2024/05/02 更新

写真a

タカハシ　マナミ
髙橋　真奈美
TAKAHASHI Manami
所属
教育研究院 医歯学系 特任助手
医歯学総合研究科 特任助手
職名
特任助手
外部リンク

学位

  • 博士（医学） （ 2012年3月   新潟大学 ）

研究分野

  • ライフサイエンス / ウイルス学

  • ライフサイエンス / 細胞生物学

  • ライフサイエンス / 腫瘍生物学

経歴（researchmap）

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

    2023年4月 - 現在

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  • 新潟大学   産学地域連携推進機構 産学地域人材育成センター   産学地域人材育成センター研究員

    2013年4月 - 2014年12月

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  • 東京医科歯科大学   医歯学研究支援センター   研究機関研究員

    2012年4月 - 2013年3月

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経歴

  • 新潟大学   医歯学総合研究科   特任助手

    2023年4月 - 現在

  • 新潟大学   教育研究院 医歯学系   特任助手

    2023年4月 - 現在

所属学協会

  • 日本癌学会

    2007年 - 現在

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論文

  • Acute type adult T-cell leukemia cells proliferate in the lymph nodes rather than in peripheral blood. 査読 国際誌

    Mariko Mizuguchi, Mitsuyoshi Takatori, Shugo Sakihama, Manami Yoshita-Takahashi, Naoki Imaizumi, Yoshiaki Takahashi, Hiroo Hasegawa, Kennosuke Karube, Takuya Fukushima, Masataka Nakamura, Yuetsu Tanaka

    Cancer gene therapy   2022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）  

    A massive increase in the number of mature CD4+ T-cells in peripheral blood (PB) is a defining characteristic of acute type of adult T-cell leukemia (ATL). To date, the site of proliferation of ATL cells in the body has been unclear. In an attempt to address this question, we examined the expression of the proliferation marker, Ki-67, in freshly isolated ATL cells from PB and lymph nodes (LNs) of patients with various types of ATL. Our findings reveal that LN-ATL cells display higher expression of the Ki-67 antigen than PB-ATL cells in acute type patients. The gene expression of T-cell quiescence regulators such as Krüppel-like factor 2/6 and forkhead box protein 1 was substantially high in acute type PB-ATL cells. The expression of human telomerase reverse transcriptase, which is involved in T-cell expansion, was significantly low in PB-ATL cells from acute type patients, similar to that in normal resting T-cells. These findings suggest that ATL cells proliferate in the LNs rather than in PB.

    DOI： 10.1038/s41417-022-00475-0

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  • Promoter CpG methylation inhibits Krüppel-like factor 2 (KLF2)-Mediated repression of hTERT gene expression in human T-cells 査読

    Mariko Mizuguchi, Toshifumi Hara, Manami Yoshita-Takahashi, Takashi Kohda, Yuetsu Tanaka, Masataka Nakamura

    Biochemistry and Biophysics Reports   26   100984 - 100984   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.bbrep.2021.100984

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

    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 - 23   2015年5月

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    記述言語：英語  

    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 T cells. 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 α-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-γ from NKT cells. RASAL3-deficient NKT cells treated with α-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 Tax oncoprotein represses the expression of the BCL11B 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：Blackwell Publishing Ltd  

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

    Masahiko Takahashi, Masaya Higuchi, Hideaki Matsuki, Manami Yoshita, Toshiaki Ohsawa, Masayasu Oie, Masahiro Fujii

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

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Informa UK Limited  

    DOI： 10.1128/mcb.00763-12

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    その他リンク： https://www.tandfonline.com/doi/pdf/10.1128/MCB.00763-12

  • 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  

    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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  • 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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    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：WILEY-BLACKWELL  

    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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  • 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）  

    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 (GLUT1ΔC). GLUT1 expression in MDBK cells induced HTLV-1-mediated syncytium formation, and the activity was much greater than that of GLUT1ΔC. 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. © 2008 Springer Science+Business Media, LLC.

    DOI： 10.1007/s11262-008-0234-0

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