Details of the Researcher

PHOTO

Kozo Tanaka
Section
Institute of Development, Aging and Cancer
Job title
Professor
Degree
  • 博士(医学) (The University of Tokyo)

e-Rad No.
00304452

Research History 10

  • 2023/04 - Present
    Institute of Development, Aging and Cancer, Tohoku University Director

  • 2011/03 - Present
    Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University Professor

  • 2008/10 - 2011/02
    Institute of Development, Aging and Cancer, Tohoku University Associate Professor

  • 2007/03 - 2008/09
    東北大学特定領域研究推進支援センター Associate Professor

  • 2002/01 - 2007/02
    College of Life Science, University of Dundee, UK Post-doctral research assistant

  • 1998/04 - 2001/12
    広島大学原爆放射能医学研究所分子病理学研究分野 助手

  • 1997/04 - 1998/03
    東京大学医学部第3内科 非常勤医員

  • 1993/04 - 1997/03
    東京大学大学院医学系研究科内科学専攻博士課程

  • 1992/06 - 1993/05
    自治医科大学附属病院 内科ジュニア・レジデント

  • 1991/06 - 1992/05
    東京大学医学部附属病院内科 研修医

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Education 2

  • The University of Tokyo Graduate School, Division of Medical Sciences Internal Medicine

    - 1997/03/28

  • The University of Tokyo Faculty of Medicine Medaical Department

    - 1991/03/28

Committee Memberships 4

  • Japan Sarcoma Association Delegate

    2024/10 - Present

  • Japan Society for Cell Biology Representative

    2018/06 - Present

  • 日本生化学会 評議員

    2015/01 - Present

  • 日本癌学会 評議員

    2010/01 - Present

Professional Memberships 5

  • THE JAPANESE BIOCHEMICAL SOCIETY

  • Japan Society for Cell Biology

  • The Japanese Society of Internal Medicine

  • The Molecular Biology Society of Japan

  • 日本癌学会(2010/01- 評議員)

Research Interests 4

  • chromosomal instability

  • chromosome segregation

  • Molecular oncology

  • Cellular biology

Research Areas 3

  • Life sciences / Pathobiochemistry /

  • Life sciences / Cell biology /

  • Life sciences / Molecular biology /

Awards 1

  1. 広島大学医学部広仁会基礎医学研究賞

    2001/06/09 広島大学医学部医学科同窓会広仁会 相同組換え遺伝子による効率的なジーン・ターゲティング法の開発

Papers 99

  1. Human fibroblasts from aged individuals exhibit chromosomal instability through replication stress caused by oxidative stress. International-journal Peer-reviewed

    Kailin Zhu, Guan Chen, Yueyi Ren, Kenji Iemura, Kozo Tanaka

    npj aging 2025/11/25

    DOI: 10.1038/s41514-025-00299-w  

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    Aneuploid cells are known to increase with age. Previously, we demonstrated an increased number of aneuploid fibroblasts isolated from aged mice due to chromosomal instability (CIN), which is caused by oxidative stress. It is unclear whether this phenomenon also occurs in human cells, which are more resistant to oxidative stress than mouse cells. Here, we found that fibroblasts from aged individuals exhibited an increase in aneuploid cells. The frequency of chromosome missegregation and micronuclei increased in these cells, indicating CIN. A DNA fiber assay revealed the presence of replication stress, accompanied by an increase in 53BP1 nuclear bodies and ultrafine bridges. Increased levels of reactive oxygen species derived from mitochondria, along with reduced mitochondrial membrane potential, imply that these cells experienced oxidative stress due to mitochondrial functional decline. Antioxidant treatment reduced the frequency of chromosome missegregation and micronuclei, suggesting that oxidative stress causes CIN. Oxidative stress also causes replication stress, which precedes CIN. Spindle microtubules were stabilized in fibroblasts from aged individuals, which was alleviated by antioxidant treatment. Taken together, these findings suggest that aging-related CIN in human fibroblasts is caused by oxidative stress associated with mitochondrial dysfunction, which induces replication stress that in turn causes CIN through microtubule stabilization. Although human fibroblasts are more resistant to the ambient oxygen environment than mouse fibroblasts, our findings showed that they undergo oxidative stress that causes CIN with age in a manner similar to mouse fibroblasts, revealing a conserved phenomenon in mammalian cells.

  2. BET family BRD3 initiates DSB-induced chromatin remodeling with TIP60 to promote R-loop-mediated HR. International-journal Peer-reviewed

    Jianghao Qian, Tomoko Watanabe, Reiko Watanabe, Shin-Ichiro Kanno, Akiko Takahashi, Shinji Kohsaka, Yuki Yoshino, Natsuko Chiba, Kozo Tanaka, Takashi Kohno, Akira Yasui, Ayako Ui

    Cell reports 44 (11) 116461-116461 2025/11/25

    DOI: 10.1016/j.celrep.2025.116461  

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    Mechanisms for genome stability in actively transcribed regions are essential for cellular homeostasis; however, these mechanisms are poorly understood. Herein, we identify the bromodomain and extraterminal domain (BET) family BRD3 as the genome caretaker in actively transcribed chromatin. We identify the protein network between BRD3 and chromatin remodeler TIP60. During transcription, BRD3 localizes to actively transcribed chromatin through its N-terminal bromodomains. Following DNA double-strand breaks (DSBs) at the actively transcribed chromatin, the C-terminal extraterminal (ET) domain of BRD3 recruits CHD4 via its KIKL-like motifs to replace HP1 with the TIP60 (Tat-interactive protein, 60 kDa) complex, promoting H4K16 acetylation and MBTD1 recruitment, which creates chromatin barriers to 53BP1. This process recruits BRCA1 and R-loop-processing factors to promote R-loop-mediated homologous recombination (HR) and suppress 53BP1 and mutagenic non-homologous end-joining. Our study elucidates the mechanism by which BRD3 initiates DSB-induced chromatin remodeling by CHD4 and TIP60 to promote R-loop-mediated HR on actively transcribed chromatin to maintain genome stability.

  3. The RB protein: more than a sentry of cell cycle entry. International-journal Peer-reviewed

    Pulari U Thangavelu, Cheng-Yu Lin, Farzaneh Forouz, Kozo Tanaka, Eloïse Dray, Pascal H G Duijf

    Trends in molecular medicine 2025/04/28

    DOI: 10.1016/j.molmed.2025.04.001  

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    Genomic instability is a hallmark of cancer. It fuels cancer progression and therapy resistance. As 'the guardian of the genome', the tumor suppressor protein p53 protects against genomic damage. Canonically, the retinoblastoma protein (RB) is 'the sentry of cell cycle entry', as it dictates whether a cell enters the cell cycle to divide. However, the RB pathway also controls myriad non-canonical cellular processes, including metabolism, stemness, angiogenesis, apoptosis, and immune surveillance. We discuss how frequent RB pathway inactivation and underlying mechanisms in cancers affect these processes. We focus on RB's - rather than p53's - 'guardian of the genome' functions in DNA replication, DNA repair, centrosome duplication, chromosome segregation, and chromatin organization. Finally, we review therapeutic strategies, challenges, and opportunities for targeting RB pathway alterations in cancer.

  4. Multi-SpinX: An advanced framework for automated tracking of mitotic spindles and kinetochores in multicellular environments Peer-reviewed

    Binghao Chai, Christoforos Efstathiou, Muntaqa S. Choudhury, Kinue Kuniyasu, Saakshi Sanjay Jain, Alexia-Cristina Maharea, Kozo Tanaka, Viji M. Draviam

    Computers in Biology and Medicine 2025/03

    DOI: 10.1016/j.compbiomed.2024.109626  

  5. Armadillo domain of ARID1A directly interacts with DNA-PKcs to couple chromatin remodeling with nonhomologous end joining (NHEJ) pathway

    Shin-ichiro Kanno, Takayasu Kobayashi, Reiko Watanabe, Akihiro Kurimasa, Kozo Tanaka, Akira Yasui, Ayako Ui

    Nucleic Acids Research 2025/02/27

    DOI: 10.1093/nar/gkaf150  

  6. Fibrous corona is reduced in cancer cell lines that attenuate microtubule nucleation from kinetochores Peer-reviewed

    Yudai Ishikawa, Hirotaka Fukue, Runa Iwakami, Masanori Ikeda, Kenji Iemura, Kozo Tanaka

    Cancer Science 2025/02

    DOI: 10.1111/cas.16406  

  7. CHAMP1 premature termination codon mutations found in individuals with intellectual disability cause a homologous recombination defect through haploinsufficiency. International-journal Peer-reviewed

    Yujiro Yoshizaki, Yunosuke Ouchi, Dicky Kurniawan, Eisuke Yumoto, Yuki Yoneyama, Faiza Ramadhani Rizqullah, Hiyori Sato, Mirjam Hanako Sarholz, Toyoaki Natsume, Masato T Kanemaki, Masanori Ikeda, Ayako Ui, Kenji Iemura, Kozo Tanaka

    Scientific reports 14 (1) 31904-31904 2024/12/30

    DOI: 10.1038/s41598-024-83435-y  

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    CHAMP1 (chromosome alignment-maintaining phosphoprotein 1) plays a role in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR). The CHAMP1 gene is one of the genes mutated in individuals with intellectual disability. The majority of the mutations are premature termination codon (PTC) mutations, while missense mutations have also been reported. How these mutations affect the functions of CHAMP1 has not been clarified yet. Here we investigated the effects of the CHAMP1 mutations on HR. In Epstein-Barr virus-induced lymphoblastoid cells and fibroblasts derived from individuals with CHAMP1 PTC mutations, truncated CHAMP1 proteins of the expected sizes were detected. When DSBs were induced in fibroblasts with PTC mutations, a defect in HR was detected. U2OS cells expressing the CHAMP1 mutants did not show an HR defect in the presence of endogenous wild-type (WT) CHAMP1, whereas they were unable to restore HR activity when CHAMP1 WT was depleted, suggesting that the PTC mutations are loss-of-function mutations. On the other hand, the CHAMP1 mutants with missense mutations restored HR activity when CHAMP1 WT was depleted. In DLD-1 cells, heterozygous depletion of CHAMP1 resulted in an HR defect, indicating haploinsufficiency. These results suggest that CHAMP1 PTC mutations cause an HR defect through a haploinsufficient mechanism, while CHAMP1 missense mutations do not affect the HR function of CHAMP1.

  8. Kinesin-like motor protein KIF23 maintains neural stem and progenitor cell pools in the developing cortex Peer-reviewed

    Sharmin Naher, Kenji Iemura, Satoshi Miyashita, Mikio Hoshino, Kozo Tanaka, Shinsuke Niwa, Jin-Wu Tsai, Takako Kikkawa, Noriko Osumi

    The EMBO Journal 2024/12/04

    DOI: 10.1038/s44318-024-00327-7  

  9. Assessment of Chromosome Oscillations in Mammalian Cells by Live Cell Imaging

    Kenji Iemura, Kozo Tanaka

    Methods in Molecular Biology 157-164 2024/12/01

    Publisher: Springer US

    DOI: 10.1007/978-1-0716-4224-5_11  

    ISSN: 1064-3745

    eISSN: 1940-6029

  10. Intracellular biliverdin dynamics during ferroptosis. International-journal Peer-reviewed

    Kazuma Nakajima, Hironari Nishizawa, Guan Chen, Shunichi Tsuge, Mie Yamanaka, Machi Kiyohara, Riko Irikura, Mitsuyo Matsumoto, Kozo Tanaka, Rei Narikawa, Kazuhiko Igarashi

    Journal of biochemistry 2024/09/28

    DOI: 10.1093/jb/mvae067  

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    Ferroptosis is a cell death mechanism mediated by iron-dependent lipid peroxidation. Although ferroptosis has garnered attention as a cancer-suppressing mechanism, there are still limited markers available for identifying ferroptotic cells or assessing their sensitivity to ferroptosis. The study focused on biliverdin, an endogenous reducing substance in cells, and examined the dynamics of intracellular biliverdin during ferroptosis using a biliverdin-binding cyanobacteriochrome. It was found that intracellular biliverdin decreases during ferroptosis and that this decrease is specific to ferroptosis among different forms of cell death. Furthermore, the feasibility of predicting sensitivity to ferroptosis by measuring intracellular biliverdin was demonstrated using a ferroptosis model induced by the re-expression of the transcription factor BACH1. These findings provide further insight into ferroptosis research and are expected to contribute to the development of cancer therapies that exploit ferroptosis.

  11. Alteration in the chromatin landscape during the DNA damage response: Continuous rotation of the gear driving cellular senescence and aging. International-journal Peer-reviewed

    Jianghao Qian, Xiangyu Zhou, Kozo Tanaka, Akiko Takahashi

    DNA repair 131 103572-103572 2023/11

    DOI: 10.1016/j.dnarep.2023.103572  

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    The DNA damage response (DDR) is a crucial biological mechanism for maintaining cellular homeostasis in living organisms. This complex process involves a cascade of signaling pathways that orchestrate the sensing and processing of DNA lesions. Perturbations in this process may cause DNA repair failure, genomic instability, and irreversible cell cycle arrest, known as cellular senescence, potentially culminating in tumorigenesis. Persistent DDR exerts continuous and cumulative pressure on global chromatin dynamics, resulting in altered chromatin structure and perturbed epigenetic regulations, which are highly associated with cellular senescence and aging. Sustained DDR activation and heterochromatin changes further promote senescence-associated secretory phenotype (SASP), which is responsible for aging-related diseases and cancer development. In this review, we discuss the diverse mechanisms by which DDR leads to cellular senescence and triggers SASP, together with the evidence for DDR-induced chromatin remodeling and epigenetic regulation in relation to aging.

  12. Oxidative stress induces chromosomal instability through replication stress in fibroblasts from aged mice. International-journal Peer-reviewed

    Guan Chen, Zhenhua Li, Kenji Iemura, Kozo Tanaka

    Journal of cell science 136 (11) 2023/06/01

    DOI: 10.1242/jcs.260688  

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    Chromosomal aneuploidy has been associated with aging. However, whether and how chromosomal instability (CIN), a condition frequently seen in cancer cells in which chromosome missegregation occurs at a high rate, is associated with aging is not fully understood. Here, we found that primary fibroblasts isolated from aged mice (24 months old) exhibit an increased level of chromosome missegregation and micronucleation compared with that from young mice (2 months old), concomitant with an increased rate of aneuploid cells, suggesting the emergence of CIN. Reactive oxygen species were increased in fibroblasts from aged mice, which was accompanied with mitochondrial functional decline, indicating that they are under oxidative stress. Intriguingly, antioxidant treatments reduced chromosome missegregation and micronucleation rates in cells from aged mice, suggesting a link between oxidative stress and CIN. As a cause of CIN, we found that cells from aged mice are under replication stress, which was ameliorated by antioxidant treatments. Microtubule stabilization is a potential cause of CIN promoted by replication stress. Our data demonstrate the emergence of CIN with age, and suggest an unprecedented link between oxidative stress and CIN in aging.

  13. Ferroptosis model system by the re-expression of BACH1. International-journal Peer-reviewed

    Riko Irikura, Hironari Nishizawa, Kazuma Nakajima, Mie Yamanaka, Guan Chen, Kozo Tanaka, Masafumi Onodera, Mitsuyo Matsumoto, Kazuhiko Igarashi

    Journal of biochemistry 2023/04/24

    DOI: 10.1093/jb/mvad036  

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    Ferroptosis is a regulated cell death induced by iron-dependent lipid peroxidation. The heme-responsive transcription factor BTB and CNC homology 1 (BACH1) promotes ferroptosis by repressing the transcription of genes involved in glutathione (GSH) synthesis and intracellular labile iron metabolism, which are key regulatory pathways in ferroptosis. We found that BACH1 re-expression in Bach1-/- immortalized mouse embryonic fibroblasts (iMEFs) can induce ferroptosis upon 2-mercaptoethanol removal, without any ferroptosis inducers. In these iMEFs, GSH synthesis was reduced, and intracellular labile iron levels were increased upon BACH1 re-expression. We used this system to investigate whether the major ferroptosis regulators glutathione peroxidase 4 (Gpx4) and apoptosis-inducing factor mitochondria-associated 2 (Aifm2), the gene for ferroptosis suppressor protein 1, are target genes of BACH1. Neither Gpx4 nor Aifm2 was regulated by BACH1 in the iMEFs. However, we found that BACH1 represses AIFM2 transcription in human pancreatic cancer cells. These results suggest that the ferroptosis regulators targeted by BACH1 may vary across different cell types and animal species. Furthermore, we confirmed that the ferroptosis induced by BACH1 re-expression exhibited a propagating effect. BACH1 re-expression represents a new strategy for inducing ferroptosis after GPX4 or system Xc- suppression, and is expected to contribute to future ferroptosis research.

  14. Autocleavage of separase suppresses its premature activation by promoting binding to cyclin B1. International-journal Peer-reviewed

    Norihisa Shindo, Kazuki Kumada, Kenji Iemura, Jun Yasuda, Haruna Fujimori, Mai Mochizuki, Keiichi Tamai, Kozo Tanaka, Toru Hirota

    Cell reports 41 (9) 111723-111723 2022/11/29

    DOI: 10.1016/j.celrep.2022.111723  

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    Accurate chromosome segregation requires timely activation of separase, a protease that cleaves cohesin during the metaphase-to-anaphase transition. However, the mechanism that maintains the inactivity of separase prior to this event remains unclear. We provide evidence that separase autocleavage plays an essential role in this process. We show that the inhibition of separase autocleavage results in premature activity before the onset of anaphase, accompanied by the formation of chromosomal bridges and spindle rocking. This deregulation is attributed to the reduced binding of cyclin B1 to separase that occurs during the metaphase-to-anaphase transition. Furthermore, when separase is mutated to render the regulation by cyclin B1 irrelevant, which keeps separase in securin-binding form, the deregulation induced by autocleavage inhibition is rescued. Our results reveal a physiological role of separase autocleavage in regulating separase, which ensures faithful chromosome segregation.

  15. Deficiency of CHAMP1, a gene related to intellectual disability, causes impaired neuronal development and a mild behavioral phenotype Peer-reviewed

    Masayoshi Nagai, Kenji Iemura, Takako Kikkawa, Sharmin Naher, Satoko Hattori, Hideo Hagihara, Koh ichi Nagata, Hayato Anzawa, Risa Kugisaki, Hideki Wanibuchi, Takaya Abe, Kenichi Inoue, Kengo Kinoshita, Tsuyoshi Miyakawa, Noriko Osumi, Kozo Tanaka

    Brain Communications 4 (5) fcac20 2022/08/30

    Publisher: Oxford University Press (OUP)

    DOI: 10.1093/braincommn/fcac220  

    eISSN: 2632-1297

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    Abstract CHAMP1 is a gene associated with intellectual disability, which was originally identified as being involved in the maintenance of kinetochore–microtubule attachment. To explore the neuronal defects caused by CHAMP1 deficiency, we established mice that lack CHAMP1. Mice that are homozygous knockout for CHAMP1 were slightly smaller than wild type mice and died soon after birth on pure C57BL/6J background. Although gross anatomical defects were not found in CHAMP1-/- mouse brains, mitotic cells were increased in the cerebral cortex. Neuronal differentiation was delayed in CHAMP1-/- neural stem cells in vitro, which was also suggested in vivo by CHAMP1 knockdown. In a behavioral test battery, adult CHAMP1 heterozygous-knockout mice showed mild memory defects, altered social interaction, and depression-like behaviors. In transcriptomic analysis, genes related to neurotransmitter transport and neurodevelopmental disorder were downregulated in embryonic CHAMP1-/- brains. These results suggest that CHAMP1 plays a role in neuronal development, and CHAMP1-deficient mice resemble some aspects of individuals with CHAMP1 mutations.

  16. High levels of chromosomal instability facilitate the tumor growth and sphere formation. International-journal Peer-reviewed

    Kenji Iemura, Hayato Anzawa, Ryo Funayama, Runa Iwakami, Keiko Nakayama, Kengo Kinoshita, Kozo Tanaka

    Cancer science 113 (8) 2727-2737 2022/06/05

    DOI: 10.1111/cas.15457  

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    Most cancer cells show chromosomal instability (CIN), a condition in which chromosome missegregation occurs at high rates. Growing evidence suggests that CIN is not just a consequence, but a driving force for oncogenic transformation, although the relationship between CIN and tumorigenesis has not been fully elucidated. Here we found that conventional two-dimensional (2D) culture of HeLa cells, a cervical cancer-derived cell line, is a heterogenous population containing cells with different CIN levels. Although cells with high CIN levels (high-CIN cells) grew slower than cells with low CIN levels (low-CIN cells) in 2D monolayer culture, they formed tumors in nude mice and larger spheres in three-dimensional (3D) culture, which is more representative of the in vivo environment. The duration of mitosis was longer in high-CIN cells, implicating their higher mitotic defects. Single cell genome sequencing revealed that high-CIN cells exhibit a higher karyotype heterogeneity compared with low-CIN cells. Intriguingly, the karyotype heterogeneity was reduced in the spheres formed by high-CIN cells, suggesting that cells with growth advantages were selected, although genomic copy number changes specific for spheres were not identified. When we examined gene expression profiles, genes related to K-ras signaling were upregulated, while those related to unfolded protein response were downregulated in high-CIN cells in 3D culture compared with 2D culture, suggesting the relevance of these genes for their survival. Our data suggest that although CIN is disadvantageous in monolayer culture, it promotes the selection of cells with growth advantages under in vivo environments, which may lead to tumorigenesis.

  17. CHAMP1-POGZ counteracts the inhibitory effect of 53BP1 on homologous recombination and affects PARP inhibitor resistance International-journal Peer-reviewed

    Hiroki Fujita, Masanori Ikeda, Ayako Ui, Yunosuke Ouchi, Yoshiko Mikami, Shin-ichiro Kanno, Akira Yasui, Kozo Tanaka

    Oncogene 41 (19) 2706-2718 2022/04/07

    Publisher: Springer Science and Business Media LLC

    DOI: 10.1038/s41388-022-02299-6  

    ISSN: 0950-9232

    eISSN: 1476-5594

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    DNA double-strand break (DSB) repair-pathway choice regulated by 53BP1 and BRCA1 contributes to genome stability. 53BP1 cooperates with the REV7-Shieldin complex and inhibits DNA end resection to block homologous recombination (HR) and affects the sensitivity to inhibitors for poly (ADP-ribose) polymerases (PARPs) in BRCA1-deficient cells. Here, we show that a REV7 binding protein, CHAMP1 (chromosome alignment-maintaining phosphoprotein 1), has an opposite function of REV7 in DSB repair and promotes HR through DNA end resection together with POGZ (POGO transposable element with ZNF domain). CHAMP1 was recruited to laser-micro-irradiation-induced DSB sites and promotes HR, but not NHEJ. CHAMP1 depletion suppressed the recruitment of BRCA1, but not the recruitment of 53BP1, suggesting that CHAMP1 regulates DSB repair pathway in favor of HR. Depletion of either CHAMP1 or POGZ impaired the recruitment of phosphorylated RPA2 and CtIP (CtBP-interacting protein) at DSB sites, implying that CHAMP1, in complex with POGZ, promotes DNA end resection for HR. Furthermore, loss of CHAMP1 and POGZ restored the sensitivity to a PARP inhibitor in cells depleted of 53BP1 together with BRCA1. These data suggest that CHAMP1and POGZ counteract the inhibitory effect of 53BP1 on HR by promoting DNA end resection and affect the resistance to PARP inhibitors.

  18. TORC1 inactivation promotes APC/C-dependent mitotic slippage in yeast and human cells. International-journal Peer-reviewed

    Chihiro Yamada, Aya Morooka, Seira Miyazaki, Masayoshi Nagai, Satoru Mase, Kenji Iemura, Most Naoshia Tasnin, Tsuneyuki Takuma, Shotaro Nakamura, Shamsul Morshed, Naoki Koike, Md Golam Mostofa, Muhammad Arifur Rahman, Tasnuva Sharmin, Haruko Katsuta, Kotaro Ohara, Kozo Tanaka, Takashi Ushimaru

    iScience 25 (2) 103675-103675 2022/02/18

    DOI: 10.1016/j.isci.2021.103675  

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    Unsatisfied kinetochore-microtubule attachment activates the spindle assembly checkpoint to inhibit the metaphase-anaphase transition. However, some cells eventually override mitotic arrest by mitotic slippage. Here, we show that inactivation of TORC1 kinase elicits mitotic slippage in budding yeast and human cells. Yeast mitotic slippage was accompanied with aberrant aspects, such as degradation of the nucleolar protein Net1, release of phosphatase Cdc14, and anaphase-promoting complex/cyclosome (APC/C)-Cdh1-dependent degradation of securin and cyclin B in metaphase. This mitotic slippage caused chromosome instability. In human cells, mammalian TORC1 (mTORC1) inactivation also invoked mitotic slippage, indicating that TORC1 inactivation-induced mitotic slippage is conserved from yeast to mammalian cells. However, the invoked mitotic slippage in human cells was not dependent on APC/C-Cdh1. This study revealed an unexpected involvement of TORC1 in mitosis and provides information on undesirable side effects of the use of TORC1 inhibitors as immunosuppressants and anti-tumor drugs.

  19. A mathematical model of kinetochore-microtubule attachment regulated by Aurora A activity gradient describes chromosome oscillation and correction of erroneous attachments Peer-reviewed

    Manuel Alejandro CAMPOS MEDINA, Kenji IEMURA, Akatsuki KIMURA, Kozo TANAKA

    Biomedical Research 42 (5) 203-219 2021/09/21

    Publisher: Biomedical Research Press

    DOI: 10.2220/biomedres.42.203  

    ISSN: 0388-6107

    eISSN: 1880-313X

  20. Attenuated Chromosome Oscillation as a Cause of Chromosomal Instability in Cancer Cells Peer-reviewed

    Kenji Iemura, Yujiro Yoshizaki, Kinue Kuniyasu, Kozo Tanaka

    Cancers 13 (18) 4531-4531 2021/09/09

    Publisher: MDPI AG

    DOI: 10.3390/cancers13184531  

    eISSN: 2072-6694

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    Chromosomal instability (CIN) is commonly seen in cancer cells, and related to tumor progression and poor prognosis. Among the causes of CIN, insufficient correction of erroneous kinetochore (KT)-microtubule (MT) attachments plays pivotal roles in various situations. In this review, we focused on the previously unappreciated role of chromosome oscillation in the correction of erroneous KT-MT attachments, and its relevance to the etiology of CIN. First, we provided an overview of the error correction mechanisms for KT-MT attachments, especially the role of Aurora kinases in error correction by phosphorylating Hec1, which connects MT to KT. Next, we explained chromosome oscillation and its underlying mechanisms. Then we introduced how chromosome oscillation is involved in the error correction of KT-MT attachments, based on recent findings. Chromosome oscillation has been shown to promote Hec1 phosphorylation by Aurora A which localizes to the spindle. Finally, we discussed the link between attenuated chromosome oscillation and CIN in cancer cells. This link underscores the role of chromosome dynamics in mitotic fidelity, and the mutual relationship between defective chromosome dynamics and CIN in cancer cells that can be a target for cancer therapy.

  21. Chromosome oscillation promotes Aurora A–dependent Hec1 phosphorylation and mitotic fidelity Peer-reviewed

    Kenji Iemura, Toyoaki Natsume, Kayoko Maehara, Masato T. Kanemaki, Kozo Tanaka

    Journal of Cell Biology 220 (7) e202006116 2021/07/05

    Publisher: Rockefeller University Press

    DOI: 10.1083/jcb.202006116  

    ISSN: 0021-9525

    eISSN: 1540-8140

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    Most cancer cells show chromosomal instability, a condition where chromosome missegregation occurs frequently. We found that chromosome oscillation, an iterative chromosome motion during metaphase, is attenuated in cancer cell lines. We also found that metaphase phosphorylation of Hec1 at serine 55, which is mainly dependent on Aurora A on the spindle, is reduced in cancer cell lines. The Aurora A–dependent Hec1-S55 phosphorylation level was regulated by the chromosome oscillation amplitude and vice versa: Hec1-S55 and -S69 phosphorylation by Aurora A is required for efficient chromosome oscillation. Furthermore, enhancement of chromosome oscillation reduced the number of erroneous kinetochore–microtubule attachments and chromosome missegregation, whereas inhibition of Aurora A during metaphase increased such errors. We propose that Aurora A–mediated metaphase Hec1-S55 phosphorylation through chromosome oscillation, together with Hec1-S69 phosphorylation, ensures mitotic fidelity by eliminating erroneous kinetochore–microtubule attachments. Attenuated chromosome oscillation and the resulting reduced Hec1-S55 phosphorylation may be a cause of CIN in cancer cell lines.

  22. CHAMP1 (CAMP) plays a role in cell survival through regulating Mcl-1 expression. International-journal Peer-reviewed

    Maho Hino, Kenji Iemura, Masanori Ikeda, Go Itoh, Kozo Tanaka

    Cancer science 2021/06/09

    DOI: 10.1111/cas.15018  

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    Anti-mitotic drugs such as vinca alkaloids and taxanes cause mitotic cell death after prolonged mitotic arrest. However, a fraction of cells escape from mitotic arrest by undergoing mitotic slippage, which is related to resistance to anti-mitotic drugs. Tipping the balance to mitotic cell death thus can be a way to overcome the drug resistance. Here we found that depletion of a mitotic regulator, CHAMP1 (chromosome alignment-maintaining phosphoprotein, CAMP), accelerates the timing of mitotic cell death after mitotic arrest. Live cell imaging revealed that CHAMP1-depleted cells died earlier than mock-treated cells in the presence of anti-mitotic drugs that resulted in the reduction of cells undergoing mitotic slippage. CHAMP1 depletion reduces the expression of anti-apoptotic Bcl-2 family proteins, especially Mcl-1. We found that CHAMP1 maintains Mcl-1 expression both at protein and mRNA levels independently of the cell cycle. At protein level, CHAMP1 maintains Mcl-1 stability by suppressing proteasome-dependent degradation. CHAMP1 depletion reduces cell viability, and exhibits synergistic effects with anti-mitotic drugs. Our data suggest that CHAMP1 plays a role in the maintenance of Mcl-1 expression, implying that CHAMP1 can be a target to overcome the resistance to anti-mitotic drugs.

  23. Kinetochore stretching-mediated rapid silencing of the spindle-assembly checkpoint required for failsafe chromosome segregation Peer-reviewed

    Kazuhiko S.K. Uchida, Minji Jo, Kota Nagasaka, Motoko Takahashi, Norihisa Shindo, Katsushi Shibata, Kozo Tanaka, Hiroshi Masumoto, Tatsuo Fukagawa, Toru Hirota

    Current Biology 31 (8) 1581-1591.e3 2021/04/26

    Publisher: Elsevier BV

    DOI: 10.1016/j.cub.2021.01.062  

    ISSN: 0960-9822

  24. Lipid peroxidation and the subsequent cell death transmitting from ferroptotic cells to neighboring cells. International-journal Peer-reviewed

    Hironari Nishizawa, Mitsuyo Matsumoto, Guan Chen, Yusho Ishii, Keisuke Tada, Masafumi Onodera, Hiroki Kato, Akihiko Muto, Kozo Tanaka, Kazuhiko Igarashi

    Cell death & disease 12 (4) 332-332 2021/03/29

    DOI: 10.1038/s41419-021-03613-y  

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    Ferroptosis regulated cell death due to the iron-dependent accumulation of lipid peroxide. Ferroptosis is known to constitute the pathology of ischemic diseases, neurodegenerative diseases, and steatohepatitis and also works as a suppressing mechanism against cancer. However, how ferroptotic cells affect surrounding cells remains elusive. We herein report the transfer phenomenon of lipid peroxidation and cell death from ferroptotic cells to nearby cells that are not exposed to ferroptotic inducers (FINs). While primary mouse embryonic fibroblasts (MEFs) and NIH3T3 cells contained senescence-associated β-galactosidase (SA-β-gal)-positive cells, they were decreased upon induction of ferroptosis with FINs. The SA-β-gal decrease was inhibited by ferroptotic inhibitors and knockdown of Atg7, pointing to the involvement of lipid peroxidation and activated autophagosome formation during ferroptosis. A transfer of cell culture medium of cells treated with FINs, type 1 or 2, caused the reduction in SA-β-gal-positive cells in recipient cells that had not been exposed to FINs. Real-time imaging of Kusabira Orange-marked reporter MEFs cocultured with ferroptotic cells showed the generation of lipid peroxide and deaths of the reporter cells. These results indicate that lipid peroxidation and its aftereffects propagate from ferroptotic cells to surrounding cells, even when the surrounding cells are not exposed to FINs. Ferroptotic cells are not merely dying cells but also work as signal transmitters inducing a chain of further ferroptosis.

  25. Cdc7 kinase stimulates Aurora B kinase in M-phase. International-journal Peer-reviewed

    Sayuri Ito, Hidemasa Goto, Kinue Kuniyasu, Mayumi Shindo, Masayuki Yamada, Kozo Tanaka, Gaik-Theng Toh, Masaaki Sawa, Masaki Inagaki, Jiri Bartek, Hisao Masai

    Scientific reports 9 (1) 18622-18622 2019/12/09

    DOI: 10.1038/s41598-019-54738-2  

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    The conserved serine-threonine kinase, Cdc7, plays a crucial role in initiation of DNA replication by facilitating the assembly of an initiation complex. Cdc7 is expressed at a high level and exhibits significant kinase activity not only during S-phase but also during G2/M-phases. A conserved mitotic kinase, Aurora B, is activated during M-phase by association with INCENP, forming the chromosome passenger complex with Borealin and Survivin. We show that Cdc7 phosphorylates and stimulates Aurora B kinase activity in vitro. We identified threonine-236 as a critical phosphorylation site on Aurora B that could be a target of Cdc7 or could be an autophosphorylation site stimulated by Cdc7-mediated phosphorylation elsewhere. We found that threonines at both 232 (that has been identified as an autophosphorylation site) and 236 are essential for the kinase activity of Aurora B. Cdc7 down regulation or inhibition reduced Aurora B activity in vivo and led to retarded M-phase progression. SAC imposed by paclitaxel was dramatically reversed by Cdc7 inhibition, similar to the effect of Aurora B inhibition under the similar situation. Our data show that Cdc7 contributes to M-phase progression and to spindle assembly checkpoint most likely through Aurora B activation.

  26. Delayed Chromosome Alignment to the Spindle Equator Increases the Rate of Chromosome Missegregation in Cancer Cell Lines Invited Peer-reviewed

    Kinue Kuniyasu, Kenji Iemura, Kozo Tanaka

    Biomolecules 9 (1) 10 2018/12/28

    DOI: 10.3390/biom9010010  

  27. Lateral attachment of kinetochores to microtubules is enriched in prometaphase rosette and facilitates chromosome alignment and bi-orientation establishment Peer-reviewed

    Go Itoh, Masanori Ikeda, Kenji Iemura, Mohammed Abdhullahel Amin, Sei Kuriyama, Masamitsu Tanaka, Natsuki Mizuno, Hiroko Osakada, Tokuko Haraguchi, Kozo Tanaka

    Scientific Reports 8 (1) 3888 2018/12/01

    Publisher: Nature Publishing Group

    DOI: 10.1038/s41598-018-22164-5  

    ISSN: 2045-2322

  28. Tetraploidy in cancer and its possible link to aging. International-journal Peer-reviewed

    Tanaka K, Goto H, Nishimura Y, Kasahara K, Mizoguchi A, Inagaki M

    Cancer science 109 (9) 2632-2640 2018/06

    DOI: 10.1111/cas.13717  

    ISSN: 1347-9032

    More details Close

    Tetraploidy, a condition in which a cell has four homologous sets of chromosomes, is often seen as a natural physiological condition but is also frequently seen in pathophysiological conditions such as cancer. Tetraploidy facilitates chromosomal instability (CIN), which is an elevated level of chromosomal loss and gain that can cause production of a wide variety of aneuploid cells that carry structural and numerical aberrations of chromosomes. The resultant genomic heterogeneity supposedly expedites karyotypic evolution that confers oncogenic potential in spite of the reduced cellular fitness caused by aneuploidy. Recent studies suggest that tetraploidy might also be associated with aging; mice with mutations in an intermediate filament protein have revealed that these tetraploidy-prone mice exhibit tissue disorders associated with aging. Cellular senescence and its accompanying senescence-associated secretory phenotype have now emerged as critical factors that link tetraploidy and tetraploidy-induced CIN with cancer, and possibly with aging. Here, we review recent findings about how tetraploidy is related to cancer and possibly to aging, and discuss underlying mechanisms of the relationship, as well as how we can exploit the properties of cells exhibiting tetraploidy-induced CIN to control these pathological conditions.

  29. Phosphorylation of BACH1 switches its function from transcription factor to mitotic chromosome regulator and promotes its interaction with HMMR Peer-reviewed

    Jie Li, Hiroki Shima, Hironari Nishizawa, Masatoshi Ikeda, Andrey Brydun, Mitsuyo Matsumoto, Hiroki Kato, Yuriko Saiki, Liang Liu, Miki Watanabe-Matsui, Kenji Iemura, Kozo Tanaka, Takuma Shiraki, Kazuhiko Igarashi

    Biochemical Journal 475 (5) 981-1002 2018/03/15

    Publisher: Portland Press Ltd

    DOI: 10.1042/BCJ20170520  

    ISSN: 1470-8728 0264-6021

    eISSN: 1470-8728

  30. Quantitative analyses of the metaphase-to-anaphase transition reveal differential kinetic regulation for securin and cyclin B1 Peer-reviewed

    Makoto Konishi, Norihisa Shindo, Masataka Komiya, Kozo Tanaka, Takehiko Itoh, Toru Hirota

    Biomedical Research (Japan) 39 (2) 75-85 2018

    Publisher: Biomedical Research Foundation

    DOI: 10.2220/biomedres.39.75  

    ISSN: 1880-313X 0388-6107

    eISSN: 1880-313X

  31. Dynamic feature of mitotic arrest deficient 2-like protein 2 (MAD2L2) and structural basis for its interaction with chromosome alignment-maintaining phosphoprotein (CAMP) Peer-reviewed

    Kodai Hara, Shota Taharazako, Masanori Ikeda, Hiroki Fujita, Yoshiko Mikami, Sotaro Kikuchi, Asami Hishiki, Hideshi Yokoyama, Yoshinobu Ishikawa, Shin-ichiro Kanno, Kozo Tanaka, Hiroshi Hashimoto

    JOURNAL OF BIOLOGICAL CHEMISTRY 292 (43) 17658-17667 2017/10

    DOI: 10.1074/jbc.M117.804237  

    ISSN: 0021-9258

    eISSN: 1083-351X

  32. Plk1 bound to Bub1 contributes to spindle assembly checkpoint activity during mitosis Peer-reviewed

    Masanori Ikeda, Kozo Tanaka

    SCIENTIFIC REPORTS 7 (1) 8794 2017/08

    DOI: 10.1038/s41598-017-09114-3  

    ISSN: 2045-2322

  33. Activation of the Hypoxia Inducible Factor 1 alpha Subunit Pathway in Steatotic Liver Contributes to Formation of Cholesterol Gallstones Peer-reviewed

    Yoichiro Asai, Tetsuya Yamada, Sohei Tsukita, Kei Takahashi, Masamitsu Maekawa, Midori Honma, Masanori Ikeda, Keigo Murakami, Yuichiro Munakata, Yuta Shirai, Shinjiro Kodama, Takashi Sugisawa, Yumiko Chiba, Yasuteru Kondo, Keizo Kaneko, Kenji Uno, Shojiro Sawada, Junta Imai, Yasuhiro Nakamura, Hiroaki Yamaguchi, Kozo Tanaka, Hironobu Sasano, Nariyasu Mano, Yoshiyuki Ueno, Tooru Shimosegawa, Hideki Katagiri

    GASTROENTEROLOGY 152 (6) 1521-+ 2017/05

    DOI: 10.1053/j.gastro.2017.01.001  

    ISSN: 0016-5085

    eISSN: 1528-0012

  34. Chromosomal instability: A common feature and a therapeutic target of cancer. Peer-reviewed

    Tanaka K, Hirota T

    Biochimica et biophysica acta 1866 (1) 64-75 2016/08

    DOI: 10.1016/j.bbcan.2016.06.002  

    ISSN: 0006-3002

    eISSN: 0006-3002

  35. De Novo Truncating Mutations in the Kinetochore-Microtubules Attachment Gene CHAMP1 Cause Syndromic Intellectual Disability Peer-reviewed

    Bertrand Isidor, Sébastien Küry, Jill A. Rosenfeld, Thomas Besnard, Sébastien Schmitt, Shelagh Joss, Sally J Davies, Robert Roger Lebel, Alex Henderson, Christian P. Schaaf, Haley E. Streff, Yaping Yang, Vani Jain, Nodoka Chida, Xenia Latypova, Cédric Le Caignec, Benjamin Cogné, Sandra Mercier, Marie Vincent, Estelle Colin, Dominique Bonneau, Anne-Sophie Denommé, Philippe Parent, Brigitte Gilbert-Dussardier, Sylvie Odent, Annick Toutain, Amélie Piton, Christian Dina, Audrey Donnart, Pierre Lindenbaum, Eric Charpentier, Richard Redon, Kenji Iemura, Masanori Ikeda, Kozo Tanaka, Stéphane Bézieau

    Human Mutation 37 (4) 354-358 2016/04/01

    Publisher: John Wiley and Sons Inc.

    DOI: 10.1002/humu.22952  

    ISSN: 1098-1004 1059-7794

  36. Phosphoproteomic analysis of human mitotic chromosomes identified a chromokinesin KIF4A Peer-reviewed

    Motoko Takahashi, Kozo Tanaka, Toshifumi Wakai, Toru Hirota

    BIOMEDICAL RESEARCH-TOKYO 37 (2) 161-165 2016

    DOI: 10.2220/biomedres.37.161  

    ISSN: 0388-6107

    eISSN: 1880-313X

  37. CLIP-170 tethers kinetochores to microtubule plus ends against poleward force by dynein for stable kinetochore-microtubule attachment Peer-reviewed

    Mohammed Abdullahel Amin, Kinue Kobayashi, Kozo Tanaka

    FEBS LETTERS 589 (19) 2739-2746 2015/09

    DOI: 10.1016/j.febslet.2015.07.036  

    ISSN: 0014-5793

    eISSN: 1873-3468

  38. Chromokinesin Kid and kinetochore kinesin CENP-E differentially support chromosome congression without end-on attachment to microtubules Peer-reviewed

    Kenji Iemura, Kozo Tanaka

    NATURE COMMUNICATIONS 6 6447 2015/03

    DOI: 10.1038/ncomms7447  

    ISSN: 2041-1723

  39. CLIP-170 recruits PLK1 to kinetochores during early mitosis for chromosome alignment Peer-reviewed

    Mohammed Abdullahel Amin, Go Itoh, Kenji Iemura, Masanori Ikeda, Kozo Tanaka

    JOURNAL OF CELL SCIENCE 127 (13) 2818-2824 2014/07

    DOI: 10.1242/jcs.150755  

    ISSN: 0021-9533

    eISSN: 1477-9137

  40. CAMP (C13orf8, ZNF828) is a novel regulator of kinetochore-microtubule attachment Peer-reviewed

    Go Itoh, Shin-ichiro Kanno, Kazuhiko S. K. Uchida, Shuhei Chiba, Shiro Sugino, Kana Watanabe, Kensaku Mizuno, Akira Yasui, Toru Hirota, Kozo Tanaka

    EMBO JOURNAL 30 (1) 130-144 2011/01

    DOI: 10.1038/emboj.2010.276  

    ISSN: 0261-4189

    eISSN: 1460-2075

  41. Kinetochores Generate Microtubules with Distal Plus Ends: Their Roles and Limited Lifetime in Mitosis Peer-reviewed

    Etsushi Kitamura, Kozo Tanaka, Shinya Komoto, Yoko Kitamura, Claude Antony, Tomoyuki U. Tanaka

    DEVELOPMENTAL CELL 18 (2) 248-259 2010/02

    DOI: 10.1016/j.devcel.2009.12.018  

    ISSN: 1534-5807

  42. Molecular mechanisms of microtubule-dependent kinetochore transport toward spindle poles Peer-reviewed

    Kozo Tanaka, Etsushi Kitamura, Yoko Kitamura, Tomoyuki U. Tanaka

    JOURNAL OF CELL BIOLOGY 178 (2) 269-281 2007/07

    DOI: 10.1083/jcb.200702141  

    ISSN: 0021-9525

    eISSN: 1540-8140

  43. Molecular mechanisms of kinetochore capture by spindle microtubules Peer-reviewed

    K Tanaka, N Mukae, H Dewar, M van Breugel, EK James, AR Prescott, C Antony, TU Tanaka

    NATURE 434 (7036) 987-994 2005/04

    DOI: 10.1038/nature03483  

    ISSN: 0028-0836

    eISSN: 1476-4687

  44. Tension between two kinetochores suffices for their bi-orientation on the mitotic spindle Peer-reviewed

    H Dewar, K Tanaka, K Nasmyth, TU Tanaka

    NATURE 428 (6978) 93-97 2004/03

    DOI: 10.1038/nature02328  

    ISSN: 0028-0836

    eISSN: 1476-4687

  45. Human Rad5413 is a double-stranded DNA-dependent ATPase and has biochemical properties different from its structural homolog in yeast, Tid1/Rdh54 Peer-reviewed

    K Tanaka, W Kagawa, T Kinebuchi, H Kurumizaka, K Miyagawa

    NUCLEIC ACIDS RESEARCH 30 (6) 1346-1353 2002/03

    DOI: 10.1093/nar/30.6.1346  

    ISSN: 0305-1048

  46. A role for RAD54B in homologous recombination in human cells Peer-reviewed

    K Miyagawa, T Tsuruga, A Kinomura, K Usui, M Katsura, S Tashiro, H Mishima, K Tanaka

    EMBO JOURNAL 21 (1-2) 175-180 2002/01

    DOI: 10.1093/emboj/21.1.175  

    ISSN: 0261-4189

  47. A novel human Rad54 homologue, Rad54B, associates with Rad51 Peer-reviewed

    K Tanaka, T Hiramoto, T Fukuda, K Miyagawa

    JOURNAL OF BIOLOGICAL CHEMISTRY 275 (34) 26316-26321 2000/08

    DOI: 10.1074/jbc.M910306199  

    ISSN: 0021-9258

  48. The AML1/ETO(MTG8) and AML1/EVI-1 leukemia-associated chimeric oncoproteins accumulate PEBP2 beta(CBF beta) in the nucleus more efficiently than wild-type AML1. Peer-reviewed

    K Tanaka, T Tanaka, M Kurokawa, Y Imai, S Ogawa, SW Hiebert, K Mitani, Y Yazaki, H Hirai

    BLOOD 88 (10) 2188-2188 1996/11

    ISSN: 0006-4971

  49. AN ACUTE MYELOID-LEUKEMIA GENE, AML1, REGULATES HEMATOPOIETIC MYELOID CELL-DIFFERENTIATION AND TRANSCRIPTIONAL ACTIVATION ANTAGONISTICALLY BY 2 ALTERNATIVE SPLICED FORMS Peer-reviewed

    T TANAKA, K TANAKA, S OGAWA, M KUROKAWA, K MITANI, J NISHIDA, Y SHIBATA, Y YAZAKI, H HIRAI

    EMBO JOURNAL 14 (2) 341-350 1995/01

    ISSN: 0261-4189

  50. Effects of mitotically active polyploid giant cancer cells on chemoresistance through interaction with cancer-associated fibroblasts

    Go Itoh, Yuma Fukushi, Kurara Takagane, Keisuke Kanetaka, Hitomi Suzuki, Yohei Kawasaki, Sei Kuriyama, Kenji Iemura, Kozo Tanaka, Akiteru Goto, Masamitsu Tanaka

    British Journal of Cancer 2025/12/21

    DOI: 10.1038/s41416-025-03317-6  

  51. がん細胞液性因子を介した染色体不安定性誘導機構(Mechanisms of CIN induction via cancer extracellular factors)

    家村 顕自, 田中 耕三

    日本癌学会総会記事 82回 1136-1136 2023/09

    Publisher: (一社)日本癌学会

    ISSN: 0546-0476

  52. 染色体不安定性に対するがん細胞の生存戦略(Survival strategies of cancer cells against chromosomal instability)

    家村 顕自, 田中 耕三

    日本癌学会総会記事 81回 J-1033 2022/09

    Publisher: (一社)日本癌学会

    ISSN: 0546-0476

  53. 染色体分配における染色体オシレーションの役割

    家村 顕自, 田中 耕三

    生化学 94 (3) 433-437 2022/06

    Publisher: (公社)日本生化学会

    ISSN: 0037-1017

    eISSN: 2189-0544

  54. 増殖選択圧を受けたがん細胞の増殖優位性獲得過程における染色体不安定性の役割

    家村 顕自, 田中 耕三

    日本細胞生物学会大会講演要旨集 72回 1-2 2020/06

    Publisher: (一社)日本細胞生物学会

  55. Kinetochore Stretching-Mediated Rapid Silencing of Mitotic Checkpoint Required for Failsafe Chromosome Segregation Peer-reviewed

    Kazuhiko S.K. Uchida, Minji Jo, Kota Nagasaka, Motoko Takahashi, Norihisa Shindo, Kozo Tanaka, Hiroshi Masumoto, Tatsuo Fukagawa, Toru Hirota

    SSRN Electronic Journal 2019

    Publisher: Elsevier BV

    DOI: 10.2139/ssrn.3473262  

    eISSN: 1556-5068

  56. Author Correction: Lateral attachment of kinetochores to microtubules is enriched in prometaphase rosette and facilitates chromosome alignment and bi-orientation establishment. International-journal Peer-reviewed

    Itoh G, Ikeda M, Iemura K, Amin MA, Kuriyama S, Tanaka M, Mizuno N, Osakada H, Haraguchi T, Tanaka K

    Scientific reports 8 (1) 7003-7003 2018/04

    DOI: 10.1038/s41598-018-25175-4  

    More details Close

    A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

  57. 染色体オシレーションと異常な結合の修正を記述する動原体-微小管結合の数学的モデル

    Campos Manuel, 家村 顕自, 田中 耕三

    生命科学系学会合同年次大会 2017年度 [4AT19-0381)] 2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  58. Mechanism for efficient chromosome alignment in mitosis Peer-reviewed

    Kenji Iemura, Kozo Tanaka

    Seikagaku 89 (1) 102-105 2017

    Publisher: Japanese Biochemical Society

    DOI: 10.14952/SEIKAGAKU.2017.890102  

    ISSN: 2189-0544 0037-1017

  59. DNA損傷と修復 染色体動態の異常による染色体不安定性の発生

    田中 耕三, 國安 絹枝, 家村 顕自

    日本癌学会総会記事 75回 S1-1 2016/10

    Publisher: (一社)日本癌学会

    ISSN: 0546-0476

  60. 効率的な染色体整列の染色体安定性への関与

    國安 絹枝, 家村 顕自, 田中 耕三

    日本生化学会大会プログラム・講演要旨集 89回 [2T14-248)] 2016/09

    Publisher: (公社)日本生化学会

  61. Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

    Klionsky, D.J., Abeliovich, H., Agostinis, P., Agrawal, D.K., Aliev, G., Askew, D.S., Baba, M., Baehrecke, E.H., Bahr, B.A., Ballabio, A., Bamber, B.A., Bassham, D.C., Bergamini, E., Bi, X., Biard-Piechaczyk, M., Blum, J.S., Bredesen, D.E., Brodsky, J.L., Brumell, J.H., Brunk, U.T., Bursch, W., Camougrand, N., Cebollero, E., Cecconi, F., Chen, Y., Chin, L.-S., Choi, A., Chu, C.T., Chung, J., Clarke, P.G.H., Clark, R.S.B., Clarke, S.G., Clav{\'e}, C., Cleveland, J.L., Codogno, P., Colombo, M.I., Cotomontes, A., Cregg, J.M., Cuervo, A.M., Debnath, J., Demarchi, F., Dennis, P.B., Dennis, P.A., Deretic, V., Devenish, R.J., Di Sano, F., Dice, J.F., DiFiglia, M., Dinesh-Kumar, S., Distelhorst, C.W., Djavaheri-Mergny, M., Dorsey, F.C., Dr{\"o}ge, W., Dron, M., Dunn, W.A., Duszenko, M., Eissa, N.T., Elazar, Z., Esclatine, A., Eskelinen, E.-L., F{\'e}s{\"u}s, L., Finley, K.D., Fuentes, J.M., Fueyo, J., Fujisaki, K., Galliot, B., Gao, F.-B., Gewirtz, D.A., Gibson, S.B., Gohla, A., Goldberg, A.L., Gonzalez, R., Gonz{\'a}lez-Est{\'e}vez, C., Gorski, S., Gottlieb, R.A., H{\"a}ussinger, D., He, Y.-W., Heidenreich, K., Hill, J.A., H?yer-Hansen, M., Hu, X., Huang, W.-P., Iwasaki, A., J, a, a}ttel{\"a}, M., Jackson, W.T., Jiang, X., Jin, S., Johansen, T., Jung, J., Kadowaki, M., Kang, C., Kelekar, A., Kessel, D.H., d Kiel, J.A.K.W., Hong, P.K., Kimchi, A., Kinsella, T.J., Kiselyov, K., Kitamoto, K., Knecht, E., Komatsu, M., Kominami, E., Kondo, S., Kov{\'a}cs, A.L., Kroemer, G., Kuan, C.-Y., Kumar, R., Kundu, M., Landry, J., Laporte, M., Le, W., Lei, H.-Y., Lenardo, M.J., Levine, B., Lieberman, A., Lim, K.-L., Lin, F.-C., Liou, W., Liu, L.F., Lopez-Berestein, G., L{\'o}pez-Ot{\'i}n, C., Lu, B., Macleod, K.F., Malorni, W., Martinet, W., Matsuoka, K., Mautner, J., Meijer, A.J., Mel{\'e}ndez, A., Michels, P., Miotto, G., Mistiaen, W.P., Mizushima, N., Mograbi, B., Monastyrska, I., Moore, M.N., Moreira, P.I., Moriyasu, Y., Motyl, T., M{\"u}nz, C., Murphy, L.O., Naqvi, N.I., Neufeld, T.P., Nishino, I., Nixon, R.A., Noda, T., N{\"u}rnberg, B., Ogawa, M., Oleinick, N.L., Olsen, L.J., Ozpolat, B., Paglin, S., Palmer, G.E., Papassideri, I., Parkes, M., Perlmutter, D.H., Perry, G., Piacentini, M., Pinkas-Kramarski, R., Prescott, M., Proikascezanne, T., Raben, N., Rami, A., Reggiori, F., Rohrer, B., Rubinsztein, D.C., Ryan, K.M., Sadoshima, J., Sakagami, H., Sakai, Y., Sandri, M., Sasakawa, C., Sass, M., Schneider, C., Seglen, P.O., Seleverstov, O., Settleman, J., Shacka, J.J., Shapiro, I.M., Sibirny, A., Silva-Zacarin, E.C.M., Simon, H.-U., Simone, C., Simonsen, A., Smith, M.A., Spanel-Borowski, K., Srinivas, V., Steeves, M., Stenmark, H., Stromhaug, P.E., Subauste, C.S., Sugimoto, S., Sulzer, D., Suzuki, T., Swanson, M.S., Tabas, I., Takeshita, F., Talbot, N.J., Tall{\'o}czy, Z., Tanaka, K., Tanaka, K., Tanida, I., Taylor, G.S., Taylor, J.P., Terman, A., Tettamanti, G., Thompson, C.B., Thumm, M., Tolkovsky, A.M., Tooze, S.A., Truant, R., Tumanovska, L.V., Uchiyama, Y., Ueno, T., Uzc{\'a}tegui, N.L., Van Der Klei, I., Vaquero, E.C., Vellai, T., Vogel, M.W., Wang, H.-G., Webster, P., Wiley, J.W., Xi, Z., Xiao, G., Yahalom, J., Yang, J.-M., Yap, G., Yin, X.-M., Yoshimori, T., Yu, L., Yue, Z., Yuzaki, M., Zabirnyk, O., Zheng, X., Zhu, X., Deter, R.L., Garg, A.D.

    Autophagy 12 (2) 2016

    DOI: 10.1080/15548627.2016.1147886  

  62. Targeting of tubulin polymerization and induction of mitotic blockage by Methyl 2-(5-fluoro-2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (MBIC) in human cervical cancer HeLa cell

    Mohadeseh Hasanpourghadi, Chandrabose Karthikeyan, Ashok Kumar Pandurangan, Chung Yeng Looi, Piyush Trivedi, Kinue Kobayashi, Kozo Tanaka, Won Fen Wong, Mohd Rais Mustafa

    Journal of Experimental and Clinical Cancer Research 35 (1) 2016

    Publisher: BioMed Central Ltd.

    DOI: 10.1186/s13046-016-0332-0  

    ISSN: 1756-9966

  63. 効率的な染色体整列の染色体安定性への関与

    小林 絹枝, 家村 顕自, 田中 耕三

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集 88回・38回 [3P0096]-[3P0096] 2015/12

    Publisher: (公社)日本生化学会

  64. 核局在MATIIalphaのセントロメア領域における役割

    蝦名 真行, 加藤 恭丈, 池田 真教, 田中 耕三, 五十嵐 和彦

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集 88回・38回 [2T25-13(2P0648)] 2015/12

    Publisher: (公社)日本生化学会

  65. 効率的な染色体整列の異常による染色体不安定性の出現

    田中 耕三, 家村 顕自

    日本癌学会総会記事 74回 IS1-2 2015/10

    Publisher: (一社)日本癌学会

    ISSN: 0546-0476

  66. A novel anti-microtubule agent with carbazole and benzohydrazide structures suppresses tumor cell growth in vivo

    Ohira, M., Iwasaki, Y., Tanaka, C., Kuroki, M., Matsuo, N., Kitamura, T., Yukuhiro, M., Morimoto, H., Pang, N., Liu, B., Kiyono, T., Amemiya, M., Tanaka, K., Yoshida, K., Sugimoto, N., Ohshima, T., Fujita, M.

    Biochimica et Biophysica Acta - General Subjects 1850 (9) 2015

    DOI: 10.1016/j.bbagen.2015.04.013  

  67. 染色体分配における核膜孔複合体構成因子Nup188の機能(Nucleoporin Nup188 is required for chromosome alignment in mitosis)

    伊藤 剛, 安井 明, 広田 亨, 田中 耕三

    日本癌学会総会記事 72回 103-103 2013/10

    Publisher: 日本癌学会

    ISSN: 0546-0476

  68. 核膜孔複合体の構成因子Nup188の分裂期における役割(Mitotic role of Nup188, a component of nuclear pore complex)

    伊藤 剛, 池田 真教, 菅野 新一郎, アミン・ムハマド, 家村 顕自, 安井 明, 広田 亨, 田中 耕三

    日本生化学会大会プログラム・講演要旨集 86回 1T14a-03 2013/09

    Publisher: (公社)日本生化学会

  69. 染色体分配における核膜孔複合体構成因子Nup188の機能

    伊藤 剛, 杉野 史郎, 池田 真教, 水口 万裕美, 菅野 新一郎, Abdullahel Amin Mohammed, 家村 顕自, 安井 明, 広田 亨, 田中 耕三

    生化学 85 (8) 722-722 2013/08

    Publisher: (公社)日本生化学会

    ISSN: 0037-1017

  70. 分裂期制御研究の新局面 キネトコアと微小管の双方向性結合の成立過程の解析

    伊藤 剛, 池田 真教, 家村 顕自, Amin Mohammed Abdullahel, 田中 耕三

    日本細胞生物学会大会講演要旨集 65回 127-127 2013/05

    Publisher: (一社)日本細胞生物学会

  71. Nucleoporin Nup188 is required for chromosome alignment in mitosis. International-journal Peer-reviewed

    Itoh, Go Sugino, Shiro Ikeda, Masanori Mizuguchi, Mayumi Kanno, Shin-Ichiro Amin, Mohammed A Iemura, Kenji Yasui, Akira Hirota, Toru Tanaka, Kozo

    Cancer Sci 85 (8) 722-9 2013/03/28

    DOI: 10.1111/cas.12159  

    ISSN: 0037-1017

    More details Close

    Most cancer cells are aneuploid, which could be caused by defects in chromosome segregation machinery. Nucleoporins (Nup) are components of the nuclear pore complex, which is essential for nuclear transport during interphase, but several nucleoporins are also known to be involved in chromosome segregation. Here we report a novel function of Nup188, one of the nucleoporins regulating chromosome segregation. Nup188 localizes to spindle poles during mitosis, through the C-terminal region of Nup188. In Nup188-depleted mitotic cells, chromosomes fail to align to the metaphase plate, which causes mitotic arrest due to the spindle assembly checkpoint. Both the middle and the C-terminal regions were required for chromosome alignment. Robust K-fibers, microtubule bundles attaching to kinetochores, were hardly formed in Nup188-depleted cells. Significantly, we found that Nup188 interacts with NuMA, which plays an instrumental role in focusing microtubules at centrosomes, and NuMA localization to spindle poles is perturbed in Nup188-depleted cells. These data suggest that Nup188 promotes chromosome alignment through K-fiber formation and recruitment of NuMA to spindle poles.

  72. Guidelines for the use and interpretation of assays for monitoring autophagy

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Zakeri, Z., Zeh III, H.J., Zeitlin, S.O., Zhang, H., Zhang, H.-L., Zhang, J., Zhang, J.-P., Zhang, L., Zhang, L., Zhang, M.-Y., Zhang, X.D., Zhao, M., Zhao, Y.-F., Zhao, Y., Zhao, Z.J., Zheng, X., Zhivotovsky, B., Zhong, Q., Zhou, C.-Z., Zhu, C., and Zhu, W.-G., and Zhu, X.-F., Zhu, X., Zhu, Y., Zoladek, T., Zong, W.-X., Zorzano, A., Zschocke, J., Zuckerbraun, B.

    Autophagy 8 (4) 2012

    DOI: 10.4161/auto.19496  

  73. Kinetochore-Dependent Microtubule Rescue Ensures Their Efficient and Sustained Interactions in Early Mitosis Peer-reviewed

    Sapan R. Gandhi, Marek Gierlinski, Akihisa Mino, Kozo Tanaka, Etsushi Kitamura, Lesley Clayton, Tomoyuki U. Tanaka

    DEVELOPMENTAL CELL 21 (5) 920-933 2011/11

    DOI: 10.1016/j.devce1.2011.09.006  

    ISSN: 1534-5807

  74. Global analysis of core histones reveals nucleosomal surfaces required for chromosome bi-orientation Peer-reviewed

    Satoshi Kawashima, Yu Nakabayashi, Kazuko Matsubara, Norihiko Sano, Takemi Enomoto, Kozo Tanaka, Masayuki Seki, Masami Horikoshi

    EMBO JOURNAL 30 (16) 3353-3367 2011/08

    DOI: 10.1038/emboj.2011.241  

    ISSN: 0261-4189

  75. 新規MAD2L2結合分子CAMPによるキネトコア-微小管結合の制御(A novel MAD2L2-interacting protein, CAMP, is a regulator of kinetochore-microtubule attachment)

    田中 耕三, 伊藤 剛, 安井 明, 広田 亨

    日本癌学会総会記事 69回 88-88 2010/08

    Publisher: 日本癌学会

    ISSN: 0546-0476

  76. Nocodazole induces mitotic cell death with apoptotic-like features in Saccharomyces cerevisiae Peer-reviewed

    Kingo Endo, Mayumi Mizuguchi, Aoi Harata, Go Itoh, Kozo Tanaka

    FEBS LETTERS 584 (11) 2387-2392 2010/06

    DOI: 10.1016/j.febslet.2010.04.029  

    ISSN: 0014-5793

  77. Biochemical analysis of the N-terminal domain of human RAD54B Peer-reviewed

    Naoyuki Sarai, Wataru Kagawa, Norie Fujikawa, Kengo Saito, Juri Hikiba, Kozo Tanaka, Kiyoshi Miyagawa, Hitoshi Kurumizaka, Shigeyuki Yokoyama

    NUCLEIC ACIDS RESEARCH 36 (17) 5441-5450 2008/10

    DOI: 10.1093/nar/gkn516  

    ISSN: 0305-1048

  78. Three-dimensional electron microscopy analysis of ndc10-1 mutant reveals an aberrant organization of the mitotic spindle and spindle pole body defects in Saccharomyces cerevisiae Peer-reviewed

    Maryse Romao, Kozo Tanaka, Jean-Baptiste Sibarita, Nga Thi Bach Ly-Hartig, Tomoyuki U. Tanaka, Claude Antony

    JOURNAL OF STRUCTURAL BIOLOGY 163 (1) 18-28 2008/07

    DOI: 10.1016/j.jsb.2008.03.015  

    ISSN: 1047-8477

  79. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes Peer-reviewed

    Daniel J. Klionsky, Hagai Abeliovich, Patrizia Agostinis, Devendra K. Agrawal, Giumrakch Aliev, David S. Askew, Misuzu Baba, Eric H. Baehrecke, Ben A. Bahr, Andrea Ballabio, Bruce A. Bamber, Diane C. Bassham, Ettore Bergamini, Xiaoning Bi, Martine Biard-Piechaczyk, Janice S. Blum, Dale E. Breclesen, Jeffrey L. Brodsky, John H. Brumell, Ulf T. Brunk, Wilfried Bursch, Nadine Camougrand, Eduardo Cebollero, Francesco Cecconi, Yingyu Chen, Lih-Shen Chin, Augustine Choi, Charleen T. Chu, Jongkyeong Chung, Peter G. H. Clarke, Robert S. B. Clark, Steven G. Clarke, Corinne Clave, John L. Cleveland, Patrice Codogno, Maria I. Colombo, Ana Coto-Montes, James M. Cregg, Ana Maria Cuervo, Jayanta Debnath, Francesca Demarchi, Patrick B. Dennis, Phillip A. Dennis, Vojo Deretic, Rodney J. Devenish, Federica Di Sano, J. Fred Dice, Marian DiFiglia, Savithramma Dinesh-Kumar, Clark W. Distelhorst, Mojgan Djavaheri-Mergny, Frank C. Dorsey, Wulf Droege, Michel Dron, William A. Dunn, Michael Duszenko, N. Tony Eissa, Zvulun Elazar, Audrey Esclatine, Eeva-Liisa Eskelinen, Laszlo Fesues, Kim D. Finley, Jose M. Fuentes, Juan Fueyo, Kozo Fujisaki, Brigitte Galliot, Fen-Biao Gao, David A. Gewirtz, Spencer B. Gibson, Antje Gohla, Alfred L. Goldberg, Ramon Gonzalez, Cristina Gonzalez-Estevez, Sharon Gorski, Roberta A. Gottlieb, Dieter Haussinger, You-Wen He, Kim Heidenreich, Joseph A. Hill, Maria Hoyer-Hansen, Xun Hu, Wei-Pang Huang, Akiko Iwasaki, Marja Jaattela, William T. Jackson, Xuejun Jiang, Shengkan Jin, Terje Johansen, Jae U. Jung, Motoni Kadowaki, Chanhee Kang, Ameeta Kelekar, David H. Kessel, Jan A. K. W. Kiel, Hong Pyo Kim, Adi Kimchi, Timothy J. Kinsella, Kirill Kiselyov, Katsuhiko Kitamoto, Erwin Knecht, Masaaki Komatsu, Eiki Kominami, Seiji Konclo, Attila L. Kovacs, Guido Kroemer, Chia-Yi Kuan, Rakesh Kumar, Mondira Kundu, Jacques Landry, Marianne Laporte, Weidong Le, Huan-Yao Lei, Michael J. Lenardo, Beth Levine, Andrew Lieberman, Kah-Leong Lim, Fu-Cheng Lin, Willisa Liou, Leroy F. Liu, Gabriel Lopez-Berestein, Carlos Lopez-Otin, Bo Lu, Kay F. Macleod, Walter Malorni, Wim Martinet, Ken Matsuoka, Josef Mautner, Alfred J. Meijer, Alicia Melendez, Paul Michels, Giovanni Miotto, Wilhelm P. Mistiaen, Noboru Mizushima, Baharia Mograbi, Iryna Monastyrska, Michael N. Moore, Paula I. Moreira, Yuji Moriyasu, Tomasz Motyl, Christian Muenz, Leon O. Murphy, Naweed I. Naqvi, Thomas P. Neufeld, Ichizo Nishino, Ralph A. Nixon, Takeshi Noda, Bernd Nuernberg, Michinaga Ogawa, Nancy L. Oleinick, Laura J. Olsen, Bulent Ozpolat, Shoshana Paglin, Glen E. Palmer, Issidora Papassideri, Miles Parkes, David H. Perlmutter, George Perry, Mauro Piacentini, Ronit Pinkas-Kramarski, Mark Prescott, Tassula Proikas-Cezanne, Nina Raben, Abdelhaq Rami, Fulvio Reggiori, Baerbel Rohrer, David C. Rubinsztein, Kevin M. Ryan, Junichi Sadoshima, Hiroshi Sakagami, Yasuyoshi Sakai, Marco Sandri, Chihiro Sasakawa, Miklos Sass, Claudio Schneider, Per O. Seglen, Oleksandr Seleverstov, Jeffre Settleman, John J. Shacka, Irving M. Shapiro, Andrei Sibirny, Elaine C. M. Silva-Zacarin, Hans-Uwe Simon, Cristiano Simone, Anne Simonsen, Mark A. Smith, Katharina Spanel-Borowski, Vickram Srinivas, Meredith Steeves, Harald Stenmark, Per E. Stromhaug, Carlos S. Subauste, Seiichiro Sugimoto, David Sulzer, Toshihiko Suzuki, Michele S. Swanson, Fumihiko Takeshita, Nicholas. J. Talbot, Zsolt Talloczy, Keiji Tanaka, Kozo Tanaka, Isei Tanida, Graham S. Taylor, J. Paul Taylor, Alexei Terman, Gianluca Tettamanti, Craig B. Thompson, Michael Thumm, Aviva M. Tolkovsky, Sharon A. Tooze, Ray Truant, Lesya V. Tumanovska, Yasuo Uchiyama, Takashi Ueno, Nestor L. Uzcategui, Ida van der Klei, Eva C. Vaquero, Tibor Vellai, Michael W. Vogel, Hong-Gang Wang, Paul Webster, John W. Wiley, Zhijun Xi, Gutian Xiao, Joachim Yahalom, Jin-Ming Yang, George Yap, Xiao-Min Yin, Tamotsu Yoshimori, Li Yu, Zhenyu Yue, Michisuke Yuzaki, Olga Zabirnyk, Xiaoxiang Zheng, Xiongwei Zhu, Russell L. Deter, Ira Tabas

    AUTOPHAGY 4 (2) 151-175 2008/02

    DOI: 10.4161/auto.5338  

    ISSN: 1554-8627

    eISSN: 1554-8635

  80. Kinetochore-microtubule interaction during S phase in Saccharomyces cerevisiae Peer-reviewed

    Etsushi Kitamura, Kozo Tanaka, Yoko Kitamura, Tomoyuki U. Tanaka

    GENES & DEVELOPMENT 21 (24) 3319-3330 2007/12

    DOI: 10.1101/gad.449407  

    ISSN: 0890-9369

  81. Stimulation of Dmc1-mediated DNA strand exchange by the human Rad54B protein Peer-reviewed

    Naoyuki Sarai, Wataru Kagawa, Takashi Kinebuchi, Ako Kagawa, Kozo Tanaka, Kiyoshi Miyagawa, Shukuko Ikawa, Takehiko Shibata, Hitoshi Kurumizaka, Shigeyuki Yokoyama

    NUCLEIC ACIDS RESEARCH 34 (16) 4429-4437 2006/09

    DOI: 10.1093/nar/gkl562  

    ISSN: 0305-1048

  82. Yeast kinesin-8 depolymerizes microtubules in a length-dependent manner Peer-reviewed

    Vladimir Varga, Jonne Helenius, Kozo Tanaka, Anthony A. Hyman, Tomoyuki U. Tanaka, Jonathon Howard

    NATURE CELL BIOLOGY 8 (9) 957-U60 2006/09

    DOI: 10.1038/ncb1462  

    ISSN: 1465-7392

  83. Structural basis for octameric ring formation and DNA interaction of the human homologous-pairing protein Dmc1 Peer-reviewed

    T Kinebuchi, W Kagawa, R Enomoto, K Tanaka, K Miyagawa, T Shibata, H Kurumizaka, S Yokoyama

    MOLECULAR CELL 14 (3) 363-374 2004/05

    DOI: 10.1016/S1097-2765(04)00218-7  

    ISSN: 1097-2765

  84. 新規相同組換え遺伝子Rad54Bの機能解析 Invited

    田中耕三, 宮川清

    広島医学 55 (3) 255-257 2002/03

  85. 新規相同組換え遺伝子Rad54BとRad51の会合 Invited

    田中耕三, 平本智樹, 福田敏勝, 宮川清

    長崎医学会雑誌 75 (特集) 257-259 2000/09

    Publisher: Nagasaki University

    ISSN: 0369-3228

  86. RAD54Bのゲノム構造の解析 Invited

    田中耕三, 平本智樹, 福田敏勝, 宮川清

    広島医学 53 (3) 198-200 2000/03

  87. RAD54関連遺伝子の腫瘍における構造異常 Invited

    田中耕三, 福田敏勝, 平本智樹, 宮川清

    長崎医学会雑誌 73 (特集) 359-361 1998/12

  88. TLE, the human homolog of Groucho, interacts with AML1 and acts as a repressor of AML1-induced transactivation Peer-reviewed

    Y Imai, M Kurokawa, K Tanaka, AD Friedman, S Ogawa, K Mitani, Y Yazaki, H Hirai

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 252 (3) 582-589 1998/11

    DOI: 10.1006/bbrc.1998.9705  

    ISSN: 0006-291X

  89. Subcellular localization of the MEN, MLL/MEN and truncated MLL proteins expressed in leukemic cells carrying the t(11;19)(q23;p13.1) translocation Peer-reviewed

    Y Kanda, K Mitani, T Tanaka, K Tanaka, S Ogawa, Y Yazaki, H Hirai

    INTERNATIONAL JOURNAL OF HEMATOLOGY 66 (2) 189-195 1997/08

    DOI: 10.1016/S0925-5710(97)00035-2  

    ISSN: 0925-5710

  90. An acute myeloid leukemia gene, AML1, regulates transcriptional activation and hemopoietic myeloid cell differentiation antagonistically by two alternative spliced forms. Peer-reviewed

    Tanaka T, Tanaka K, Ogawa S, Kurokawa M, Mitani K, Yazaki Y, Shibata Y, Hirai H

    Leukemia 11 Suppl 3 299-302 1997/04

  91. The extracellular signal-regulated kinase pathway phosphorylates AML1, an acute myeloid leukemia gene product, and potentially regulates its transactivation ability Peer-reviewed

    T Tanaka, M Kurokawa, K Ueki, K Tanaka, Y Imai, K Mitani, K Okazaki, N Sagata, Y Yazaki, Y Shibata, T Kadowaki, H Hirai

    MOLECULAR AND CELLULAR BIOLOGY 16 (7) 3967-3979 1996/07

    ISSN: 0270-7306

    eISSN: 1098-5549

  92. Structurally altered Evi-1 protein generated in the 3q21q26 syndrome Peer-reviewed

    S Ogawa, M Kurokawa, T Tanaka, K Mitani, J Inazawa, A Hangaishi, K Tanaka, Y Matsuo, J Minowada, T Tsubota, Y Yazaki, H Hirai

    ONCOGENE 13 (1) 183-191 1996/07

    ISSN: 0950-9232

  93. A conserved cysteine residue in the runt homology domain of AML1 is required for the DNA binding ability and the transforming activity on fibroblasts Peer-reviewed

    M Kurokawa, T Tanaka, K Tanaka, N Hirano, S Ogawa, K Mitani, Y Yazaki, H Hirai

    JOURNAL OF BIOLOGICAL CHEMISTRY 271 (28) 16870-16876 1996/07

    DOI: 10.1074/jbc.271.28.16870  

    ISSN: 0021-9258

  94. Increased Evi-1 expression is frequently observed in blastic crisis of chronic myelocytic leukemia Peer-reviewed

    S Ogawa, M Kurokawa, T Tanaka, K Tanaka, A Hangaishi, K Mitani, N Kamada, Y Yazaki, H Hirai

    LEUKEMIA 10 (5) 788-794 1996/05

    ISSN: 0887-6924

  95. Overexpression of the AML1 proto-oncoprotein in NIH3T3 cells leads to neoplastic transformation depending on the DNA-binding and transactivational potencies Peer-reviewed

    M Kurokawa, T Tanaka, K Tanaka, S Ogawa, K Mitani, Y Yazaki, H Hirai

    ONCOGENE 12 (4) 883-892 1996/02

    ISSN: 0950-9232

  96. INCREASED EXPRESSION OF AML1 DURING RETINOIC-ACID-INDUCED DIFFERENTIATION OF U937 CELLS Peer-reviewed

    K TANAKA, T TANAKA, S OGAWA, M KUROKAWA, K MITANI, Y YAZAKI, H HIRAI

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 211 (3) 1023-1030 1995/06

    DOI: 10.1006/bbrc.1995.1913  

    ISSN: 0006-291X

  97. DUAL FUNCTIONS OF THE AML1/EVI-1 CHIMERIC PROTEIN IN THE MECHANISM OF LEUKEMOGENESIS IN T(3-21) LEUKEMIAS Peer-reviewed

    T TANAKA, K MITANI, M KUROKAWA, S OGAWA, K TANAKA, J NISHIDA, Y YAZAKI, Y SHIBATA, H HIRAI

    MOLECULAR AND CELLULAR BIOLOGY 15 (5) 2383-2392 1995/05

    ISSN: 0270-7306

  98. 両側乳糜胸水にて発症した悪性リンパ腫の2症例 Peer-reviewed

    田中耕三

    臨床血液 35 (10) 1247-1247 1994/10

  99. 下咽頭癌術後に生じたGVHD様症候群の1例

    田中耕三

    日本内科学会関東地方会抄録集 (4) 78-78 1993/03

Show all ︎Show first 5

Misc. 57

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    家村顕自, 田中耕三

    日本分子生物学会年会プログラム・要旨集(Web) 45th 2022

  2. Understanding of a spatiotemporal regulation of α-tubulin detyrosination

    池田真教, 鈴木康弘, 田中耕三, 佐藤靖史

    日本分子生物学会年会プログラム・要旨集(Web) 44th 2021

  3. Mitotic chromosome oscillation maintains chromosomal stability

    家村顕自, 田中耕三

    日本細胞生物学会大会(Web) 73rd 2021

  4. 分裂期染色体動態異常を介した染色体不安定性の発生機構

    家村顕自, 田中耕三

    日本癌学会学術総会抄録集(Web) 80th 2021

  5. Chromosome oscillation-mediated robust equal segregation system is suppressed together with progression of cellular senescence

    家村顕自, 田中耕三

    日本分子生物学会年会プログラム・要旨集(Web) 44th 2021

  6. がん細胞の増殖優位性獲得過程における染色体不安定性の役割

    家村顕自, 田中耕三

    日本生化学会大会(Web) 94th 2021

  7. 分裂期中期における染色体動態は染色体均等分配の堅牢性に寄与する

    家村顕自, 田中耕三

    日本分子生物学会年会プログラム・要旨集(Web) 43rd 2020

  8. 分裂期中期動原体のリン酸化における空間的制御は染色体均等分配の堅牢性に寄与する

    家村顕自, 田中耕三

    日本生化学会大会(Web) 93rd 2020

  9. 染色体整列因子CAMP(CHAMP1)欠損による知的障害発症メカニズムの解明

    永井正義, 永井正義, 家村顕自, 服部聡子, 吉川貴子, 萩原英雄, 安澤隼人, 木下賢吾, 大隅典子, 宮川剛, 田中耕三

    日本分子生物学会年会プログラム・要旨集(Web) 42nd 2019

  10. 加齢に伴う初代線維芽細胞の染色体安定性変化の実態とその分子基盤の解明

    陳冠, 家村顕自, 田中耕三

    日本分子生物学会年会プログラム・要旨集(Web) 42nd 2019

  11. 新規分子CAMPによる分裂期細胞死制御機構の解明

    樋野真帆, 家村顕自, 田中耕三

    日本分子生物学会年会プログラム・要旨集(Web) 42nd 2019

  12. がん細胞の増殖における染色体不安定性の役割(The role of chromosomal instability in cancer cell proliferation)

    家村 顕自, 田中 耕三

    日本癌学会総会記事 77回 1555-1555 2018/09

    Publisher: 日本癌学会

    ISSN: 0546-0476

  13. 分裂期染色体動態による染色体安定性の維持機構

    家村顕自, 田中耕三

    日本遺伝学会大会プログラム・予稿集 90th 102 2018/08/27

  14. 染色体整列の効率性の低下による高頻度な誤ったキネトコア-微小管結合の形成が染色体不安定性を引き起こす

    國安絹枝, 家村顕自, 田中耕三

    日本生化学会大会(Web) 91st 2018

  15. 染色体整列の遅延により染色体不安定性が生じる機構

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    日本分子生物学会年会プログラム・要旨集(Web) 41st 2018

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    永井 正義, 家村 顕自, 吉川 貴子, 大隅 典子, 田中 耕三

    生命科学系学会合同年次大会 2017年度 [3LBA-131] 2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  18. 染色体の安定性を保障する染色体均等分配の新たな制御機構

    家村 顕自, 田中 耕三

    日本癌学会総会記事 76回 IS5-2 2017/09

    Publisher: 日本癌学会

    ISSN: 0546-0476

  19. 染色体不安定性の病態生理 Aurora Aは正常細胞における染色体均等分配システムの堅牢性を保証する

    家村 顕自, 田中 耕三

    日本細胞生物学会大会講演要旨集 69回 8-8 2017/05

    Publisher: (一社)日本細胞生物学会

  20. 脂肪肝における低酸素応答はアクアポリン8の発現抑制により胆石形成を促進する

    浅井 洋一郎, 山田 哲也, 突田 壮平, 高橋 圭, 前川 正充, 本間 緑, 池田 真教, 村上 圭吾, 近藤 泰輝, 澤田 正二郎, 中村 保宏, 田中 耕三, 笹野 公伸, 眞野 成康, 上野 義之, 下瀬川 徹, 片桐 秀樹

    糖尿病 60 (Suppl.1) S-138 2017/04

    Publisher: (一社)日本糖尿病学会

    ISSN: 0021-437X

    eISSN: 1881-588X

  21. 脂肪肝における低酸素応答はアクアポリン8の発現抑制により胆石形成を促進する

    浅井 洋一郎, 山田 哲也, 突田 壮平, 高橋 圭, 前川 正充, 本間 緑, 池田 真教, 村上 圭吾, 近藤 泰輝, 澤田 正二郎, 中村 保宏, 田中 耕三, 笹野 公伸, 眞野 成康, 上野 義之, 下瀬川 徹, 片桐 秀樹

    糖尿病 60 (Suppl.1) S-491 2017/04

    Publisher: (一社)日本糖尿病学会

    ISSN: 0021-437X

    eISSN: 1881-588X

  22. 分裂期において染色体を効率よく運ぶための仕組み

    家村 顕自, 田中 耕三

    生化学 89 (1) 102-104 2017/02

    Publisher: (公社)日本生化学会

    DOI: 10.14952/SEIKAGAKU.2017.890102  

    ISSN: 0037-1017

    eISSN: 2189-0544

  23. 神経細胞の発生及び分化における染色体整列因子CAMPの機能解析

    永井正義, 永井正義, 家村顕自, 池田真教, 田中耕三

    日本細胞生物学会大会(Web) 69th 2017

  24. 染色体整列の時空間的な遅延が染色体不安定性を引き起こす

    國安絹枝, 家村顕自, 田中耕三

    日本細胞生物学会大会(Web) 69th 2017

  25. 脂肪肝における低酸素応答はアクアポリン8の発現抑制により胆石形成を促進する

    浅井洋一郎, 山田哲也, 突田壮平, 高橋圭, 前川正充, 本間緑, 池田真教, 村上圭吾, 近藤泰輝, 澤田正二郎, 中村保宏, 田中耕三, 笹野公伸, 眞野成康, 上野義之, 下瀬川徹, 片桐秀樹

    糖尿病(Web) 60 (Suppl) S.491(J‐STAGE) 2017

    ISSN: 1881-588X

  26. 脂肪肝における低酸素応答はアクアポリン8の発現抑制により胆石形成を促進する

    浅井洋一郎, 山田哲也, 突田壮平, 高橋圭, 前川正充, 本間緑, 池田真教, 村上圭吾, 近藤泰輝, 澤田正二郎, 中村保宏, 田中耕三, 笹野公伸, 眞野成康, 上野義之, 下瀬川徹, 片桐秀樹

    糖尿病(Web) 60 (Suppl) S.138(J‐STAGE) 2017

    ISSN: 1881-588X

  27. 天然変性タンパク質としての細胞周期関連分子CAMPの機能

    池田真教, 家村顕自, 古寺哲幸, 有田恭平, 西村善文, 田中耕三

    日本蛋白質科学会年会プログラム・要旨集 16th 36 2016/05/19

  28. 細胞骨格、形態、運動を制御する分子機構 中心体キナーゼAurora Aは分裂期中期おけるキネトコア-微小管結合の修正に寄与する

    家村 顕自, 田中 耕三

    日本細胞生物学会大会講演要旨集 68回 41-41 2016/05

    Publisher: (一社)日本細胞生物学会

  29. 中心体キナーゼAurora Aは分裂期染色体動態に応答して動原体分子をリン酸化する

    家村顕自, 田中耕三

    日本分子生物学会年会プログラム・要旨集(Web) 39th 2016

  30. 脳における染色体整列因子CAMPの機能解析

    永井正義, 永井正義, 家村顕自, 池田真教, 田中耕三

    日本分子生物学会年会プログラム・要旨集(Web) 39th 2016

  31. 効率的な染色体整列の異常が染色体不安定性を引き起こす

    國安絹枝, 家村顕自, 田中耕三

    日本分子生物学会年会プログラム・要旨集(Web) 39th 2016

  32. 効率的な染色体整列におけるKid及びCENP-Eの機能解析

    家村 顕自, 田中 耕三

    日本細胞生物学会大会講演要旨集 67回 131-131 2015/06

    Publisher: (一社)日本細胞生物学会

  33. 染色体整列制御分子CAMPは分裂期停止時におけるがん細胞の生存に寄与する(CAMP is required for cell survival during mitotic arrest by anti-mitotic drugs)

    家村 顕自, 伊藤 剛, 田中 耕三

    日本癌学会総会記事 73回 J-3002 2014/09

    Publisher: 日本癌学会

    ISSN: 0546-0476

  34. Structure and function of Mad2/Mad2L2 (Rev7)

    TANAKA Kozo

    85 (8) 629-637 2013/08/25

    Publisher: 日本生化学会

    ISSN: 0037-1017

  35. Interplay between kinetochores and microtubules driving chromosome segregation

    Kozo Tanaka

    Cell Technology 32 (3) 291-296 2013/02/22

    Publisher: 学研メディカル秀潤社

    ISSN: 0287-3796

  36. Regulatory mechanisms of kinetochore-microtubule interaction in mitosis

    Kozo Tanaka

    CELLULAR AND MOLECULAR LIFE SCIENCES 70 (4) 559-579 2013/02

    DOI: 10.1007/s00018-012-1057-7  

    ISSN: 1420-682X

    eISSN: 1420-9071

  37. 分裂期初期におけるキネトコア-微小管結合の解析

    池田真教, 伊藤剛, 家村顕自, AMIN Mohammed Abdullahel, 田中耕三

    日本分子生物学会年会プログラム・要旨集(Web) 36th 2013

  38. 染色体整列制御分子CAMPは分裂期停止時における細胞の生存に関与する

    家村顕自, 伊藤剛, 田中耕三

    日本分子生物学会年会プログラム・要旨集(Web) 36th 2013

  39. Chromokinesin Kid and kinetochore kinesin CENP-E differentially support chromosome congression during prometaphase

    K. Iemura, G. Itoh, M. Ikeda, M. A. Amin, K. Tanaka

    MOLECULAR BIOLOGY OF THE CELL 24 2013

    ISSN: 1059-1524

    eISSN: 1939-4586

  40. Molecular mechanism of chromosome segregation and its relevance to anti-cancer therapy

    Kozo Tanaka

    Experimental Medicine 30 (19) 3118-3124 2012/11/30

    Publisher: 羊土社

  41. Dynamic regulation of kinetochore-microtubule interaction during mitosis

    Kozo Tanaka

    JOURNAL OF BIOCHEMISTRY 152 (5) 415-424 2012/11

    DOI: 10.1093/jb/mvs109  

    ISSN: 0021-924X

    eISSN: 1756-2651

  42. キネトコアが微小管の側面に結合する分子メカニズムの解明

    伊藤剛, ABDULLAHEL Amin Mohammed, 家村顕自, 池田真教, 田中耕三

    日本分子生物学会年会プログラム・要旨集(Web) 35th 2012

  43. 【細胞核-構造と機能】 染色体 キネトコアと微小管の結合を制御するタンパク質CAMP (生体の科学)

    田中耕三

    生体の科学 62 (5) 468-469 2011/10

    DOI: 10.11477/mf.2425101212  

  44. Live-cell analysis of kinetochore-microtubule interaction in budding yeast

    Kozo Tanaka, Etsushi Kitamura, Tomoyuki U. Tanaka

    METHODS 51 (2) 206-213 2010/06

    DOI: 10.1016/j.ymeth.2010.01.017  

    ISSN: 1046-2023

  45. Chromosome segregation machinery and cancer

    Kozo Tanaka, Toru Hirota

    CANCER SCIENCE 100 (7) 1158-1165 2009/07

    DOI: 10.1111/j.1349-7006.2009.01178.x  

    ISSN: 1349-7006

  46. Live cell imaging of kinetochore capture by microtubules in budding yeast

    Kozo Tanaka, Tomoyuki U. Tanaka

    Methods in Molecular Biology 545 233-242 2009

    DOI: 10.1007/978-1-60327-993-2_14  

    ISSN: 1064-3745

  47. 【染色体サイクル 複製・分配・組換え・修復・クロマチン制御のメカニズムとその異常による疾患】 染色体分配の準備 微小管による染色体キネトコアの捕捉の分子機構 (実験医学)

    田中耕三, 田中智之

    実験医学 25 (5) 671-678 2007/03

  48. Molecular mechanisms of kinetchore microtubule interaction

    Tanaka, K., Tanaka, T.

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 51 (1) 1-9 2006/01

  49. Kinetochore capture and bi-orientation on the mitotic spindle

    TU Tanaka, MJR Stark, K Tanaka

    NATURE REVIEWS MOLECULAR CELL BIOLOGY 6 (12) 929-942 2005/12

    DOI: 10.1038/nrm1764  

    ISSN: 1471-0072

    eISSN: 1471-0080

  50. The AML1/ETO(MTG8) and AML1/Evi-1 leukemia-associated chimeric oncoproteins accumulate PEBP2 beta(CBF beta) in the nucleus more efficiently than wild-type AML1

    K Tanaka, T Tanaka, M Kurokawa, Y Imai, S Ogawa, K Mitani, Y Yazaki, H Hirai

    BLOOD 91 (5) 1688-1699 1998/03

    ISSN: 0006-4971

    eISSN: 1528-0020

  51. 造血幹細胞制御の逸脱(悪性化) AML1遺伝子と白血病 (医学のあゆみ)

    田中耕三

    医学のあゆみ 180 (13) 909-913 1997/03

  52. Structurally altered EVI-1 protein generated in the 3Q21Q26 syndrome.

    S Ogawa, M Kurokawa, T Tanaka, K Mitani, J Inazawa, A Hangaishi, K Tanaka, Y Matsuo, J Minowada, T Tsubota, Y Yazaki, H Hirai

    BLOOD 88 (10) 2190-2190 1996/11

    ISSN: 0006-4971

  53. Overexpression of the human AML1b proto-oncoprotein leads to neoplastic transformation of NIH3T3 cells.

    Kurokawa, M, Tanaka, T, Tanaka, K, Ogawa, S, Mitani, K, Yazaki, Y, Hirai, H

    Oncogene 12 883-892 1996

  54. Overexpression of the AML1 proto-oncoprotein in NIH3T3 cells leads to neoplastic transformation requiring the conserved cysteine residue in the runt homology domain

    M Kurokawa, T Tanaka, K Tanaka, S Ogawa, K Mitani, Y Yazaki, H Hirai

    BLOOD 86 (10) 2373-2373 1995/11

    ISSN: 0006-4971

  55. HOMOZYGOUS LOSS OF THE CYCLIN-DEPENDENT KINASE-4 INHIBITOR (CDK4I-P16) GENE IN HUMAN LEUKEMIAS

    S OGAWA, A HANGAISHI, N SATO, M TAKATOKU, N HIRANO, K TANAKA, M KUROKAWA, T TANAKA, K MITANI, Y YAZAKI, H HIRAI

    BLOOD 84 (10) A296-A296 1994/11

    ISSN: 0006-4971

  56. MECHANISM OF LEUKEMOGENESIS BY DUAL FUNCTIONS OF AML1/EVI-1 CHIMERIC PROTEIN IN T(3-21) LEUKEMIAS

    T TANAKA, K MITANI, M KUROKAWA, S OGAWA, K TANAKA, J NISHIDA, Y YAZAKI, Y SHIBATA, H HIRAI

    BLOOD 84 (10) A230-A230 1994/11

    ISSN: 0006-4971

  57. HOMOZYGOUS LOSS OF THE CYCLIN-DEPENDENT KINASE 4-INHIBITOR (P16) GENE IN HUMAN LEUKEMIAS

    S OGAWA, N HIRANO, N SATO, T TAKAHASHI, A HANGAISHI, K TANAKA, M KUROKAWA, T TANAKA, K MITANI, Y YAZAKI, H HIRAI

    BLOOD 84 (8) 2431-2435 1994/10

    ISSN: 0006-4971

Show all ︎Show first 5

Research Projects 28

  1. Mechanisms of accurate chromosome segregation Competitive

    System: Basic Science Research Program

    2007/03 - Present

  2. Mitosis-targeted anti-cancer therapies Competitive

    System: Basic Science Research Program

    2007/03 - Present

  3. 分裂期染色体の可塑性が染色体分配に及ぼす影響の解明

    田中 耕三

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 学術変革領域研究(A)

    Category: 学術変革領域研究(A)

    Institution: 東北大学

    2023/04/01 - 2025/03/31

  4. Mechanisms of attenuated chromosome oscillation as a cause of chromosomal instability in cancer cells

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2022/04/01 - 2025/03/31

  5. がん細胞の染色体不安定性の原因としての染色体オシレーション減弱機構の解明

    田中 耕三

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(B)

    Category: 基盤研究(B)

    Institution: 東北大学

    2022/04/01 - 2025/03/31

  6. Role of oxidative stress in chromosomal insability with age

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)

    Category: Grant-in-Aid for Challenging Research (Exploratory)

    Institution: Tohoku University

    2022/06/30 - 2024/03/31

  7. 染色体分配に最適化した分裂期染色体の物性の解明

    田中 耕三

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 学術変革領域研究(A)

    Category: 学術変革領域研究(A)

    Institution: 東北大学

    2021/09/10 - 2023/03/31

    More details Close

    本研究では、分裂期染色体の物性に着目し、その形状や可塑性がどのように染色体分配に最適化されているのかを明らかにすることを目的とする。分裂期の染色体は、凝縮して個別化される一方、染色体分配の過程で大きく形を変えるが、その基盤となる物性や、染色体分配への寄与については不明な点が多い。本研究では、特定の染色体の末端を可視化し、染色体の形状変化をリアルタイムで観察することにより、この点を明らかにする。2021年度には、以下のような成果が得られた。 1. 特定の染色体末端を可視化した細胞の作成 正常ヒト網膜色素上皮細胞株RPE-1と骨肉腫由来細胞株U2OSにおいて、特定の染色体の繰り返し配列に特異的なsgRNAにアプタマー配列を付加し、dCas9およびアプタマー配列に結合するGFPタンパク質を発現させることにより可視化することを試みた。その結果、1番染色体短腕を可視化したRPE-1細胞、2番染色体の両腕を可視化したU2OS細胞を樹立することに成功した。これらの細胞でさらにセントロメアも可視化した。 2. 分裂期における染色体の形状変化の解析 1番染色体を可視化したRPE-1細胞において、分裂後期における染色体分離のタイミングについての検討を開始した。また、2番染色体両腕を可視化したU2OS細胞については、紡錘体の双極性の維持に必要なEg5を阻害することによって形成される単極紡錘体上での染色体の反復運動(オシレーション)に着目した。その結果、染色体が紡錘体極に近づく時には染色体腕部の作る角度が減少し、紡錘体極から遠ざかる時にはその角度が増加することが明らかになった。このことから、セントロメアに結合した微小管の伸縮によって染色体に力が加わると、腕部はそれに追随して動く際に細胞質の抵抗を受けて変形することが示唆された。

  8. 液-液相分離によるヘテロクロマチン領域での2本鎖DNA切断修復機構の解明

    田中 耕三

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 挑戦的研究(萌芽)

    Category: 挑戦的研究(萌芽)

    Institution: 東北大学

    2019/06/28 - 2021/03/31

  9. Relationship between cancer cell-specific reduction of chromosome oscillation and chromosomal instability

    Tanaka Kozo

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2018/04/01 - 2021/03/31

    More details Close

    In this project, we revealed the involvement of reduced chromosome oscillation, an iterative chromosome motion on the spindle, in chromosomal instability in cancer cells. When kinetochores get closer to spindle poles through chromosome oscillation, a kinetochore molecule Hec1 is phosphorylated by Aurora A on the spindle, facilitating the correction of erroneous kinetochore-microtubule attachments. In cancer cells, this mechanism is defective due to reduced chromosome oscillation, resulting in the increase in chromosome missegregation. Our study revealed a mechanism of chromosomal instability frequently found in cancer cells, paving a way to a novel anti-cancer strategy.

  10. Chromosome structure and dynamics as a basis for oncogenesis in the cellular context of aging

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Institution: Tohoku University

    2018/04/01 - 2020/03/31

  11. Maintenance of genomic stability by the heterochromatin-binding complex including a novel molecule, CAMP

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Institution: Tohoku University

    2016/04/01 - 2018/03/31

  12. Induction of chromosomal instability by aberrant expression of motor proteins working on the spindle

    Tanaka Kozo, IKEDA Masanori

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2016/04/01 - 2018/03/31

    More details Close

    Chromosomal instability, which is found in most cancer cells, is supposedly caused by defects permissive for cell survival. As causes of such mild defects, we focused on motor proteins that regulates chromosome dynamics on the spindle, and investigated the relationship between dysregulated expression of these proteins and chromosomal instability. When we reduced the expression of motor-related proteins on the spindle, time required to align chromosomes to the spindle equator was elongated, and chromosomal instability was induced. We also found that the late-aligning chromosomes are prone to show abnormal kinetochore-microtubule attachment as well as chromosome missegregation. These results suggest that delay in chromosome alignment causes chromosomal instability.

  13. Maintenance of chromosomal stability by efficient chromosome alignment

    Tanaka Kozo, IKEDA Masanori, YASUI Akira, KANNO Shin-ichiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2015/04/01 - 2018/03/31

    More details Close

    We investigated the mechanisms of chromosome alignment on the spindle and faithful chromosome segregation. In the process of chromosome alignment, kinetochores on chromosomes first attach to the lateral surface of spindle microtubules (lateral attachment), and then attach to the end of microtubules (end-on attachment). We searched for molecules involved in lateral attachment, and found the involvement of the motor proteins, dynein and CENP-E. We also found that lateral attachment and end-on attachment cooperatively contribute to chromosome alignment and faithful chromosome segregation (Sci Rep, 2018). Furthermore, we revealed that a mitotic kinase Plk1 plays a role in the spindle assemble checkpoint, which is important for the maintenance of chromosomal stability (Sci Rep, 2017).

  14. 紡錘体微小管と非コードDNA領域の相互作用による染色体の空間的制御

    田中 耕三

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 新学術領域研究(研究領域提案型)

    Category: 新学術領域研究(研究領域提案型)

    Institution: 東北大学

    2014/04/01 - 2016/03/31

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    遺伝情報の伝達は染色体の空間的制御によって成立しており、この制御にはゲノムの大部分を占める非コードDNA領域が主要な役割を果たしている。本研究では、紡錘体微小管との相互作用(末端結合 vs 側面結合)という観点から、セントロメアを中心とした非コードDNA領域による染色体の動態制御機構を明らかにすることを目的とする。H26年度には染色体が紡錘体上を移動する分子機構について、染色体腕部に局在するKidおよびキネトコアに局在するCENP-Eという2つのモーター分子が微小管の安定性に応じて互いに相補的に機能することを明らかにした(Nat Commun, 2016)。H27年度には以下のような成果が得られた。 1.側面結合の分子機構 モーター分子ダイニンおよび紡錘体チェックポイント分子Mad1, Mad2のキネトコア局在に関与するRZZ複合体が側面結合に関与することが判明した。 2. 側面結合から末端結合への移行の過程とその機構 微小管結合因子CLIP-170がモーター分子ダイニンのはたらきに対抗して、キネトコアを微小管末端へとつなぎとめる作用を有することが明らかになった(FEBS Lett, 2015)。この結果は、CLIP-170が側面結合しているキネトコアを微小管末端につなぎとめることによって、末端結合への変換を促進している可能性を示唆していると考えられた。 3. 側面結合・染色体腕部への結合が染色体分配の正確性に果たす役割 側面結合した染色体の移動に関与するモーター分子Kidの発現を抑制した細胞では、染色体分配自体は起こるものの染色体整列の時間の遅延が認められた。このような細胞では染色体分配異常や微小核の出現が認められ、染色体不安定性がひきおこされていることがわかった。このことは、細胞生存に重大な影響を及ぼさない側面結合や染色体腕部への結合が、染色体分配の正確性に関与することを示唆していると考えられた。

  15. へテロクロマチン結合複合体によるゲノム安定性の動的制御

    田中 耕三

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 新学術領域研究(研究領域提案型)

    Category: 新学術領域研究(研究領域提案型)

    Institution: 東北大学

    2014/04/01 - 2016/03/31

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    ヘテロクロマチン形成はクロマチン動構造制御の重要な一翼を担っており、これにはHP1(heterochromatin protein 1)が関与している。HP1は研究代表者らが同定した新規分子CAMP(EMBO J, 2011)およびDNA損傷応答に関連するRev7と複合体を形成して機能することが示唆されている。そこで本研究では、クロマチン構造変化とDNA損傷応答、染色体分配の関連について解析し、CAMP, REV7, HP1 からなる複合体(CRH複合体と呼ぶ)がこれらの機能を統合している可能性を検討することを目的とする。H26年度には、CAMP, Rev7, HP1がそれぞれDNA損傷応答と染色体分配に関与することが明らかになった。またCAMPノックアウトマウスを作成したところ、出生直後に死亡することがわかった。これらの結果をふまえ、H27年度には以下のような成果が得られた。 1. 培養細胞でのCRH複合体の機能解析 C端側のZnフィンガー領域が、CAMPのヘテロクロマチン領域への局在に必要であることがわかった。 2. CRH複合体の生化学的解析 精製したCAMP, REV7, HP1の結合を解析したところ、CAMPのWK領域とREV7がstoichiometricに結合することが明らかになった。またCAMPがC端側のZnフィンガー領域でHP1と結合することがわかった。 3. CAMPの神経系での機能についての解析 フランス、イギリス、アメリカの研究者との共同研究により、小児の重度発達障害でCAMPの変異が見られることがわかった(Hum Mutat, 2016)。このCAMPの変異は、いずれもC端側のZnフィンガー領域を欠く変異タンパク質を出現させる。解析の結果、このような変異タンパク質は細胞内局在の異常を示し、同じく発達障害で変異が認められるPOGZとの結合ができないことがわかった。現在CAMPノックアウトマウスでの神経系の異常を解析している。

  16. Elucidating chromosomal instability by chromosome tracking in live cell imaging

    Tanaka Kozo, ITOH GO, IKEDA MASANORI

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2014/04/01 - 2016/03/31

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    We aimed to elucidate the mechanism of chromosomal instability commonly seen in cancer cells. We hypothesized that modest chromosomal instability that allows cell survival, not severe instability causing cell death, is involved in cancer formation and progression, and focused on the defect in efficient chromosome alignment to the spindle equator. To address the point, we developed methods to visualize single chromosome and observe its dynamics. We also found that two motor proteins, CENP-E and Kid, is involved in chromosome alignment (Nat Commun, 2015). In Kid-depleted cells, there was a delay in chromosome alignment and chromosomal instability was induced, exemplifying the occurrence of chromosomal instability by modest mitotic defects.

  17. Regulatory system of chromosomal stability by molecules including a novel molecule, CAMP

    TANAKA Kozo, ITOH Go, HIROTA Toru, YASUI Akira, KANNO Shin-ichiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2012/04/01 - 2015/03/31

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    We addressed the regulatory mechanism of chromosomal stability, and following findings were obtained. 1) A novel molecule CAMP functions as a complex with HP1, REV7, and POGZ. CAMP knockout mice die soon after birth. 2) A nuclear pore complex component Nup188 recruits NuMA to spindle poles for chromosome segregation. 3) A microtubule associated factor CLIP-170 regulates chromosome segregation through the mechanisms such as Plk1 recruitment to kinetochores. 4) Two motor molecules, Kid and CENP-E, function for chromosome alignment on the spindle.

  18. セントロメアと微小管の位置関係による染色体分配制御機構の解明

    田中 耕三

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 新学術領域研究(研究領域提案型)

    Category: 新学術領域研究(研究領域提案型)

    Institution: 東北大学

    2012/04/01 - 2014/03/31

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    本研究は、染色体分配の過程を微小管とセントロメアの位置関係の変化という新たな視点からとらえ、セントロメアによる染色体分配制御機構を再構築することを目的とする。分裂期に染色体が微小管と結合する際には、微小管がセントロメアに対して垂直に位置する場合(垂直結合)と平行に位置する場合(平行結合)がある。そこでこの2種類の結合の使い分けにより、どのように染色体分配が制御されているのかを明らかにする。平成25年度には、平行結合と垂直結合の違いを明らかにし、平行結合に関与する分子を同定した。 1.平行結合と垂直結合でのキネトコア構築の特性の解析:分裂前中期ををいくつかのステップに分け、キネトコア分子の局在やキネトコア間にかかる張力を各ステップ毎に測定した。その結果、垂直結合時と平行結合時のそれぞれのキネトコアの構成分子が明らかになった。 2.平行結合と垂直結合に関与する分子の同定:1.で平行結合時のキネトコアに存在する分子を、垂直結合に重要な役割を果たしているNdc80複合体の構成分子と共にノックダウンすることにより、微小管との結合が完全に失われるかどうかを検討した。その結果Spindly, Zw10, CENP-E, KNL1等の分子が平行結合に関与することが示唆された。 3.超高解像度蛍光顕微鏡や電子顕微鏡での平行結合と垂直結合の可視化:蛍光顕微鏡と電子顕微鏡の画像を対比する観察法であるCLEM(correlative light and electron microscopy)法によって分裂期初期の染色体と微小管の結合を調べたところ、平行結合が観察された。 4.平行結合に関与する分子のネットワークの解明:2.で平行結合に関与することが示唆された分子を様々な組み合わせでノックダウンし、染色体の整列異常の頻度を検討した。これにより各分子間の関係を明らかにした。

  19. Basic research to overcome resistance to anti-mitotic drugs

    TANAKA Kozo, ITOH Go, HIROTA Toru, YASUI Akira, KANNO Shinichiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2012/04/01 - 2014/03/31

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    We aimed to identify molecules involved in cell death after prolonged mitotic arrest by anti-cancer drugs. When cells depleted of CAMP, a novel molecule we identified, were treated with microtubule inhibitors, we found the acceleration of cell death after mitotic arrest specifically in cancer cell lines. There was a tendency that cancer cell lines showed higher expression of CAMP than normal cell lines, implying that cancer cell survival is dependent on CAMP. Expression of Mcl-1 and Bcl-xL, anti-apoptotic Bcl-2 family members, was decreased in CAMP-depleted cells, suggesting that CAMP can be a target for anti-cancer therapy.

  20. 抗がん剤開発に向けての微小管によるキネトコア捕捉および染色体異数性成立機構の解明

    田中 耕三, AMINMOHAMMED Abdullahel

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特別研究員奨励費

    Category: 特別研究員奨励費

    Institution: 東北大学

    2012 - 2013

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    がん細胞の大部分では染色体数の異常(異数性)が認められ、その多くでは正常細胞より染色体数が多い。染色体分配は、中心体から伸長する微小管が染色体上のキネトコアと結合して染色体を中心体へと引っ張ることによって起こる。そこで本研究では、新たな抗がん剤のターゲットとして、効率的なキネトコア捕捉の分子機構を明らかにすることを目的とする。平成25年度には、平成24年度に効率的なキネトコア捕捉に重要な分子として同定したCLIP-170の作用機構の解明を目指した。 1. CLIP-170によるPlk1のキネトコア局在の制御(J Cell Sci, in press) CLIP-170をノックダウンすると分裂期キナーゼPlk1のキネトコア局在が減少した。解析の結果、Plk1はCdk1によるCLIP-170のリン酸化依存性にCLIP-170と結合することが判明した。CLIP-170をノックダウンした細胞でCdk1によるリン酸化部位に変異をもつCLIP-170を発現させてもPlk1のキネトコア局在は回復せず、CdklによるCLIP-170のリン酸化依存性にPlk1のキネトコア局在が制御されていることが示唆された。 2. CLIP-170とダイニンの拮抗作用(投稿準備中) CLIP-170をノックダウンすると高度の染色体整列異常が起こるが、CLIP-170と結合してそのキネトコア局在に関与するダイナクチンのノックダウンでは軽度の染色体整列異常しか見られない。ダイナクチンはモーター分子ダイニンと結合してその制御を行っていることが知られている。解析の結果、CLIP-170がダイニンの過剰なはたらきを抑えることにより染色体整列に寄与していることが示唆された。 以上の結果から、CLIP-170が他のキネトコア分子と相互作用しながら効率的なキネトコア捕捉に関与することが明らかになった。

  21. Molecular network supporting chromosomal stability

    TANAKA Kozo, YASUI Akira, ITOH Go, KANNO Shinichiro, TANAKA Tomoyuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2009 - 2011

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    We searched for molecules involved in chromosomal stability, and identified a novel molecule, CAMP(chromosome alignment-maintaining phosphoprotein ; C13orf8, ZNF828). CAMP is supposed to contribute to chromosome segregation through the maintenance of kinetochore-microtubule attachment. Mutations in CAMP were suggested to be related to oncogenesis.

  22. Novel DNA damage responses and repair regulated by poly-ADP ribosylation and chromatin remodeling

    YASUI Akira, NAKAJIMA Satoshi, KANNO Shinichirou, TANAKA Kouzo, TAKAO Masashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)

    Category: Grant-in-Aid for Scientific Research (A)

    Institution: Tohoku University

    2008 - 2010

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    Using laser micro-irradiation of living human cell and identification of protein complexes recruited to DNA damaged site by proteomics, we have analyzed and identified DNA damage response of proteins within human cell. For DNA single-strand breaks we have identified two novel human proteins with DNA end-and exo-nuclease activities, which activate poly(ADP-ribose polymerase 1 (PARP1)by creating gap at a nick in DNA. For DNA double-strand breaks (DSB)we identified an ATP-dependent chromatin remodeling complex belonging to ISWI family, CHRAC, which is required for the loading of KU complex at DSB. Especially, ACF1 becomes bound to KU70 more tightly by treatment of cells with chemical agents creating DSB and initiates non-homologous end joining of DSB. Thus, we showed that chromatin remodeling is essential for the initiation of repair of DNA strand breaks.

  23. 紡錘体チェックポイントによる染色体分配制御ネットワークの解明

    田中 耕三, 安井 明

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究

    Category: 特定領域研究

    Institution: 東北大学

    2008 - 2009

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    細胞分裂期における染色体の均等な分配を制御する代表的な機構として、紡錘体チェックポイントが存在する。本研究では、ヒト細胞において紡錘体チェックポイントに関連する新規分子を同定し、それらの分子のネットワークによる染色体分配制御機構を解明することを目的とする。平成20年度には、紡錘体チェックポイントに関連する分子と結合する分子の同定を行った。まずFLAGタグのついた紡錘体チェックポイント関連分子を発現するヒト293細胞を樹立した。次にこれらの細胞の抽出液について、FLAGに対する抗体による免疫沈降を行い、紡錘体チェックポイント関連分子と結合している分子をマススペクトロメトリーにて同定した。このうち酵母の紡錘体チェックポイント分子であるMad2のヒトホモローグの1つであるMAD2L2と結合する新規分子として、C13orf8を同定した。解析の結果C13orf8は染色体および紡錘体に局在し、染色体分配に関与していることが示唆された。 平成21年度には、平成20年度の成果をふまえ、C13orf8による染色体分配制御機構について詳細な解析を行った。その結果C13orf8をノックダウンした細胞では、細胞分裂期における染色体の赤道面への整列に異常が生じており、C13orf8がキネトコア-微小管結合に関与していることが示唆された。このような分子は、動物細胞でのより繊細な染色体分配制御機構に関連していることが予想され、その異常は染色体不安定性を引きおこし、がん化と関連している可能性がある。現在さらにC13orf8の機能解析を進めている。

  24. 出芽酵母をモデルとした、細胞周期停止の持続による細胞死誘導機構の解明

    田中 耕三

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究

    Category: 特定領域研究

    Institution: 東北大学

    2008 - 2009

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    本研究は、遺伝学的解析に優れた出芽酵母を用い、紡錘体チェックポイントの活性化が持続した場合の細胞死誘導機構を解明することを目的とする。微小管とキネトコアの結合に異常がある場合には、紡錘体チェックポイントが活性化され細胞周期の停止が起こる。これが持続すると最終的に細胞死に至るが、この細胞死の機構については不明な点が多い。我々は平成20年度に、出芽酵母を微小管重合阻害剤であるノコダゾールで長時間処理した際の変化を観察し、10時間後で約40%の細胞死が起こることを明らかにした。細胞周期解析の結果、この細胞死は細胞が細胞分裂期にとどまった状態で起こっていた。またノコダゾール処理した細胞の核を観察したところ、変形、断片化が認められ、アポトーシスが起こっている可能性が示唆された。 平成20年度の結果をふまえ、平成21年度にはノコダゾール処理による細胞死の過程についてさらに詳細な検討を行った。その結果、ノコダゾール処理した細胞ではアポトーシスに特徴的なDNAの断片化が起こっていることがわかった。さらに、別のアポトーシスの指標であるフォスファチジルセリンの細胞外への露出が起こっていることも明らかになった。一方、細胞融解やオートファジーなど、アポトーシス以外の細胞死に特徴的な指標は認められなかった。これらのことから、ノコダゾールで持続処理した酵母では、アポトーシスによる細胞死が起こることが示唆された。Vinca alkaloidやtaxolといった微小管に作用する薬剤は、多くのがんの治療に広く用いられている。本研究により、ノコダゾール処理した出芽酵母が、微小管に作用する薬剤による細胞死機構を解析するモデルになることが示唆された。酵母でこの細胞死機構に関与する分子を明らかにすることにより、抗がん剤の作用機序の解明およびより有効ながん治療の開発に貢献することが期待される。

  25. 腫瘍発生における相同組換え遺伝子異常の役割とその診断・治療への応用

    田中 耕三

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究(C)

    Category: 特定領域研究(C)

    Institution: 広島大学

    2001 - 2001

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    相同組換え遺伝子の異常は二本鎖DNA切断の正しい修復を妨げ、染色体不安定性をひき起こすことが予想される。当研究室ではRAD54と相同性を有する新規ヒト遺伝子RAD54Bを同定し、ヒトの腫瘍の一部の症例においてRAD54,RAD54Bの変異が存在することを見出した。当研究では相同組換え遺伝子の異常とがんの遺伝的不安定性の関係を明らかにする目的で、Rad54,Rad54Bの機能解析を行った。まずRad54,Rad54B蛋白質を精製し生化学的機能を検討したところ、共に2本鎖DNA依存性ATPase活性を有し、1本鎖および2本鎖DNAと結合することがわかった。酵母にはRAD54類似遺伝子TID1/RDH54が存在し、Rad54BとTid1/Rdh54は、N端側に種を超えて保存されている相同領域を有することから、RAD54BはTID1/RDH54のヒトホモローグであると考えられた。しかしRad54BはTid1/Rdh54と異なりRad51,Dmc1と直接には会合せず、機能的差異を有することが示された。次にヒト大腸癌細胞株HCT116においてRAD54Bをノックアウトして生物学的機能を検討したところ、相同組換えの頻度の著明な低下が認められた。酵母ではRAD54が姉妹染色分体を介した組換えに関与するのに対して、TID1/RDH54は相同染色体を介した組換えに関与することが知られている。RAD54BがTID1/RDH54のヒトホモローグであるとすると、RAD54Bも相同染色体を介した組換えに関与していることが予想される。腫瘍において認められる染色体転座などの異常は、姉妹染色分体以外の染色体間での組換えの結果である可能性があり、RAD54Bがこの過程に関与していることが予想されるため、今後この可能性を検討していく予定である。

  26. 慢性骨髄性白血病の急性転化における染色体レベルでの遺伝的不安定性の機構の解明

    田中 耕三

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 奨励研究(A)

    Category: 奨励研究(A)

    Institution: 広島大学

    2000 - 2001

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    慢性骨髄性白血病をはじめとする腫瘍において認められる染色体異常と、相同組換え遺伝子との関連を調べる目的で、当研究室でクローニングした新規ヒト相同組換え遺伝子RAD54Bの機能解析を行った。Rad54Bは、Rad51による組換え反応を促進する作用を持つRad54と相同性を有している。Rad54B蛋白質を精製し生化学的機能を検討したところ、Rad54BはRad54同様2本鎖DNA依存性ATPase活性を有し、1本鎖および2本鎖DNAと結合することがわかった。一方酵母にはRAD54類似遺伝子TID1/RDH54が存在する。Rad54BとTid1/Rdh54は、Rad54との相同性が低いN端側の領域で相同性を有し、この相同領域が種を超えて保存されていることから、RAD54BはTID1/RDH54のヒトホモローグであると考えられる。しかしRad54BはTid1/Rdh54と異なりRad51,Dmclと直接には会合せず、機能的に異なる部分を有することが示された。次にヒト大腸癌細胞株HCT116においてRAD54Bをノックアウトして生物学的機能を検討したところ、著明なtargeted integrationの頻度の低下が認められ、RAD54Bが相同組換えに関与していることが示された。酵母ではRAD54が姉妹染色分体を介した組換えに関与するのに対して、TID1/RDH54は相同染色体を介した組換えに関与することが知られている。RAD54BがTID1/RDH54のヒトホモローグであるとすると、RAD54Bも相同染色体を介した組換えに関与していることが予想される。腫瘍において認められる染色体転座などの異常は、姉妹染色分体以外の染色体間での組換えの結果である可能性があり、RAD54Bがこの過程に関与していることが予想されるため、今後この可能性を検討していく予定である。

  27. 転写因子WT1の造血発生分化における標的遺伝子の同定

    宮川 清, 田中 耕三

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究(A)

    Category: 特定領域研究(A)

    Institution: 広島大学

    1999 - 1999

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    転写因子WT1はその造血系の分化調節における役割が明らかになりつつある。一方、残存白血病マーカーとして臨床応用されながらも、白血病に分子レベルでどのように関わるかは不明である。そこで、WT1の機能異常と白血病との関係を明らかにする目的で、4つの相異なる造血器腫瘍グループでWT1の変異解析を行った。その結果WT1の変異は急性骨髄性白血病に限られるが、成人・小児、病型を問わずその15%に見られること、及び予後不良と明らかな相関があることを発見した。 このようにWT1の機能異常が急性骨髄性白血病の病態に深く関わっている可能性が示唆されたため、その標的遺伝子の解析をES細胞におけるノックアウト実験で行った。この細胞においてはWT1のDNA結合能に重要であるZnフィンガードメインにneo耐性遺伝子を導入した。これらをDNAマクロアレイによるスクリーニングにかけたところ、WT1の変異の有無によって発現の変化が生じる約40個のクローンが同定された。しかし、その発現の差はわずかであり、しかもこれまでWT1の標的遺伝子として同定されている約20種類の遺伝子の発現の差は全く検出できなかった。この事実はWT1が単に転写調節によって発生分化を調整しているのではなく、別の機能がより重要である可能性を示唆する。 一方、WT1の核内局在を免疫組織染色で検討すると、タンパクレベルでスプライス因子と結合していることも明らかとなり、WT1の造血系における役割は複数の経路によって調節されているものと考えられた。

  28. 転座関連遺伝子によるがんの診断・病態研究

    鎌田 七男, 田中 耕三, 田中 公夫, 宮川 清, 阿部 達生, 広沢 信作, 森 茂郎, 瀬戸 加大, 大木 操, 三谷 絹子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究(A)

    Category: 特定領域研究(A)

    Institution: 広島大学

    1996 - 1999

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    遺伝子検査をもとに疾病の確定診断、および治療法の開発を行う研究の一端として、慢性骨髄性白血病のインターフェロン(IFN)治療効果をFISH法を用いて判定し、効果の有無とHLA遺伝子多型との相関をみた。治療効果判定を行った116例の解析で、IFN有効例では、A2601,DRB1-0802が、また、無効例ではCw1403のHLAが関与している所見が得られた。IFNの有効性を個体レベル、特にHLA多型性から追求し、関連性の見出されたのは初めてであり、IFN治療対象患者の選択に役立ち、また、ひいては医療費の経済性においても大きく貢献するものと考えられる。 また、転座関連遺伝子の単離を目的として研究し、急性骨髄性白血病(FABM2)でt(12;15)(p13;q25)を持つ症例から、12番染色体上のETV6遺伝子プローブをもとに、12番染色体と転座している15番染色体領域を検出した。解析の結果、ETV6遺伝子のPNTドメインとチロシンキナーゼC(TRKC)遺伝子のPTKドメイン部の結合によることを初めて明らかにした。一方、白血病初期転座に続く悪性化関連遺伝子の1つとして、WT1変異が骨髄性白血病において、また、相同組換え遺伝子RAD54が悪性リンパ腫において関与することを明らかにした。 急性骨髄性白血病の悪性化には、WT1遺伝子変異が一部関与しているため、今後、初診のみならず、治療中、治療後においてもWT1遺伝子変異のスクリーニングを導入する必要がある。

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  1. 分裂期チェックポイントアダプテーション阻害による抗がん剤耐性克服

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    がん治療に広く用いられているタキサン系やビンカアルカロイドといった微小管阻害剤は、分裂期チェックポイントによる細胞周期停止を持続させることによりアポトーシスを引き起こす。しかし一部の細胞では細胞周期停止からの逸脱(アダプテーション)が起こり、これが抗がん剤耐性の一因となっている。そこで本研究では、抗がん剤耐性の大きな原因であるチェックポイントに対するアダプテーションを抑える薬剤を開発することにより、抗がん剤治療の有効性の改善を目指す。

  2. 新規分子CAMPが細胞分裂期に作用する抗がん剤の効果に与える影響の解明

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    新規分子CAMPが細胞分裂期に作用する抗がん剤の効果に与える影響の解明

  3. 染色体分配に関与する新規分子CAMPの異常と発がんとの関係の解明

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    染色体分配に関与する新規分子CAMPの異常と発がんとの関係の解明

  4. 新規染色体分配制御因子CAMPの染色体不安定性および発がんとの関連の解明

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    新規染色体分配制御因子CAMPの染色体不安定性および発がんとの関連の解明

  5. 新規分子CAMPの異常による染色体不安定性の発生機構の解明

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    新規分子CAMPによる染色体分配の制御機構を解析し、CAMPの異常と染色体不安定性の関係を明らかにする

  6. 染色体-微小管結合と紡錘体チェックポイントを統合する新規分子MAD2BP1の機能解析

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    染色体-微小管結合と紡錘体チェックポイントを統合する新規分子MAD2BP1の機能解析

  7. 紡錘体チェックポイント関連分子による染色体分配制御ネットワークの解明

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    紡錘体チェックポイント関連分子による染色体分配制御ネットワークの解明

  8. がん化、がん治療の標的としての染色体安定性ネットワークの解明

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    がん化、がん治療の標的としての染色体安定性ネットワークの解明

  9. 発がん機構との関連におけるゲノム安定性維持機構の解析

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    発がん機構との関連におけるゲノム安定性維持機構の解析

  10. 紡錘体チェックポイントを活性化させる抗がん剤による細胞死の機構の解析

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    紡錘体チェックポイントを活性化させる抗がん剤による細胞死の機構の解析

  11. 微小管に作用する抗がん剤による細胞死機構の解明

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    微小管に作用する抗がん剤による細胞死機構の解明

  12. DNA損傷チェックポイントを活性化させる抗がん剤による細胞死の機構の解析

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    DNA損傷チェックポイントを活性化させる抗がん剤による細胞死の機構の解析

  13. 細胞分裂制御装置に作用する薬剤による細胞死誘導機構の解明

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    細胞分裂制御装置に作用する薬剤による細胞死誘導機構の解明

  14. 染色体の正確な分配を司る制御機構の解析

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    染色体の正確な分配を司る制御機構の解析

  15. 染色体の正確な分配を司る制御機構の解明

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    染色体の正確な分配を司る制御機構の解明

  16. 相同組換え遺伝子の変異による発癌機構の解明

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    相同組換え遺伝子の変異による発癌機構の解明

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