing cells by Tax2 was earlier than that induced by Tax1. Nevertheless, both Tax2 and Tax1 preferentially immortalized CD4(+) T cells, but not CD8(+) T cells. Our study showed that HTLV-2 Tax2 can immortalize human CD4(+) T cells, and the activity is much higher than that of Tax1. The distinct T cell immortalization activities of Tax2 and Tax1 might therefore play a role in the different pathogeneses observed for these two viruses.

    DOI: 10.1007/s11262-012-0831-9

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  • Mechanisms of pathogenesis induced by bovine leukemia virus as a model for human T-cell leukemia virus 査読

    Yoko Aida, Hironobu Murakami, Masahiko Takahashi, Shin-Nosuke Takeshima

    Frontiers in Microbiology   4 ( 328 )   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Frontiers Media SA  

    Bovine leukemia virus (BLV) and human T-cell leukemia virus type 1 (HTLV-1) make up a unique retrovirus family. Both viruses induce chronic lymphoproliferative diseases with BLV affecting the B-cell lineage and HTLV-1 affecting the T-cell lineage. The pathologies of BLV- and HTLV-induced infections are notably similar, with an absence of chronic viraemia and a long latency period. These viruses encode at least two regulatory proteins, namely, Tax and Rex, in the pX region located between the env gene and the 3' long terminal repeat. The Tax protein is a key contributor to the oncogenic potential of the virus, and is also the key protein involved in viral replication. However, BLV infection is not sufficient for leukemogenesis, and additional events such as gene mutations must take place. In this review, we first summarize the similarities between the two viruses in terms of genomic organization, virology, and pathology. We then describe the current knowledge of the BLV model, which may also be relevant for the understanding of leukemogenesis caused by HTLV-1. In addition, we address our improved understanding of Tax functions through the newly identified BLVTax mutants, which have a substitution between amino acids 240 and 265.

    DOI: 10.3389/fmicb.2013.00328

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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 査読

    Manami Yoshita, Masaya Higuchi, Masahiko Takahashi, Masayasu Oie, Yuetsu Tanaka, Masahiro Fujii

    Cancer Science   103 ( 2 )   369 - 374   2012年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    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)

    DOI: 10.1111/j.1349-7006.2011.02123.x

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  • The PDZ domain binding motif (PBM) of human T-cell leukemia virus type 1 Tax can be substituted by heterologous PBMs from viral oncoproteins during T-cell transformation 査読

    Tomoya Aoyagi, Masahiko Takahashi, Masaya Higuchi, Masayasu Oie, Yuetsu Tanaka, Tohru Kiyono, Yutaka Aoyagi, Masahiro Fujii

    Virus Genes   40 ( 2 )   193 - 199   2010年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Several tumor viruses, such as human T-cell leukemia virus (HTLV), human papilloma virus (HPV), human adenovirus, have high-oncogenic and low-oncogenic subtypes, and such subtype-specific oncogenesis is associated with the PDZ-domain binding motif (PBM) in their transforming proteins. HTLV-1, the causative agent of adult T-cell leukemia, encodes Tax1 with PBM as a transforming protein. The Tax1 PBM was substituted with those from other oncoviruses, and the transforming activity was examined. Tax1 mutants with PBM from either HPV-16 E6 or adenovirus type 9 E4ORF1 are fully active in the transformation of a mouse T-cell line from interleukin-2-dependent growth into independent growth. Interestingly, one such Tax1 PBM mutant had an extra amino acid insertion derived from E6 between PBM and the rest of Tax1, thus suggesting that the amino acid sequences of the peptides between PBM and the rest of Tax1 and the numbers only slightly affect the function of PBM in the transformation. Tax1 and Tax1 PBM mutants interacted with tumor suppressors Dlg1 and Scribble with PDZ-domains. Unlike E6, Tax1 PBM mutants as well as Tax1 did not or minimally induced the degradations of Dlg1 and Scribble, but instead induced their subcellular translocation from the detergent-soluble fraction into the insoluble fraction, thus suggesting that the inactivation mechanism of these tumor suppressor proteins is distinct. The present results suggest that PBMs of high-risk oncoviruses have a common function(s) required for these three tumor viruses to transform cells, which is likely associated with the subtype-specific oncogenesis of these tumor viruses.

    DOI: 10.1007/s11262-009-0447-x

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  • Human T-cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF-κB 査読

    Tiejun Zhao, Jun-ichirou Yasunaga, Yorifumi Satou, Mitsuyoshi Nakao, Masahiko Takahashi, Masahiro Fujii, Masao Matsuoka

    Blood   113 ( 12 )   2755 - 2764   2009年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:American Society of Hematology  

    <title>Abstract</title>Adult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). The activation of NF-κB by Tax has been reported to play a crucial role in HTLV-1–induced transformation. The HTLV-1 bZIP factor (HBZ), which is encoded by an mRNA of the opposite polarity of the viral genomic RNA, is involved in both T cell proliferation and suppression of Tax-mediated viral gene transcription, suggesting that HBZ cooperates closely with Tax. In the present study, we observed that HBZ specifically suppressed NF-κB–driven transcription mediated by p65 (the classical pathway) without inhibiting the alternative NF-κB signaling pathway. In an immunoprecipitation assay, HBZ bound to p65 and diminished the DNA binding capacity of p65. In addition, HBZ induced p65 degradation through increasing the expression of the PDLIM2 gene, which encodes a ubiquitin E3 ligase for p65. Finally, HBZ actually repressed the transcription of some classical NF-κB target genes, such as IL-8, IL2RA, IRF4, VCAM-1, and VEGF. Selective suppression of the classical NF-κB pathway by HBZ renders the alternative NF-κB pathway predominant after activation of NF-κB by Tax or other stimuli, which might be critical for oncogenesis.

    DOI: 10.1182/blood-2008-06-161729

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  • Identification of a novel motif responsible for the distinctive transforming activity of human T-cell leukemia virus (HTLV) type 1 Tax1 protein from HTLV-2 Tax2 査読

    Toshiyuki Shoji, Masaya Higuchi, Rie Kondo, Masahiko Takahashi, Masayasu Oie, Yuetsu Tanaka, Yutaka Aoyagi, Masahiro Fujii

    Retrovirology   6 ( 1 )   83 - 83   2009年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Background: Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of adult T-cell leukemia (ATL), whereas its relative HTLV-2 is not associated with any malignancies including ATL. HTLV-1 Tax1 transformed a T-cell line from interleukin (IL)-2-dependent growth to IL-2-independent growth, with an activity that was much more potent in comparison to HTLV-2 Tax2. This distinction was mediated by at least two Tax1 specific functions, an interaction with host cellular factors through the PDZ domain binding motif (PBM) and the activation of NF-kappaB2 (NF-kappa B2)/p100.
    Results: Using a series of Tax1 chimeric proteins with Tax2, we found that amino acids 225-232 of Tax1, the Tax1(225-232) region, was essential for the activation of NF-kappa B2 as well as for the high transforming activity. The strict amino acid conservation of Tax1(225-232) among HTLV-1 and simian T-cell leukemia virus type 1 (STLV-1), but not HTLV-2 and STLV-2, indicates that function(s) through the Tax1(225-232) region are biologically significant. Interestingly, another HTLV-1 relative, HTLV-3, has a PBM, but does not conserve the Tax1(225-232) motif in Tax3, thus indicating that these two motifs classify the three HTLVs into the separate groups.
    Conclusion: These results suggest that the combinatory functions through Tax1(225-232) and PBM play crucial roles in the distinct biological properties of the three HTLVs, perhaps also including their pathogenesis.

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  • Human T-cell leukemia virus type 1 Tax induces an aberrant clustering of the tumor suppressor Scribble through the PDZ domain-binding motif dependent and independent interaction 査読

    Masaaki Okajima, Masahiko Takahashi, Masaya Higuchi, Toshiaki Ohsawa, Sakiko Yoshida, Yutaka Yoshida, Masayasu Oie, Yuetsu Tanaka, Fumitake Gejyo, Masahiro Fujii

    Virus Genes   37 ( 2 )   231 - 240   2008年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of adult T-cell leukemia. HTLV-1 Tax1 transforming protein interacts with several PDZ domain-containing proteins, and the interaction is associated with the transforming activities of Tax1 as well as persistent HTLV-1 infection. In this study, we show that Tax1 interacts with the tumor suppressor Scribble containing PDZ domains. Unlike other Tax1-interacting PDZ domain proteins, the PDZ domain-binding motif (PBM) of Tax1 was not required for the interaction with transiently expressed Scribble in 293T cells, but it was essential for the interaction with endogenous Scribble. Endogenous Scribble in 293T cells was primarily localized at the plasma membrane and colocalized with Tax1 but not Tax1 Delta C lacking PBM, whereas transiently expressed Scribble was localized in the cytoplasm and colocalized with Tax1 Delta C as well as Tax1, thus suggesting that Tax1 is recruited to the site of endogenous Scribble, such as the plasma membrane, in a PBM-dependent manner, and thereafter it interacts with Scribble in a PBM-independent and PBM-dependent manner. Endogenous Scribble was diffusely localized at the plasma membrane of HTLV-1-uninfected T-cell lines, whereas it colocalized with Tax1 as small and large aggregate at the plasma membranes. These results suggest that Tax1 through two binding sites induce aberrant clustering of Scribble, thereby altering the functions in HTLV-1-infected cells, which may thus play a role in persistent HTLV-1 infection and the pathogenesis.

    DOI: 10.1007/s11262-008-0259-4

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  • Knockdown of synapse-associated protein Dlg1 reduces syncytium formation induced by human T-cell leukemia virus type 1 査読

    Sakiko Yoshida, Masaya Higuchi, Toshiyuki Shoji, Manami Yoshita, Kojiro Ishioka, Masahiko Takahashi, Masayasu Oie, Yuetsu Tanaka, Makoto Uchiyama, Masahiro Fujii

    Virus Genes   37 ( 1 )   9 - 15   2008年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Human T-cell leukemia virus type 1 (HTLV-1) spreads through cell-to-cell contact by forming a virological synapse. Based on the finding that HTLV-1 envelope glycoprotein (Env) binds to a PDZ domain containing scaffold protein Dlg1, whose function has been implicated in the organization of neuronal and immunological synapses, we examined the role of Dlg1 in the cell-cell infection by HTLV-1. The coculture of an HTLV-1-infected T-cell line MT-2 with an uninfected MOLT-4 induced syncytium, a marker of cell-cell HTLV-1 infection, but an RNA interference-mediated knockdown of Dlg1 in both cells cooperatively reduced the syncytium formation. In HTLV-1-uninfected 293T cells, Dlg1 induced the clustering of GLUT1, a cellular receptor for HTLV-1, but such clustering was abrogated by a deletion of the PDZ domain binding motif of GLUT1 (GLUT1 Delta C). GLUT1 expression in MDBK cells induced HTLV-1-mediated syncytium formation, and the activity was much greater than that of GLUT1 Delta C. These results suggest that Dlg1, through the interaction with GLUT1 as well as Env, plays a positive role in the syncytium formation induced by HTLV-1.

    DOI: 10.1007/s11262-008-0234-0

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  • Rearranged NF-κB2 gene in an adult T-cell leukemia cell line 査読

    Masato Isogawa, Masaya Higuchi, Masahiko Takahashi, Masayasu Oie, Naoki Mori, Yuetsu Tanaka, Yutaka Aoyagi, Masahiro Fujii

    Cancer Science   99 ( 4 )   792 - 798   2008年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    Adult T-cell leukemia (ATL) is an aggressive type of leukemia, originating from T-cells infected with human T-cell leukemia virus type 1. Accumulating evidence suggests the aberrant activation of NF-kappa B to be a causative factor mediating the abnormal proliferation of leukemic cells, thus resulting in the development of ATL. A rearranged NF-kappa B2/p100 gene was isolated from an ATL-derived cell line, which was generated by a chromosomal translocation. The isolated NF-kappa B2 mutant is fused with the with no (lysine) deficient protein kinase 1 gene, coding for a 58 kDa protein that retains the DNA binding Rel homology domain, but it lacks the entire ankyrin repeat inhibitory domain, thus suggesting its constitutive activation. This rearranged NF-kappa B2 gene product (p58) was localized in the nucleus, and formed a complex with NF-kappa B p65 or RelB. Moreover, a T-cell line expressing p58 increased the amount of an NF-kappa B2-inducible gene, NF-kappa B2/p100 by itself. These results suggest that such NF-kappa B2 gene rearrangement may therefore be a factor in the constitutive activation of NF-kappa B in ATL, and thereby playing a role in the ATL pathogenesis.

    DOI: 10.1111/j.1349-7006.2008.00750.x

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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 査読

    Masaya Higuchi, Chikako Tsubata, Rie Kondo, Sakiko Yoshida, Masahiko Takahashi, Masayasu Oie, Yuetsu Tanaka, Renaud Mahieux, Masao Matsuoka, Masahiro Fujii

    Journal of Virology   81 ( 21 )   11900 - 11907   2007年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:American Society for Microbiology  

    <title>ABSTRACT</title>
    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-κB2/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-κB2/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-κB2/p100 plays a crucial role in the Tax1-mediated transformation of T cells and that NF-κB2/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.

    DOI: 10.1128/jvi.00532-07

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  • A novel KRAB-Zinc finger protein interacts with latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus and activates transcription via terminal repeat sequences. 査読

    Watanabe A, Higuchi M, Fukushi M, Ohsawa T, Takahashi M, Oie M, Fujii M

    Virus Genes   34 ( 2 )   127 - 136   2007年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s11262-006-0048-x

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  • Human T-cell leukemia virus type 2 Tax protein induces interleukin 2-independent growth in a T-cell line. 査読

    Rie Kondo, Masaya Higuchi, Masahiko Takahashi, Masayasu Oie, Yuetsu Tanaka, Fumitake Gejyo, Masahiro Fujii

    Retrovirology   3 ( 1 )   88 - 88   2006年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1186/1742-4690-3-88

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  • Inactivation of tumor suppressor Dlg1 augments transformation of a T-cell line induced by human T-cell leukemia virus type 1 Tax protein. 査読

    Kojiro Ishioka, Masaya Higuchi, Masahiko Takahashi, Sakiko Yoshida, Masayasu Oie, Yuetsu Tanaka, Sugata Takahashi, Li Xie, Patrick L Green, Masahiro Fujii

    Retrovirology   3 ( 1 )   71 - 71   2006年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1186/1742-4690-3-71

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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 査読

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

    Journal of Virology   79 ( 18 )   11925 - 11934   2005年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:American Society for Microbiology  

    <title>ABSTRACT</title>
    Human T-cell leukemia virus type 1 (HTLV-1) but not HTLV-2 is associated with adult T-cell leukemia. We found that HTLV-2 Tax2 protein stimulated reporter gene expression regulated by the interleukin (IL)-2 promoter through the nuclear factor of activated T cells (NFAT) in a human T-cell line (Jurkat). However, the activity of HTLV-1 Tax1 was minimal in this system. T-cell lines immortalized by HTLV-2 but not HTLV-1 constitutively exhibited activated NFAT in the nucleus and constitutively expressed IL-2 mRNA. Cyclosporine A, an inhibitor of NFAT activation, abrogated the induction of IL-2 mRNA in HTLV-2-immortalized T-cell lines and concomitantly inhibited cell growth. This growth inhibition was rescued by the addition of IL-2 to the culture. Furthermore, anti-IL-2 receptor antibodies significantly reduced the proliferation of HTLV-2-infected T-cell lines but not that of HTLV-1-infected cells. Our results suggest that Tax2 activates an IL-2 autocrine loop mediated through NFAT that supports the growth of HTLV-2-infected cells under low-IL-2 conditions. This mechanism would be especially important in vivo, where this autocrine mechanism establishes a nonleukemogenic life-long HTLV-2 infection. The results also suggest that differences in long-term cytokine production between HTLV-1 and HTLV-2 infection are another factor for the differences in pathogenesis.

    DOI: 10.1128/jvi.79.18.11925-11934.2005

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  • Involvement of bovine leukemia virus in induction and inhibition of apoptosis 査読

    Masahiko Takahashi, Shigeru Tajima, Kosuke Okada, William C. Davis, Yoko Aida

    Microbes and Infection   7 ( 1 )   19 - 28   2005年1月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    In a previous study, we identified an interesting mutant form of the Tax protein of bovine leukemia virus (BLV), designated D247G. that has an enhanced capacity to transactivate the long terminal repeat (LTR) of BLV and the cellular proto-oncogene c-fos when compared with wild-type Tax (wt-Tax). We domonstrate here that an infectious strain of BLV containing the mutant D247G form of Tax also differs in its capacity to modulate cell survival both positively and negatively. When peripheral blood mononuclear cells (PBMCs) infected with wild-type or mutant BLV are cultured ex vivo with staurosporine, an agent known to induce a mitochondrial caspase cascade pathway regulating apoptosis, the rate of apoptosis is reduced to a greater extent in cells infected with mutant BLV than wild-type BLV, consistent with previous observations in cultures without staurosporine. The increase in survival was associated with an increase in expression of mRNA of bcl-xl but not bcl-2 and bax ex vivo. In contrast, when a tissue culture-adapted cell line, 293T, was transiently transfected with either wild-type or mutant BLV, apoptosis was induced. The increase in the rate of apoptosis was higher in cells transfected with mutant BLV. The same difference was noted in cells transiently transfected with wild-type and mutant D247G Tax, suggesting that the observed positive and negative modulation of cell survival is attributed to the functional characteristics of mutant D247G Tax. (C) 2004 Elsevier SAS. All rights reserved.

    DOI: 10.1016/j.micinf.2004.09.014

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  • Bovine Leukemia Virus High Tax Molecular Clone Experimentally Induces Leukemia/Lymphoma in Sheep 査読

    Kosuke OKADA, Norihiro NAKAE, Konomi KURAMOCHI, Shan-ai YIN, Manabu IKEDA, Shigeaki TAKAMI, Tou-ichi HIRATA, Masanobu GORYO, Shigeru NUMAKUNAI, Shin-nosuke TAKESHIMA, Masahiko TAKAHASHI, Shigeru TAJIMA, Satoru KONNAI, Misao ONUMA, Yoko AIDA

    Journal of Veterinary Medical Science   67 ( 12 )   1231 - 1235   2005年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Society of Veterinary Science  

    Sheep were inoculated with high tax coded pBLV-IF (H group, Nos.1-5) of bovine leukemia virus (BLV), wild tax coded pBLV-IF (W group, Nos. 6-11), or control plasmid (C group, Nos. 12-14). During the observation period (4 to 46 months), 5 of 5 cases in H group and 3 of 6 cases (Nos. 6, 7, 9) in W group became positive tor gp51. Only 1 case in H group became leukemic, and one case each of H and W groups developed lymphoma. In No. 3, lesions Were found in multiple organs including the lymph nodes, gastrointestinal tract following abomasum, and heart. In No. 6, lesions of lymphoma were found only in the jejunum, and heart. Morphologically, small to middle-sized lymphocytic neoplastic (NP) cells were found in both cases, but lymphoblastic NP cells were found only in No. 3. By immunohistochemical examination, the phenotypes of NP dwells were determined as CD1(-), CD4(-), CD5(-)-, CD8 alpha(-), sIgM(+), lambda light chain(+), B-B4(+), MHC class II+ in both case. The results of this study indicate that inoculation of pBLV-IF can induce lymphocytic and lymphoblastic leukemia/lymphoma in sheep. Additionally, it is suggested that the expression rate of tax gene is not associated with the development of leukemia/lymphoma in sheep experimentally inoculated with pBLV-IF.

    DOI: 10.1292/jvms.67.1231

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  • Elevated expression of CD30 in adult T-cell leukemia cell lines: possible role in constitutive NF-kappaB activation. 査読

    Masaya Higuchi, Takehiro Matsuda, Naoki Mori, Yasuaki Yamada, Ryouichi Horie, Toshiki Watanabe, Masahiko Takahashi, Masayasu Oie, Masahiro Fujii

    Retrovirology   2 ( 1 )   29 - 29   2005年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1186/1742-4690-2-29

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  • PDZ domain-binding motif of human T-cell leukemia virus type 1 Tax oncoprotein is essential for the interleukin 2 independent growth induction of a T-cell line. 査読

    Chikako Tsubata, Masaya Higuchi, Masahiko Takahashi, Masayasu Oie, Yuetsu Tanaka, Fumitake Gejyo, Masahiro Fujii

    Retrovirology   2 ( 1 )   46 - 46   2005年

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    DOI: 10.1186/1742-4690-2-46

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  • Ex vivo survival of peripheral blood mononuclear cells in sheep induced by bovine leukemia virus (BLV) mainly occurs in CD5– B cells that express BLV 査読

    Masahiko Takahashi, Shigeru Tajima, Shin-Nosuke Takeshima, Satoru Konnai, Shan Ai Yin, Kosuke Okada, William C. Davis, Yoko Aida

    Microbes and Infection   6 ( 6 )   584 - 595   2004年5月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.micinf.2004.02.014

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  • A Mutant Form of the Tax Protein of Bovine Leukemia Virus (BLV), with Enhanced Transactivation Activity, Increases Expression and Propagation of BLV In Vitro but Not In Vivo 査読

    Shigeru Tajima, Masahiko Takahashi, Shin-nosuke Takeshima, Satoru Konnai, Shan Ai Yin, Shinobu Watarai, Yoshimasa Tanaka, Misao Onuma, Kosuke Okada, Yoko Aida

    Journal of Virology   77 ( 3 )   1894 - 1903   2003年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1128/jvi.77.3.1894-1903.2003

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MISC

  • 成人T細胞白血病ウイルス癌蛋白TaxとHBZはBCL11B遺伝子発現を抑制する(Human T-cell leukemia virus type 1 oncoproteins Tax and HBZ represses BCL11B gene expression)

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    日本癌学会総会記事   72回   240 - 240   2013年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • Aberrant activation of the interleukin 2 autocrine loop through Nfat by non-leukemogenic human T-cell leukemia virus type 2 but not leukemogenic type 1 virus

    M Fujii, M Takahashi, M Higuchi

    AIDS RESEARCH AND HUMAN RETROVIRUSES   21 ( 5 )   451 - 451   2005年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:MARY ANN LIEBERT INC  

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  • Regulation of apoptosis by bovine leukemia virus encoding Tax with elevated transactivation activity.

    M Takahashi, S Tajima, S Takeshima, K Okada, Y Aida

    AIDS RESEARCH AND HUMAN RETROVIRUSES   19   S69 - S70   2003年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:MARY ANN LIEBERT INC PUBL  

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  • In vitro and in vivo analyses of infectious molecular clone of BLV encoding tax with elevated transactivation activity

    S Tajima, M Takahashi, K Okada, Y Aida

    AIDS RESEARCH AND HUMAN RETROVIRUSES   17   S48 - S48   2001年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:MARY ANN LIEBERT INC PUBL  

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共同研究・競争的資金等の研究

  • 新規NF-κB抑制因子による炎症性腸疾患における慢性炎症の制御機構

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  • プロテアソーム阻害薬に対する感受性を抑制する新しい分子機構の解明

    2017年4月 - 2020年3月

    日本学術振興会  科学研究費助成事業 

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  • ストレス顆粒とオートファジーによるTDP-43蛋白の分解機構

    2016年 - 2018年

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  • 活性酸素制御異常による成人T細胞白血病発症機構の解明

    2014年4月 - 2017年3月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

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  • 新規Tax1結合因子を介したHTLV-1発癌の悪性化機構

    2011年4月 - 2013年3月

    日本学術振興会  科学研究費助成事業  若手研究(B)

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  • HTLV1遺伝子発現のエピジェネティックな抑制機構

    2005年4月 - 2007年3月

    日本学術振興会  科学研究費助成事業  若手研究(B)

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:3500000円 ( 直接経費:3500000円 )

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