研究者詳細

顔写真

カンノ　シンイチロウ
菅野　新一郎
Shinichiro Kanno
所属
大学院医学系研究科　病態液性制御学分野
職名
特任研究員
学位

  • 医学博士 （東北大学）

e-Rad 研究者番号
10400417

所属学協会 1

  • 日本分子生物学会

研究キーワード 3

  • プロテオーム解析

  • タンパク質機能解析

  • DNA修復

研究分野 1

  • ライフサイエンス / ゲノム生物学 / DNA修復

論文 83

  1. A Novel Dysferlin-Binding Kinase CK2α Promotes Plasma Membrane Repair in Dysferlinopathy. 国際誌

    Naoko Nakamura, Naoki Suzuki, Shin-Ichiro Kanno, Rei Yamanaka, Hiroya Ono, Rumiko Izumi, Rui Muliang, Christian Borgo, Akiyuki Ohno, Ryuhei Harada, Saki Saito, Yukino Funayama, Kensuke Ikeda, Shio Mitsuzawa, Yasuaki Watanabe, Tomomi Shijo, Tetsuya Akiyama, Toshiaki Takahashi, Makoto Kanzaki, Shion Osana, Hitoshi Warita, Yoshitsugu Aoki, Satoru Ebihara, Mauro Salvi, Ryoichi Nagatomi, Akira Yasui, Katsuya Miyake, Masashi Aoki

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology　40　(6)　e71677　2026年3月31日

    DOI： 10.1096/fj.202500773RRR 　

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    Dysferlinopathy is an adult-onset form of muscular dystrophy caused by mutations in the dysferlin gene and is inherited in an autosomal recessive manner. Dysferlin is primarily known for its role in plasma membrane repair. Although several proteins associated with dysferlin have been identified, many aspects of its signaling pathways and protein-protein interactions remain unclear. Here, we focused on the region between the third and fourth C2 domains, where frequent genetic mutations occur and functional domains are concentrated, and identified the protein kinase CK2α (formerly known as casein kinase 2) as a novel dysferlin-binding protein. CK2α was found to accumulate at membrane injury sites along with dysferlin in mouse skeletal muscle, and membrane repair was delayed in CK2α knockout cells. Furthermore, overexpression of CK2α in dysferlin-deficient mouse muscle led to improved membrane repair. Additionally, we revealed that CK2α plays a role in phosphorylating annexin A1, which is known to bind to dysferlin and is involved in plasma membrane repair. Our results indicated that CK2α controls membrane repair by participating in the phosphorylation of annexin A1. The molecular interplay among dysferlin, CK2α, and phosphorylated annexin A1 represents a novel therapeutic target for promoting membrane repair.

  2. The Role of Myoferlin in Vesicle Trafficking and the Effects of Its Overexpression in Prostate Cancer.

    Yuki Katsumata, Shuichi Shimada, Hiromichi Katayama, Tomonori Sato, Takuma Sato, Yoshihide Kawasaki, Naoki Kawamorita, Shinichi Yamashita, Mai Mochizuki, Keiichi Tamai, Shin-Ichiro Kanno, Akihiro Ito

    The Tohoku journal of experimental medicine　2026年2月12日

    DOI： 10.1620/tjem.2025.J161 　

  3. BET family BRD3 initiates DSB-induced chromatin remodeling with TIP60 to promote R-loop-mediated HR. 国際誌

    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年11月25日

    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.

  4. Responses of Regulator of G Protein Signaling Proteins and Circadian Clock Components to Sustained Depolarization-Induced Dedifferentiation in MIN6 β-Cells

    Satoshi Okano, Yu Sasaki, Akira Yasui, Shin-ichiro Kanno, Kennichi Satoh, Masahiko Igarashi, Osamu Nakajima

    Experimental and Clinical Endocrinology & Diabetes　2025年11月7日

    出版者・発行元： Georg Thieme Verlag KG

    DOI： 10.1055/a-2741-4294 　

    ISSN：0947-7349

    eISSN：1439-3646

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    Background:Regulators of G protein signaling (RGSs) are key modulators of β-cell function and stress adaptation. Similarly, circadian clock components are intricately implicated in the regulation of insulin secretion and β-cell physiology. However, their responses to sustained cellular stimulation under depolarizing conditions remain incompletely understood.Methods:We used MIN6 cells subjected to prolonged potassium chloride (KCl) exposure to induce sustained membrane depolarization, mimicking conditions of chronic β-cell stimulation. We analyzed the expression levels of Rgs and core clock genes, and assessed associated changes in cellular stress and differentiation markers.Results:KCl treatment led to the upregulation of endoplasmic reticulum (ER) stress markers, including Chop and Atf4, without inducing oxidative stress. Expression of Rgs2, Rgs4, and Rgs16 was elevated. RGS2 partially co-localized with eIF2α, suggesting a role in translational control during stress. Furthermore, KCl-induced depolarization was associated with characteristic changes in β-cell differentiation markers and disallowed genes, indicative of a dedifferentiation-like state. Transcript levels of several circadian genes were altered, including significant downregulation of Dbp and upregulation of its repressor E4bp4. Notably, Dec1, a clock gene known to be inducible by various external stimuli, was also upregulated, suggesting broader circadian disruption under depolarizing conditions.Conclusion:Sustained membrane depolarization induces ER stress and transcriptional remodeling in MIN6 β-cells, including the modulation of RGS proteins and key circadian regulators such as DBP, E4BP4, and DEC1. These alterations may contribute to functional impairment and a dedifferentiation-like state of β-cells under chronic stimulatory conditions.

  5. FAXC depletion contributes to tumor progression via the c-MET pathway in renal cell carcinoma. 国際誌

    Masato Konno, Haruna Fujimori, Shin-Ichiro Kanno, Rie Shibuya-Takahashi, Mai Mochizuki, Kazunori Yamaguchi, Jun Yasuda, Shigekazu Murakami, Kennichi Satoh, Hisanobu Adachi, Akihiro Ito, Keiichi Tamai, Naoki Asano

    Biochemical and biophysical research communications　778　152388-152388　2025年7月18日

    DOI： 10.1016/j.bbrc.2025.152388 　

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    Renal cell carcinoma (RCC), the most common types of kidney cancer, still requires novel therapeutic targets to improve patients' outcome. In this study, we focus on Failed Axon Connections Homolog (FAXC) gene, a newly identified and potentially important cancer target, and investigated its detailed role in RCC. In RCC cells, FAXC knockdown resulted in increased cell proliferation, and elevated c-MET expression and phosphorylation. Blockade of c-MET phosphorylation inhibited cell proliferation promoted by FAXC knockdown. In contrast, FAXC overexpression reduced cell proliferation and downregulated c-MET expression in RCC cells. We also found that FAXC is localized to the mitochondria in RCC cells. Additionally, an investigation of RCC patient specimens revealed that FAXC expression was negatively correlated with c-MET phosphorylation and was downregulated in tumor region compared with adjacent normal tissues. Taken together, our findings indicate that FAXC depletion promotes cell proliferation through the activation of c-MET in RCC cells.

  6. Cover Image

    Yoshiyasu Tongu, Tomoko Kasahara, Tetsuro Matsuhashi, Yoshitsugu Oikawa, Ryota Akimoto, Yuhan Luo, Sayaka Sekine, Momoka Suzuki, Hitomi Kashiwagi, Shinichiro Kanno, Yoshikazu Tanaka, Kyohei Sato, Yusuke Okubo, Akihiko Muto, Hidetaka Tokuno, Chitose Suzuki, Chiharu Kawabe, Takamasa Ishikawa, Shun Watanabe, Koichi Kikuchi, Shun Itai, Takeya Sato, Takehiro Suzuki, Kazuhiro Igarashi, Shinji Fukuda, Tomoyoshi Soga, Kei Murayama, Erina Kuranaga, Takafumi Toyohara, Takaaki Abe

    The FASEB Journal　39　(12)　2025年6月30日

    出版者・発行元： Wiley

    DOI： 10.1096/fsb2.70816 　

    ISSN：0892-6638

    eISSN：1530-6860

  7. Mitochondria-Homing Drug Mitochonic Acid 5 Improves Barth Syndrome Myopathy in a Human-Induced Pluripotent Stem Cell Model and Barth Syndrome Drosophila Model. 国際誌

    Yoshiyasu Tongu, Tomoko Kasahara, Tetsuro Matsuhashi, Yoshitsugu Oikawa, Ryota Akimoto, Yuhan Luo, Sayaka Sekine, Momoka Suzuki, Hitomi Kashiwagi, Shinichiro Kanno, Yoshikazu Tanaka, Kyohei Sato, Yusuke Okubo, Akihiko Muto, Hidetaka Tokuno, Chitose Suzuki, Chiharu Kawabe, Takamasa Ishikawa, Shun Watanabe, Koichi Kikuchi, Shun Itai, Takeya Sato, Takehiro Suzuki, Kazuhiro Igarashi, Shinji Fukuda, Tomoyoshi Soga, Kei Murayama, Erina Kuranaga, Takafumi Toyohara, Takaaki Abe

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology　39　(12)　e70739　2025年6月30日

    DOI： 10.1096/fj.202401856RRR 　

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    Barth syndrome (BTHS) is a rare disease caused by mutations in the tafazzin gene that affects the heart and muscles; however, to date, no clinically effective drugs are available. In BTHS, mitochondrial function is reduced owing to changes in cardiolipin metabolism. We developed mitochonic acid 5 (MA-5), a small-molecule compound that increases ATP levels, improves mitochondrial dynamics, and is effective in treating mitochondrial and muscle diseases. Therefore, this study examined the effectiveness of MA-5 in treating BTHS. The mitochondrial functions of four isolated BTHS skin fibroblasts were examined. Human BTHS induced pluripotent stem cell (iPSC) were differentiated into myoblasts and cardiolipin metabolism and mitochondrial functions were analyzed. RNA-seq was performed to clarify the metabolic changes. Using a Drosophila melanogaster model of BTHS, the effects of MA-5 on motor performance and cardiac phenotype were examined. MA-5 improved mitochondrial function and reduced cell death due to oxidative stress in skin fibroblasts of patients with BTHS. MA-5 promoted ATP production and reduced oxidative stress in human BTHS iPS cell-derived myoblasts. RNA-seq analysis revealed that MA-5 alleviated endoplasmic reticulum stress in BTHS cells. Administration of MA-5 to BTHS Drosophila improved locomotor ability and tachycardia observed in patients with BTHS. Protein interaction analyses suggested colocalization of ATPase and the MA-5-binding protein mitofilin. These data suggested that MA-5 improves BTHS dysfunction and may serve as a novel therapeutic agent for BTHS.

  8. Non-DNA-damaging DNA-PK activation improving hearing and prolonging life due to NAD+and SIRT upregulation

    Yohei Honkura, Takehiro Suzuki, Ryota Kujirai, Shinichiro Kanno, Yotaro Matsumoto, Yoshikazu Tanaka, Hengphasatporn Kowit, Satoru Nagatoishi, Alexander Tyshkovskiy, Tomoko Kasahara, Yoshiyasu Tongu, Zhang Bohan, Hitomi Kashiwagi, Chika Saegusa, Msato Fujioka, Reina Usami, Shunsuke Chikuma, Yukiko Tokifuji, Tetsuro Matsuhashi, Yoshitsugu Oikawa, Hiroka Komatsu, Kei Murayama, Takehito Sugasawa, Fumika Nanto-Hara, Kensei Taguchi, Daisuke Saigusa, Chitose Suzuki, Takeya Sato, Jun Suzuki, Yuji Owada, Kuniyasu Niizuma, Hidenori Endo, Ko Hashimoto, Takafumi Toyohara, Kohei Tsumoto, Paul Anderson, Vadim N. Gladyshev, Ken-ichiro Hayashi, Yukio Katori, Yoshihisa Tomioka, Takaaki Abe

    2025年4月23日

    出版者・発行元： Cold Spring Harbor Laboratory

    DOI： 10.1101/2025.04.18.649305 　

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    SUMMARY Emerging evidence strongly supports a close relationship between age-related hearing loss and frailty, highlighting the importance of early detection and intervention. Recently, we invented a mitochondria-homing drug named mitochonic acid 5 (MA-5), that increases the adenosine triphosphate (ATP) levels, rescue mitochondrial function, and protect tissue damages. Currently, the phase I clinical trial has been finished in Japan (jRCT2031210495) and the phase 2 clinical trial has already been approved by PMDA. Here we show that MA-5 improved various types of hearing loss in mouse models. Structural chemical bioanalysis revealed that MA-5 is a mixture of equal amount of S- and R- enantiomer and both S- and R- enantiomer increase ATP by binding mitochondrial protein, mitofilin. However, S-enantiomer significantly increased the NAD+levels by binding to the NAD+-producing key enzyme nicotinamide phosphoribosyltransferase (NAMPT). Moreover, the S-enantiomer increased the sirtuin 1 protein by suppressing polyubiquitination induced by tripartite motif containing 28 (TRIM28) phosphorylation which was triggered by DNA-dependent protein kinase (DNA-PK) activation in the absence of DNA damage. Transcriptomic signatures showed that the signature of MA-5 shows an inverse correlation with aging and mortality and is oriented in the same direction as the OSKM-related iPSCs, suggesting the modification of aging pathways. Oral administration of MA-5 to mitochondrial disease model mouse showed increased survival. Our findings suggest that, in addition to enhancing ATP levels, the coordinated regulation of NAD+metabolism, SIRT protein expression, and DNA-PK activity-constituting a novel therapeutic triad may contribute to the amelioration of hearing impairment and mitochondrial dysfunction, thereby improving life prognosis.

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

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

    Nucleic acids research　53　(5)　2025年2月27日

    DOI： 10.1093/nar/gkaf150 　

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    The SWI/SNF chromatin-remodeling complex that comprises multiple subunits orchestrates diverse cellular processes, including gene expression, DNA repair, and DNA replication, by sliding and releasing nucleosomes. AT-interacting domain-rich protein 1A (ARID1A) and ARID1B (ARID1A/B), a pivotal subunit, have significant relevance in cancer management because they are frequently mutated in a broad range of cancer types. To delineate the protein network involving ARID1A/B, we investigated the interactions of this with other proteins under physiological conditions. The ARID domain of ARID1A/B interacts with proteins involved in transcription and DNA/RNA metabolism. Several proteins are responsible for genome integrity maintenance, including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), bound to the armadillo (ARM) domain of ARID1A/B. Introducing a knock-in mutation at the binding amino acid of DNA-PKcs in HCT116 cells reduced the autophosphorylation of DNA-PKcs and the recruitment of LIG4 in response to ionizing radiation. Our findings suggest that within the SWI/SNF complex, ARID1A couples DNA double-strand break repair processes with chromatin remodeling via the ARM domains to directly engage with DNA-PKcs to maintain genome stability.

  10. Zn結合不全型CRY1発現マウスの特異な膵管病変におけるTFF2の発現と膵α細胞の新生

    岡野 聡, 安井 明, 菅野 新一郎, 佐々木 悠, 佐藤 賢一, 五十嵐 雅彦, 中島 修

    膵臓　39　(3)　A519-A519　2024年7月

    出版者・発行元： (一社)日本膵臓学会

    ISSN：0913-0071

    eISSN：1881-2805

  11. CD271 mRNA/hnRNPA2B1 complex promotes proliferation and stemness in oral and head and neck squamous cell carcinoma. 国際誌

    Mai Mochizuki, Rie Shibuya-Takahashi, Shin-Ichiro Kanno, Shungo Adachi, Haruna Fujimori, Akira Nakazato, Keitaro Fujii, Shinkichi Morita, Satoshi Saijoh, Tomoko Yamazaki, Takayuki Imai, Yukinori Asada, Kazunori Yamaguchi, Jun Yasuda, Norihisa Shindo, Kazuo Sugamura, Keiichi Tamai

    Cancer science　2024年5月6日

    DOI： 10.1111/cas.16187 　

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    RNAs, such as noncoding RNA, microRNA, and recently mRNA, have been recognized as signal transduction molecules. CD271, also known as nerve growth factor receptor, has a critical role in cancer, although the precise mechanism is still unclear. Here, we show that CD271 mRNA, but not CD271 protein, facilitates spheroid cell proliferation. We established CD271-/- cells lacking both mRNA and protein of CD271, as well as CD271 protein knockout cells lacking only CD271 protein, from hypopharyngeal and oral squamous cell carcinoma lines. Sphere formation was reduced in CD271-/- cells but not in CD271 protein knockout cells. Mutated CD271 mRNA, which is not translated to a protein, promoted sphere formation. CD271 mRNA bound to hnRNPA2B1 protein at the 3'-UTR region, and the inhibition of this interaction reduced sphere formation. In surgical specimens, the CD271 mRNA/protein expression ratio was higher in the cancerous area than in the noncancerous area. These data suggest CD271 mRNA has dual functions, encompassing protein-coding and noncoding roles, with its noncoding RNA function being predominant in oral and head and neck squamous cell carcinoma.

  12. FAXC interacts with ANXA2 and SRC in mitochondria and promotes tumorigenesis in cholangiocarcinoma. 国際誌

    Haruna Fujimori, Mao Shima-Nakamura, Shin-Ichiro Kanno, Rie Shibuya-Takahashi, Mai Mochizuki, Masamichi Mizuma, Michiaki Unno, Yuta Wakui, Makoto Abue, Wataru Iwai, Daisuke Fukushi, Kennich Satoh, Kazunori Yamaguchi, Norihisa Shindo, Jun Yasuda, Keiichi Tamai

    Cancer science　2024年3月13日

    DOI： 10.1111/cas.16140 　

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    Cholangiocarcinoma (CCA) is one of the most difficult malignancies to treat as the therapeutic options are limited. Although several driver genes have been identified, most remain unknown. In this study, we identified a failed axon connection homolog (FAXC), whose function is unknown in mammals, by analyzing serially passaged CCA xenograft models. Knockdown of FAXC reduced subcutaneous tumorigenicity in mice. FAXC was bound to annexin A2 (ANXA2) and c-SRC, which are tumor-promoting genes. The FAXC/ANXA2/c-SRC complex forms in the mitochondria. FAXC enhances SRC-dependent ANXA2 phosphorylation at tyrosine-24, and the C-terminal amino acid residues (351-375) of FAXC are required for ANXA2 phosphorylation. Transcriptome data from a xenografted CCA cell line revealed that FAXC correlated with epithelial-mesenchymal transition, hypoxia, and KRAS signaling genes. Collectively, these findings advance our understanding of CCA tumorigenesis and provide candidate therapeutic targets.

  13. LZTR1欠損はEMT誘導とKLHL12依存的なコラーゲン分泌を制御することで腫瘍増殖と腫瘍転移を促進する

    阿部 太紀, 菅野 新一郎, 新堀 哲也, 寺尾 美穂, 高田 修治, 青木 洋子

    日本生化学会大会プログラム・講演要旨集　96回　[1P-666]　2023年10月

    出版者・発行元： (公社)日本生化学会

  14. LZTR1欠損はEMT誘導とKLHL12依存的なコラーゲン分泌を制御することで腫瘍増殖と腫瘍転移を促進する

    阿部 太紀, 菅野 新一郎, 新堀 哲也, 寺尾 美穂, 高田 修治, 青木 洋子

    日本生化学会大会プログラム・講演要旨集　96回　[1P-666]　2023年10月

    出版者・発行元： (公社)日本生化学会

  15. LZTR1 deficiency exerts high metastatic potential by enhancing sensitivity to EMT induction and controlling KLHL12-mediated collagen secretion. 国際誌

    Taiki Abe, Shin-Ichiro Kanno, Tetsuya Niihori, Miho Terao, Shuji Takada, Yoko Aoki

    Cell death & disease　14　(8)　556-556　2023年8月25日

    DOI： 10.1038/s41419-023-06072-9 　

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    Leucine zipper-like transcriptional regulator 1 (LZTR1), a substrate adaptor of Cullin 3 (CUL3)-based E3 ubiquitin ligase, regulates proteostasis of the RAS subfamily. Mutations in LZTR1 have been identified in patients with several types of cancer. However, the role of LZTR1 in tumor metastasis and the target molecules of LZTR1, excluding the RAS subfamily, are not clearly understood. Here, we show that LZTR1 deficiency increases tumor growth and metastasis. In lung adenocarcinoma cells, LZTR1 deficiency induced the accumulation of the RAS subfamily and enhanced cell proliferation, invasion, and xenograft tumor growth. Multi-omics analysis to clarify the pathways related to tumor progression showed that MAPK signaling, epithelial-mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling-related gene ontology terms were enriched in LZTR1 knockout cells. Indeed, LZTR1 deficiency induced high expression of EMT markers under TGF-β1 treatment. Our search for novel substrates that interact with LZTR1 resulted in the discovery of a Kelch-like protein 12 (KLHL12), which is involved in collagen secretion. LZTR1 could inhibit KLHL12-mediated ubiquitination of SEC31A, a component of coat protein complex II (COPII), whereas LZTR1 deficiency promoted collagen secretion. LZTR1-RIT1 and LZTR1-KLHL12 worked independently regarding molecular interactions and did not directly interfere with each other. Further, we found that LZTR1 deficiency significantly increases lung metastasis and promotes ECM deposition around metastatic tumors. Since collagen-rich extracellular matrix act as pathways for migration and facilitate metastasis, increased expression of RAS and collagen deposition may exert synergistic or additive effects leading to tumor progression and metastasis. In conclusion, LZTR1 deficiency exerts high metastatic potential by enhancing sensitivity to EMT induction and promoting collagen secretion. The functional inhibition of KLHL12 by LZTR1 provides important evidence that LZTR1 may be a repressor of BTB-Kelch family members. These results provide clues to the mechanism of LZTR1-deficiency carcinogenesis.

  16. 亜鉛結合不全型の時計蛋白質CRY1発現マウスの膵島内膵管における膵α細胞の新生

    岡野 聡, 安井 明, 菅野 新一郎, 佐々木 悠, 佐藤 賢一, 五十嵐 雅彦, 中島 修

    膵臓　38　(3)　A475-A475　2023年7月

    出版者・発行元： (一社)日本膵臓学会

    ISSN：0913-0071

    eISSN：1881-2805

  17. Novel Calcium-Binding Ablating Mutations Induce Constitutive RET Activity and Drive Tumorigenesis. 国際誌

    Junya Tabata, Takashi Nakaoku, Mitsugu Araki, Ryunosuke Yoshino, Shinji Kohsaka, Ayaka Otsuka, Masachika Ikegami, Ayako Ui, Shin-Ichiro Kanno, Keiko Miyoshi, Shigeyuki Matsumoto, Yukari Sagae, Akira Yasui, Masakazu Sekijima, Hiroyuki Mano, Yasushi Okuno, Aikou Okamoto, Takashi Kohno

    Cancer research　82　(20)　3751-3762　2022年10月17日

    DOI： 10.1158/0008-5472.CAN-22-0834 　

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    Distinguishing oncogenic mutations from variants of unknown significance (VUS) is critical for precision cancer medicine. Here, computational modeling of 71,756 RET variants for positive selection together with functional assays of 110 representative variants identified a three-dimensional cluster of VUSs carried by multiple human cancers that cause amino acid substitutions in the calmodulin-like motif (CaLM) of RET. Molecular dynamics simulations indicated that CaLM mutations decrease interactions between Ca2+ and its surrounding residues and induce conformational distortion of the RET cysteine-rich domain containing the CaLM. RET-CaLM mutations caused ligand-independent constitutive activation of RET kinase by homodimerization mediated by illegitimate disulfide bond formation. RET-CaLM mutants possessed oncogenic and tumorigenic activities that could be suppressed by tyrosine kinase inhibitors targeting RET. This study identifies calcium-binding ablating mutations as a novel type of oncogenic mutation of RET and indicates that in silico-driven annotation of VUSs of druggable oncogenes is a promising strategy to identify targetable driver mutations. SIGNIFICANCE: Comprehensive proteogenomic and in silico analyses of a vast number of VUSs identify a novel set of oncogenic and druggable mutations in the well-characterized RET oncogene.

  18. CHAMP1-POGZ counteracts the inhibitory effect of 53BP1 on homologous recombination and affects PARP inhibitor resistance. 国際誌

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

    Oncogene　41　(19)　2706-2718　2022年5月

    DOI： 10.1038/s41388-022-02299-6 　

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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.

  19. USP39 is essential for mammalian epithelial morphogenesis through upregulation of planar cell polarity components. 国際誌

    Chiharu Kimura-Yoshida, Kyoko Mochida, Shin-Ichiro Kanno, Isao Matsuo

    Communications biology　5　(1)　378-378　2022年4月19日

    DOI： 10.1038/s42003-022-03254-7 　

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    Previously, we have shown that the translocation of Grainyhead-like 3 (GRHL3) transcription factor from the nucleus to the cytoplasm triggers the switch from canonical Wnt signaling for epidermal differentiation to non-canonical Wnt signaling for epithelial morphogenesis. However, the molecular mechanism that underlies the cytoplasmic localization of GRHL3 protein and that activates non-canonical Wnt signaling is not known. Here, we show that ubiquitin-specific protease 39 (USP39), a deubiquitinating enzyme, is involved in the subcellular localization of GRHL3 as a potential GRHL3-interacting protein and is necessary for epithelial morphogenesis to up-regulate expression of planar cell polarity (PCP) components. Notably, mouse Usp39-deficient embryos display early embryonic lethality due to a failure in primitive streak formation and apico-basal polarity in epiblast cells, resembling those of mutant embryos of the Prickle1 gene, a crucial PCP component. Current findings provide unique insights into how differentiation and morphogenesis are coordinated to construct three-dimensional complex structures via USP39.

  20. Responses of Regulator of G Protein Signaling Proteins and Circadian Clock Proteins to Induction of Dedifferentiation in Pancreatic β-cells

    Satoshi Okano, Akira Yasui, Shin-ichiro Kanno, Kennichi Satoh, Masahiko Igarashi, Osamu Nakajima

    2022年3月3日

    出版者・発行元： Research Square Platform LLC

    DOI： 10.21203/rs.3.rs-1395694/v1 　

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    Abstract Regulator of G protein signaling proteins (RGSs) are involved in regulating β-cell functions. This study was conducted to examine the cellular responses to the occurrence of β-cell dedifferentiation in terms of the changes of expression levels of Rgs and clock genes: We used MIN6 cells, for which the cellular contents of zinc were reduced by prolonged treatment of the cells by potassium chloride, in this way inducing the cells to a progenitor-like state. The results indicate that endoplasmic reticulum (ER)-stress markers were up-regulated in the treated cells. All examined RGS were up-regulated in treated cells compared with control cells. RGS2 partly co-localized eIF2 α in the treated cells, although no discernable co-localization was observed for RGS4 and 16, suggesting that RGS2 specifically participates in the translational control of protein in response to cellular stresses. Altered mRNA levels of a uniquely specific set of clock genes were observed, suggesting malfunction of the molecular clock in β-cells. Taken together, G protein signaling and translation process are probably fine-tuned by RGSs. Thereby β-cells can cope with stress attributable to the decrease of zinc. The attenuation of circadian rhythm, in addition to some G protein signaling, can be prerequisites for induction of β-cell dedifferentiation.

  21. Loss of Axdnd1 causes sterility due to impaired spermatid differentiation in mice.

    Yuki Hiradate, Ryua Harima, Rin Yanai, Kenshiro Hara, Kazue Nagasawa, Makoto Osada, Tomoe Kobayashi, Makoto Matsuyama, Shin-Ichiro Kanno, Akira Yasui, Kentaro Tanemura

    Reproductive medicine and biology　21　(1)　e12452　2022年

    DOI： 10.1002/rmb2.12452 　

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    PURPOSE: Spermiogenesis, the process of deformation of sperm head morphology and flagella formation, is a phenomenon unique to sperm. Axonemal dynein light chain proteins are localized to sperm flagella and are known to be involved in sperm motility. Here, we focused on the gene axonemal dynein light chain domain containing 1 (Axdnd1) with the aim to determine the function of its protein product AXDND1. METHODS: To elucidate the role of AXDND1 in spermatogenesis, we generated Axdnd1 knockout (KO) mice using the CRISPR/Cas9 system. The generated mice were subjected to fertility tests and analyzed by immunohistochemistry. RESULT: The Axdnd1 KO mouse exhibited sterility caused by impaired spermiogenesis during the elongation step as well as abnormal nuclear shaping and manchette, which are essential for spermiogenesis. Moreover, AXDND1 showed enriched testicular expression and was localized from the mid-pachytene spermatocytes to the early spermatids. CONCLUSION: Axdnd1 is essential for spermatogenesis in the mouse testes. These findings improve our understanding of spermiogenesis and related defects. According to a recent report, deleterious heterozygous mutations in AXDND1 were found in non-obstructive azoospermia (NOA) patients. Therefore, Axdnd1 KO mice could be used as a model system for NOA, which will greatly contribute to future NOA treatment studies.

  22. Identification of Binding Proteins for TSC22D1 Family Proteins Using Mass Spectrometry. 国際誌

    Ryouta Kamimura, Daisuke Uchida, Shin-Ichiro Kanno, Ryo Shiraishi, Toshiki Hyodo, Yuta Sawatani, Michiko Shimura, Tomonori Hasegawa, Maki Tsubura-Okubo, Erika Yaguchi, Yuske Komiyama, Chonji Fukumoto, Sayaka Izumi, Atsushi Fujita, Takahiro Wakui, Hitoshi Kawamata

    International journal of molecular sciences　22　(20)　2021年10月9日

    DOI： 10.3390/ijms222010913 　

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    TSC-22 (TGF-β stimulated clone-22) has been reported to induce differentiation, growth inhibition, and apoptosis in various cells. TSC-22 is a member of a family in which many proteins are produced from four different family genes. TSC-22 (corresponding to TSC22D1-2) is composed of 144 amino acids translated from a short variant mRNA of the TSC22D1 gene. In this study, we attempted to determine the intracellular localizations of the TSC22D1 family proteins (TSC22D1-1, TSC-22 (TSC22D1-2), and TSC22(86) (TSC22D1-3)) and identify the binding proteins for TSC22D1 family proteins by mass spectrometry. We determined that TSC22D1-1 was mostly localized in the nucleus, TSC-22 (TSC22D1-2) was localized in the cytoplasm, mainly in the mitochondria and translocated from the cytoplasm to the nucleus after DNA damage, and TSC22(86) (TSC22D1-3) was localized in both the cytoplasm and nucleus. We identified multiple candidates of binding proteins for TSC22D1 family proteins in in vitro pull-down assays and in vivo binding assays. Histone H1 bound to TSC-22 (TSC22D1-2) or TSC22(86) (TSC22D1-3) in the nucleus. Guanine nucleotide-binding protein-like 3 (GNL3), which is also known as nucleostemin, bound to TSC-22 (TSC22D1-2) in the nucleus. Further investigation of the interaction of the candidate binding proteins with TSC22D1 family proteins would clarify the biological roles of TSC22D1 family proteins in several cell systems.

  23. BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma. 国際誌

    Keiichi Tamai, Mao Nakamura-Shima, Rie Shibuya-Takahashi, Shin-Ichiro Kanno, Akira Yasui, Mai Mochizuki, Wataru Iwai, Yuta Wakui, Makoto Abue, Kuniharu Yamamoto, Koh Miura, Masamichi Mizuma, Michiaki Unno, Sadafumi Kawamura, Ikuro Sato, Jun Yasuda, Kazunori Yamaguchi, Kazuo Sugamura, Kennichi Satoh

    Scientific reports　10　(1)　21592-21592　2020年12月9日

    DOI： 10.1038/s41598-020-78539-0 　

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    Cancer stem cells (CSCs) define a subpopulation of cancer cells that are resistant to therapy. However, little is known of how CSC characteristics are regulated. We previously showed that dormant cancer stem cells are enriched with a CD274low fraction of cholangiocarcinoma cells. Here we found that BEX2 was highly expressed in CD274low cells, and that BEX2 knockdown decreased the tumorigenicity and G0 phase of cholangiocarcinoma cells. BEX2 was found to be expressed predominantly in G0 phase and starvation induced the USF2 transcriptional factor, which induced BEX2 transcription. Comprehensive screening of BEX2 binding proteins identified E3 ubiquitin ligase complex proteins, FEM1B and CUL2, and a mitochondrial protein TUFM, and further demonstrated that knockdown of BEX2 or TUFM increased mitochondria-related oxygen consumption and decreased tumorigenicity in cholangiocarcinoma cells. These results suggest that BEX2 is essential for maintaining dormant cancer stem cells through the suppression of mitochondrial activity in cholangiocarcinoma.

  24. FABP7 Regulates Acetyl-CoA Metabolism Through the Interaction with ACLY in the Nucleus of Astrocytes. 国際誌

    Yoshiteru Kagawa, Banlanjo Abdulaziz Umaru, Hiroki Shima, Ryo Ito, Ryo Zama, Ariful Islam, Shin-Ichiro Kanno, Akira Yasui, Shun Sato, Kosuke Jozaki, Subrata Kumar Shil, Hirofumi Miyazaki, Shuhei Kobayashi, Yui Yamamoto, Hiroshi Kogo, Chie Shimamoto-Mitsuyama, Akira Sugawara, Norihiro Sugino, Masayuki Kanamori, Teiji Tominaga, Takeo Yoshikawa, Kohji Fukunaga, Kazuhiko Igarashi, Yuji Owada

    Molecular neurobiology　57　(12)　4891-4910　2020年12月

    DOI： 10.1007/s12035-020-02057-3 　

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    Fatty acid binding protein 7 (FABP7) is an intracellular fatty acid chaperon that is highly expressed in astrocytes, oligodendrocyte-precursor cells, and malignant glioma. Previously, we reported that FABP7 regulates the response to extracellular stimuli by controlling the expression of caveolin-1, an important component of lipid raft. Here, we explored the detailed mechanisms underlying FABP7 regulation of caveolin-1 expression using primary cultured FABP7-KO astrocytes as a model of loss of function and NIH-3T3 cells as a model of gain of function. We discovered that FABP7 interacts with ATP-citrate lyase (ACLY) and is important for acetyl-CoA metabolism in the nucleus. This interaction leads to epigenetic regulation of several genes, including caveolin-1. Our novel findings suggest that FABP7-ACLY modulation of nuclear acetyl-CoA has more influence on histone acetylation than cytoplasmic acetyl-CoA. The changes to histone structure may modify caveolae-related cell activity in astrocytes and tumors, including malignant glioma.

  25. 骨格筋疾患の動物モデルの実験的治療 Dysferlinopathyに対する治療法の開発

    小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 割田 仁, 林 由起子, 三宅 克也, 青木 正志

    神経治療学　37　(6)　S101-S101　2020年10月

    出版者・発行元： (一社)日本神経治療学会

    ISSN：0916-8443

    eISSN：2189-7824

  26. 骨格筋疾患の動物モデルの実験的治療 Dysferlinopathyに対する治療法の開発

    小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 割田 仁, 林 由起子, 三宅 克也, 青木 正志

    神経治療学　37　(6)　S101-S101　2020年10月

    出版者・発行元： (一社)日本神経治療学会

    ISSN：0916-8443

    eISSN：2189-7824

  27. がん原遺伝子産物RASの恒常性維持機構の解明

    阿部 太紀, 梅木 郁美, 菅野 新一郎, 井上 晋一, 新堀 哲也, 青木 洋子

    日本生化学会大会プログラム・講演要旨集　93回　[P-190]　2020年9月

    出版者・発行元： (公社)日本生化学会

  28. AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy. 国際誌 査読有り

    Hiroya Ono, Naoki Suzuki, Shin-Ichiro Kanno, Genri Kawahara, Rumiko Izumi, Toshiaki Takahashi, Yasuo Kitajima, Shion Osana, Naoko Nakamura, Tetsuya Akiyama, Kensuke Ikeda, Tomomi Shijo, Shio Mitsuzawa, Ryoichi Nagatomi, Nobukazu Araki, Akira Yasui, Hitoshi Warita, Yukiko K Hayashi, Katsuya Miyake, Masashi Aoki

    Molecular therapy : the journal of the American Society of Gene Therapy　28　(4)　1133-1153　2020年4月8日

    DOI： 10.1016/j.ymthe.2020.02.006 　

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    Mutations in dysferlin are responsible for a group of progressive, recessively inherited muscular dystrophies known as dysferlinopathies. Using recombinant proteins and affinity purification methods combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), we found that AMP-activated protein kinase (AMPK)γ1 was bound to a region of dysferlin located between the third and fourth C2 domains. Using ex vivo laser injury experiments, we demonstrated that the AMPK complex was vital for the sarcolemmal damage repair of skeletal muscle fibers. Injury-induced AMPK complex accumulation was dependent on the presence of Ca2+, and the rate of accumulation was regulated by dysferlin. Furthermore, it was found that the phosphorylation of AMPKα was essential for plasma membrane repair, and treatment with an AMPK activator rescued the membrane-repair impairment observed in immortalized human myotubes with reduced expression of dysferlin and dysferlin-null mouse fibers. Finally, it was determined that treatment with the AMPK activator metformin improved the muscle phenotype in zebrafish and mouse models of dysferlin deficiency. These findings indicate that the AMPK complex is essential for plasma membrane repair and is a potential therapeutic target for dysferlinopathy.

  29. Oxidation resistance 1 prevents genome instability through maintenance of G2/M arrest in gamma-ray-irradiated cells. 国際誌

    Ako Matsui, Junya Kobayashi, Shin-Ichiro Kanno, Kazunari Hashiguchi, Masahiro Miyaji, Yukihiro Yoshikawa, Akira Yasui, Qiu-Mei Zhang-Akiyama

    Journal of radiation research　61　(1)　1-13　2020年1月23日

    DOI： 10.1093/jrr/rrz080 　

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    Human oxidation resistance 1 (OXR1) was identified as a protein that decreases genomic mutations in Escherichia coli caused by oxidative DNA damage. However, the mechanism by which OXR1 defends against genome instability has not been elucidated. To clarify how OXR1 maintains genome stability, the effects of OXR1-depletion on genome stability were investigated in OXR1-depleted HeLa cells using gamma-rays (γ-rays). The OXR1-depleted cells had higher levels of superoxide and micronucleus (MN) formation than control cells after irradiation. OXR1-overexpression alleviated the increases in reactive oxygen species (ROS) level and MN formation after irradiation. The increased MN formation in irradiated OXR1-depleted cells was partially attenuated by the ROS inhibitor N-acetyl-L-cysteine, suggesting that OXR1-depeletion increases ROS-dependent genome instability. We also found that OXR1-depletion shortened the duration of γ-ray-induced G2/M arrest. In the presence of the cell cycle checkpoint inhibitor caffeine, the level of MN formed after irradiation was similar between control and OXR1-depleted cells, demonstrating that OXR1-depletion accelerates MN formation through abrogation of G2/M arrest. In OXR1-depleted cells, the level of cyclin D1 protein expression was increased. Here we report that OXR1 prevents genome instability by cell cycle regulation as well as oxidative stress defense.

  30. LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases. 国際誌 査読有り

    Taiki Abe, Ikumi Umeki, Shin-Ichiro Kanno, Shin-Ichi Inoue, Tetsuya Niihori, Yoko Aoki

    Cell death and differentiation　27　(3)　1023-1035　2019年7月23日

    DOI： 10.1038/s41418-019-0395-5 　

    ISSN：1350-9047

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    Leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a member of the BTB-Kelch superfamily, which interacts with the Cullin3 (CUL3)-based E3 ubiquitin ligase complex. Mutations in LZTR1 have been identified in glioblastoma, schwannomatosis, and Noonan syndrome. However, the functional role of LZTR1 in carcinogenesis or human development is not fully understood. Here, we demonstrate that LZTR1 facilitates the polyubiquitination and degradation of RAS via the ubiquitin-proteasome pathway, leading to the inhibition of the RAS/MAPK signaling. The polyubiquitination and degradation of RAS was also observed in cells expressing MRAS, HRAS, NRAS, and KRAS as well as oncogenic RAS mutants and inhibited the activation of ERK1/2 and cell growth. In vivo ubiquitination assays showed that MRAS-K127 and HRAS-K170 were ubiquitinated by LZTR1 and that the polyubiquitinated-chains contained mainly Ub-K48, K63, and K33-linked chains, suggesting its possible involvement in autophagy. Immunoprecipitation analyses showed the interaction of LZTR1 and RAS-GTPases with autophagy-related proteins, including LC3B and SQSTM1/p62. Co-expression of LZTR1 and RAS increased the expression of lipidated form of LC3B. However, long-term treatment with chloroquine had little effect on RAS protein levels, suggesting that the contribution of autophagy to LZTR1-mediated RAS degradation is minimal. Taken together, these results show that LZTR1 functions as a "RAS killer protein" mainly via the ubiquitin-proteasome pathway regardless of the type of RAS GTPase, controlling downstream signal transduction. Our results also suggest a possible association of LZTR1 and RAS-GTPases with the autophagy. These findings provide clues for the elucidation of the mechanisms of RAS degradation and regulation of the RAS/MAPK signaling cascade.

  31. RACK1 regulates centriole duplication by controlling localization of BRCA1 to the centrosome in mammary tissue-derived cells. 国際誌 査読有り

    Yuki Yoshino, Huicheng Qi, Ryo Kanazawa, Mami Sugamata, Kenta Suzuki, Akihiro Kobayashi, Kazuha Shindo, Ayako Matsuzawa, Shun Shibata, Shino Endo, Yutaro Miyanishi, Tatsuro Shimaoka, Chikashi Ishioka, Shin-Ichiro Kanno, Akira Yasui, Natsuko Chiba

    Oncogene　38　(16)　3077-3092　2019年4月

    DOI： 10.1038/s41388-018-0647-8 　

    ISSN：0950-9232

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    Breast cancer gene 1 (BRCA1) is a tumor suppressor that is associated with hereditary breast and ovarian cancer. BRCA1 functions in DNA repair and centrosome regulation together with BRCA1-associated RING domain protein (BARD1), a heterodimer partner of BRCA1. Obg-like ATPase 1 (OLA1) was identified as a protein that interacts with BARD1. OLA1 regulates the centrosome by binding to and collaborating with BRCA1 and BARD1. We identified receptor for activated C kinase (RACK1) as a protein that interacts with OLA1. RACK1 directly bound to OLA1, the N-terminal region of BRCA1, and γ-tubulin, associated with BARD1, and localized the centrosomes throughout the cell cycle. Knockdown of RACK1 caused abnormal centrosomal localization of BRCA1 and abrogated centriole duplication. Overexpression of RACK1 increased the centrosomal localization of BRCA1 and caused centrosome amplification due to centriole overduplication. The number of centrioles in cells with two γ-tubulin spots was higher in cell lines derived from mammary tissue compared to those derived from other tissues. The effects of aberrant RACK1 expression level on centriole duplication were observed in cell lines derived from mammary tissue, but not in those derived from other tissues. Two BRCA1 variants, R133H and E143K, and a RACK1 variant, K280E, associated with cancer, which weakened the BRCA1-RACK1 interaction, interfered with the centrosomal localization of BRCA1 and reduced centrosome amplification induced by overexpression of RACK1. These results suggest that RACK1 regulates centriole duplication by controlling the centrosomal localization of BRCA1 in mammary tissue-derived cells and that this is dependent on the BRCA1-RACK1 interaction.

  32. Cep128 associates with Odf2 to form the subdistal appendage of the centriole. 国際誌 査読有り

    Hiroka Kashihara, Shuhei Chiba, Shin-Ichiro Kanno, Koya Suzuki, Tomoki Yano, Sachiko Tsukita

    Genes to cells : devoted to molecular & cellular mechanisms　24　(3)　231-243　2019年3月

    DOI： 10.1111/gtc.12668 　

    ISSN：1356-9597

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    The mother centriole in a cell has two appendages, the distal appendage (DA) and subdistal appendage (SDA), which have roles in generating cilia and organizing the cellular microtubular network, respectively. In the knockout (KO) cells of Odf2, the component of the DA and SDA, both appendages simultaneously disappear. However, the molecular mechanisms by which the DA and SDA form independently but close to each other downstream of Odf2 are unknown. Here, using super-resolution structured illumination microscopy (SR-SIM), we found that the signal for GFP-tagged Odf2 overlapped considerably with that of immunofluorescently labeled Cep128. We further found that Cep128 knockdown (KD) caused the dissociation of other SDA components from the centriole, including centriolin, Ndel1, ninein and Cep170, whereas Odf2 was still associated with the centriole. In contrast, the DA components remained associated with the centriole in Cep128 KD cells. Consistent with this observation, we identified Cep128 as an Odf2-interacting protein by immunoprecipitation. Taken with the finding that Cep128 deletion decreased the stability of centriolar microtubules, our results indicate that Cep128 associates with Odf2 in the hierarchical assembly of SDA components to elicit the microtubule-organizing function.

  33. Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes. 国際誌 査読有り

    Ikumi Umeki, Tetsuya Niihori, Taiki Abe, Shin-Ichiro Kanno, Nobuhiko Okamoto, Seiji Mizuno, Kenji Kurosawa, Keisuke Nagasaki, Makoto Yoshida, Hirofumi Ohashi, Shin-Ichi Inoue, Yoichi Matsubara, Ikuma Fujiwara, Shigeo Kure, Yoko Aoki

    Human genetics　138　(1)　21-35　2019年1月

    DOI： 10.1007/s00439-018-1951-7 　

    ISSN：0340-6717

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    RASopathies are a group of developmental disorders caused by mutations in genes that regulate the RAS/MAPK pathway and include Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome and other related disorders. Whole exome sequencing studies recently identified LZTR1, PPP1CB and MRAS as new causative genes in RASopathies. However, information on the phenotypes of LZTR1 mutation-positive patients and functional properties of the mutations are limited. To identify variants of LZTR1, PPP1CB, and MRAS, we performed a targeted next-generation sequencing and reexamined previously analyzed exome data in 166 patients with suspected RASopathies. We identified eight LZTR1 variants, including a de novo variant, in seven probands who were suspicious for NS and one known de novo PPP1CB variant in a patient with NS. One of the seven probands had two compound heterozygous LZTR1 variants, suggesting autosomal recessive inheritance. All probands with LZTR1 variants had cardiac defects, including hypertrophic cardiomyopathy and atrial septal defect. Five of the seven probands had short stature or intellectual disabilities. Immunoprecipitation of endogenous LZTR1 followed by western blotting showed that LZTR1 bound to the RAF1-PPP1CB complex. Cells transfected with a small interfering RNA against LZTR1 exhibited decreased levels of RAF1 phosphorylated at Ser259. These are the first results to demonstrate LZTR1 in association with the RAF1-PPP1CB complex as a component of the RAS/MAPK pathway.

  34. Karyopherin Alpha 2-Expressing Pancreatic Duct Glands and Intra-Islet Ducts in Aged Diabetic C414A-Mutant-CRY1 Transgenic Mice. 国際誌 査読有り

    Okano S, Yasui A, Kanno SI, Satoh K, Igarashi M, Nakajima O

    Journal of diabetes research　2019　7234549-7234549　2019年

    DOI： 10.1155/2019/7234549 　

    ISSN：2314-6745

  35. DNMTs and SETDB1 function as co-repressors in MAX-mediated repression of germ cell-related genes in mouse embryonic stem cells. 国際誌 査読有り

    Daiki Tatsumi, Yohei Hayashi, Mai Endo, Hisato Kobayashi, Takumi Yoshioka, Kohei Kiso, Shinichiro Kanno, Yuji Nakai, Ikuma Maeda, Kentaro Mochizuki, Makoto Tachibana, Haruhiko Koseki, Akihiko Okuda, Akira Yasui, Tomohiro Kono, Yasuhisa Matsui

    PloS one　13　(11)　e0205969　2018年

    DOI： 10.1371/journal.pone.0205969 　

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    In embryonic stem cells (ESCs), the expression of development-related genes, including germ cell-related genes, is globally repressed. The transcription factor MAX represses germ cell-related gene expression in ESCs via PCGF6-polycomb repressive complex 1 (PRC1), which consists of several epigenetic factors. However, we predicted that MAX represses germ cell-related gene expression through several additional mechanisms because PCGF6-PRC1 regulates the expression of only a subset of genes repressed by MAX. Here, we report that MAX associated with DNA methyltransferases (DNMTs) and the histone methyltransferase SETDB1 cooperatively control germ cell-related gene expression in ESCs. Both DNA methylation and histone H3 lysine 9 tri-methylation of the promoter regions of several germ cell-related genes were not affected by knockout of the PRC1 components, indicating that the MAX-DNMT and MAX-SETDB1 pathways are independent of the PCGF6-PRC1 pathway. Our findings provide insights into our understanding of MAX-based repressive mechanisms of germ cell-related genes in ESCs.

  36. mCRY1-C414A変異体過剰発現マウスの膵臓におけるtubular complexからの膵β細胞の新生とKPNA2の発現

    岡野 聡, 安井 明, 菅野 新一郎, 佐藤 賢一, 早坂 清, 五十嵐 雅彦, 中島 修

    生命科学系学会合同年次大会　2017年度　[2P-0788]　2017年12月

    出版者・発行元： 生命科学系学会合同年次大会運営事務局

  37. Nucleosome remodelling, DNA repair and transcriptional regulation build negative feedback loops in cancer and cellular ageing 査読有り

    Reiko Watanabe, Shin-ichiro Kanno, Amaneh Mohammadi Roushandeh, Ayako Ui, Akira Yasui

    PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES　372　(1731)　2017年10月

    DOI： 10.1098/rstb.2016.0473 　

    ISSN：0962-8436

    eISSN：1471-2970

  38. Dynamic feature of mitotic arrest deficient 2-like protein 2 (MAD2L2) and structural basis for its interaction with chromosome alignment-maintaining phosphoprotein (CAMP) 査読有り

    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年10月

    DOI： 10.1074/jbc.M117.804237 　

    ISSN：0021-9258

    eISSN：1083-351X

  39. DNA Polymerase Beta Participates in Mitochondrial DNA Repair 査読有り

    P. Sykora, S. Kanno, M. Akbari, T. Kulikowicz, B. A. Baptiste, G. S. Leandro, H. Lu, J. Tian, A. May, K. A. Becker, D. L. Croteau, D. M. Wilson, R. W. Sobol, A. Yasui, V. A. Bohr

    MOLECULAR AND CELLULAR BIOLOGY　37　(16)　2017年8月

    DOI： 10.1128/MCB.00237-17 　

    ISSN：0270-7306

    eISSN：1098-5549

  40. Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases 査読有り

    Tetsuro Matsuhashi, Takeya Sato, Shin-ichiro Kanno, Takehiro Suzuki, Akihiro Matsuo, Yuki Oba, Motoi Kikusato, Emi Ogasawara, Tai Kudo, Kosuke Suzuki, Osamu Ohara, Hiroko Shimbo, Fumika Nanto, Hiroaki Yamaguchi, Daisuke Saigusa, Yasuno Mukaiyama, Akiko Watabe, Koichi Kikuchi, Hisato Shima, Eikan Mishima, Yasutoshi Akiyama, Yoshitsugu Oikawa, Hsin-Jung Ho, Yukako Akiyama, Chitose Suzuki, Mitsugu Uematsu, Masaki Ogata, Naonori Kumagai, Masaaki Toyomizu, Atsushi Hozawa, Nariyasu Mano, Yuji Owada, Setsuya Aiba, Teruyuki Yanagisawa, Yoshihisa Tomioka, Shigeo Kure, Sadayoshi Ito, Kazuto Nakada, Ken-ichiro Hayashi, Hitoshi Osaka, Takaaki Abe

    EBIOMEDICINE　20　27-38　2017年6月

    DOI： 10.1016/j.ebiom.2017.05.016 　

    ISSN：2352-3964

  41. 分子の集合・離脱がつかさどる動的な細胞機能 中心体機能制御インターフェースとしてのアペンデージ構造の分子基盤

    柏原 宏香, 千葉 秀平, 菅野 新一郎, 月田 早智子

    日本細胞生物学会大会講演要旨集　69回　11-11　2017年5月

    出版者・発行元： (一社)日本細胞生物学会

  42. A pleckstrin homology-like domain is critical for F-actin binding and cofilin-phosphatase activity of Slingshot-1 査読有り

    Katsunori Takahashi, Haruka Okabe, Shin-ichiro Kanno, Tomoaki Nagai, Kensaku Mizuno

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　482　(4)　686-692　2017年1月

    DOI： 10.1016/j.bbrc.2016.11.095 　

    ISSN：0006-291X

    eISSN：1090-2104

  43. Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage 査読有り

    Takehiro Suzuki, Hiroaki Yamaguchi, Motoi Kikusato, Osamu Hashizume, Satoru Nagatoishi, Akihiro Matsuo, Takeya Sato, Tai Kudo, Tetsuro Matsuhashi, Kazutaka Murayanna, Yuki Ohba, Shun Watanabe, Shin-ichiro Kanno, Daichi Minaki, Daisuke Saigusa, Hiroko Shinbo, Nobuyoshi Mori, Akinori Yuri, Miyuki Yokoro, Eikan Mishima, Hisato Shima, Yasutoshi Akiyama, Yoichi Takeuchi, Koichi Kikuchi, Takafumi Toyohara, Chitose Suzuki, Takaharu Ichimura, Jun-ichi Anzai, Masahiro Kohzuki, Nariyasu Mario, Shigeo Kure, Teruyuki Yanagisawa, Yoshihisa Tomioka, Masaaki Toyomizu, Kohei Tsumoto, Kazuto Nakada, Joseph V. Bonventre, Sadayoshi Ito, Hitoshi Osaka, Ken-ichi Hayashi, Takaaki Abe

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY　27　(7)　1925-1932　2016年7月

    DOI： 10.1681/ASN.2015060623 　

    ISSN：1046-6673

    eISSN：1533-3450

  44. Activation of cytosolic Slingshot-1 phosphatase by gelsolin-generated soluble actin filaments 査読有り

    Katsunori Takahashi, Shin-ichiro Kanno, Kensaku Mizuno

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　454　(3)　471-477　2014年11月

    DOI： 10.1016/j.bbrc.2014.10.108 　

    ISSN：0006-291X

    eISSN：1090-2104

  45. Insulin receptor substrate-4 binds to Slingshot-1 phosphatase and promotes cofilin dephosphorylation. 国際誌 査読有り

    Yuta Homma, Shin-ichiro Kanno, Kazutaka Sasaki, Michiru Nishita, Akira Yasui, Tomoichiro Asano, Kazumasa Ohashi, Kensaku Mizuno

    The Journal of biological chemistry　289　(38)　26302-13　2014年9月19日

    DOI： 10.1074/jbc.M114.565945 　

    ISSN：0021-9258

    詳細を見る 詳細を閉じる

    Cofilin plays an essential role in cell migration and morphogenesis by enhancing actin filament dynamics via its actin filament-severing activity. Slingshot-1 (SSH1) is a protein phosphatase that plays a crucial role in regulating actin dynamics by dephosphorylating and reactivating cofilin. In this study, we identified insulin receptor substrate (IRS)-4 as a novel SSH1-binding protein. Co-precipitation assays revealed the direct endogenous binding of IRS4 to SSH1. IRS4, but not IRS1 or IRS2, was bound to SSH1. IRS4 was bound to SSH1 mainly through the unique region (amino acids 335-400) adjacent to the C terminus of the phosphotyrosine-binding domain of IRS4. The N-terminal A, B, and phosphatase domains of SSH1 were bound to IRS4 independently. Whereas in vitro phosphatase assays revealed that IRS4 does not directly affect the cofilin phosphatase activity of SSH1, knockdown of IRS4 increased cofilin phosphorylation in cultured cells. Knockdown of IRS4 decreased phosphatidylinositol 3-kinase (PI3K) activity, and treatment with an inhibitor of PI3K increased cofilin phosphorylation. Akt preferentially phosphorylated SSH1 at Thr-826, but expression of a non-phosphorylatable T826A mutant of SSH1 did not affect insulin-induced cofilin dephosphorylation, and an inhibitor of Akt did not increase cofilin phosphorylation. These results suggest that IRS4 promotes cofilin dephosphorylation through sequential activation of PI3K and SSH1 but not through Akt. In addition, IRS4 co-localized with SSH1 in F-actin-rich membrane protrusions in insulin-stimulated cells, which suggests that the association of IRS4 with SSH1 contributes to localized activation of cofilin in membrane protrusions.

  46. SWI/SNF Factors Required for Cellular Resistance to DNA Damage Include ARID1A and ARID1B and Show Interdependent Protein Stability 査読有り

    Reiko Watanabe, Ayako Ui, Shin-ichiro Kanno, Hideaki Ogiwara, Takahiro Nagase, Takashi Kohno, Akira Yasui

    CANCER RESEARCH　74　(9)　2465-2475　2014年5月

    DOI： 10.1158/0008-5472.CAN-13-3608 　

    ISSN：0008-5472

    eISSN：1538-7445

  47. Possible involvement of LKB1-AMPK signaling in non-homologous end joining 査読有り

    A. Ui, H. Ogiwara, S. Nakajima, S. Kanno, R. Watanabe, M. Harata, H. Okayama, C. C. Harris, J. Yokota, A. Yasui, T. Kohno

    ONCOGENE　33　(13)　1640-1648　2014年3月

    DOI： 10.1038/onc.2013.125 　

    ISSN：0950-9232

    eISSN：1476-5594

  48. The Novel Zinc Finger Protein dASCIZ Regulates Mitosis in Drosophila via an Essential Role in Dynein Light-Chain Expression 査読有り

    Olga Zaytseva, Nora Tenis, Naomi Mitchell, Shin-ichiro Kanno, Akira Yasui, Joerg Heierhorst, Leonie M. Quinn

    GENETICS　196　(2)　443-+　2014年2月

    DOI： 10.1534/genetics.113.159541 　

    ISSN：0016-6731

    eISSN：1943-2631

  49. The BRCA1/BARD1-Interacting Protein OLA1 Functions in Centrosome Regulation 査読有り

    Ayako Matsuzawa, Shin-ichiro Kanno, Masahiro Nakayama, Hironori Mochiduki, Leizhen Wei, Tatsuro Shimaoka, Yumiko Furukawa, Kei Kato, Shun Shibata, Akira Yasui, Chikashi Ishioka, Natsuko Chiba

    MOLECULAR CELL　53　(1)　101-114　2014年1月

    DOI： 10.1016/j.molcel.2013.10.028 　

    ISSN：1097-2765

  50. Damage response of XRCC1 at sites of DNA single strand breaks is regulated by phosphorylation and ubiquitylation after degradation of poly(ADP-ribose) 査読有り

    Leizhen Wei, Satoshi Nakajima, Ching-Lung Hsieh, Shinichiro Kanno, Mitsuko Masutani, Arthur S. Levine, Akira Yasui, Li Lan

    JOURNAL OF CELL SCIENCE　126　(19)　4414-4423　2013年10月

    DOI： 10.1242/jcs.128272 　

    ISSN：0021-9533

  51. Furry promotes acetylation of microtubules in the mitotic spindle by inhibition of SIRT2 tubulin deacetylase 査読有り

    Tomoaki Nagai, Masanori Ikeda, Shuhei Chiba, Shin-ichiro Kanno, Kensaku Mizuno

    JOURNAL OF CELL SCIENCE　126　(19)　4369-4380　2013年10月

    DOI： 10.1242/jcs.127209 　

    ISSN：0021-9533

  52. 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年9月

    出版者・発行元： (公社)日本生化学会

  53. Nucleoporin Nup188 is required for chromosome alignment in mitosis 査読有り

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

    CANCER SCIENCE　104　(7)　871-879　2013年7月

    DOI： 10.1111/cas.12159 　

    ISSN：1349-7006

  54. Nucleoporin Nup188 is required for chromosome alignment in mitosis 査読有り

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

    Cancer Science　104　(7)　871-879　2013年7月

    DOI： 10.1111/cas.12159 　

    ISSN：1347-9032 1349-7006

    eISSN：1349-7006

  55. Over-expression of ATR causes autophagic cell death 査読有り

    Chihiro Mori, Yoshihiro Yamaguchi, Mika Teranishi, Takako Takanami, Takahiro Nagase, Shinichiro Kanno, Akira Yasui, Atsushi Higashitani

    Genes to Cells　18　(4)　278-287　2013年4月

    DOI： 10.1111/gtc.12034 　

    ISSN：1356-9597 1365-2443

  56. 微小管結合蛋白質Furryによる微小管アセチル化制御機構

    永井 友朗, 千葉 秀平, 池田 真教, 菅野 新一郎, 水野 健作

    生化学　84　(6)　507-507　2012年6月

    出版者・発行元： (公社)日本生化学会

    ISSN：0037-1017

    eISSN：2189-0544

  57. Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair 査読有り

    Xue Zhang, Katsuyoshi Horibata, Masafumi Saijo, Chie Ishigami, Akiko Ukai, Shin-ichiro Kanno, Hidetoshi Tahara, Edward G. Neilan, Masamitsu Honma, Takehiko Nohmi, Akira Yasui, Kiyoji Tanaka

    NATURE GENETICS　44　(5)　593-+　2012年5月

    DOI： 10.1038/ng.2228 　

    ISSN：1061-4036

  58. WRNIP1 accumulates at laser light irradiated sites rapidly via its ubiquitin-binding zinc finger domain and independently from its ATPase domain 査読有り

    Hironoshin Nomura, Akari Yoshimura, Takato Edo, Shin-ichiro Kanno, Syusuke Tada, Masayuki Seki, Akira Yasui, Takemi Enomoto

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　417　(4)　1145-1150　2012年1月

    DOI： 10.1016/j.bbrc.2011.12.080 　

    ISSN：0006-291X

  59. Polynucleotide Kinase and Aprataxin-like Forkhead-associated Protein (PALF) Acts as Both a Single-stranded DNA Endonuclease and a Single-Stranded DNA 3 ' Exonuclease and Can Participate in DNA End Joining in a Biochemical System 査読有り

    Sicong Li, Shin-ichiro Kanno, Reiko Watanabe, Hideaki Ogiwara, Takashi Kohno, Go WatanabeO, Akira Yasui, Michael R. Lieber

    JOURNAL OF BIOLOGICAL CHEMISTRY　286　(42)　36368-36377　2011年10月

    DOI： 10.1074/jbc.M111.287797 　

    ISSN：0021-9258

  60. CAMP (C13orf8, ZNF828) is a novel regulator of kinetochore-microtubule attachment 査読有り

    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年1月

    DOI： 10.1038/emboj.2010.276 　

    ISSN：0261-4189

    eISSN：1460-2075

  61. The ACF1 Complex Is Required for DNA Double-Strand Break Repair in Human Cells 査読有り

    Li Lan, Ayako Ui, Satoshi Nakajima, Kotomi Hatakeyama, Mikiko Hoshi, Reiko Watanabe, Susan M. Janicki, Hideaki Ogiwara, Takashi Kohno, Shin-ichiro Kanno, Akira Yasui

    MOLECULAR CELL　40　(6)　976-987　2010年12月

    DOI： 10.1016/j.molcel.2010.12.003 　

    ISSN：1097-2765

  62. Solution structure of a zinc-finger domain that binds to poly-ADP-ribose 査読有り

    Shin Isogai, Shin-Ichiro Kanno, Mariko Ariyoshi, Hidehito Tochio, Yutaka Ito, Akira Yasui, Masahiro Shirakawa

    Genes to Cells　15　(2)　101-110　2010年2月

    DOI： 10.1111/j.1365-2443.2009.01369.x 　

    ISSN：1356-9597 1365-2443

  63. Phosphorylation of protein phosphatase 2C zeta by c-Jun NH2-terminal kinase at Ser(92) attenuates its phosphatase activity 査読有り

    Kenjiro Awano, Kazutaka Amano, Yuko Nagaura, Shin-ichiro Kanno, Seishi Echigo, Shinri Tamura, Takayasu Kobayashi

    BIOCHEMISTRY　47　(27)　7248-7255　2008年7月

    DOI： 10.1021/bi800067p 　

    ISSN：0006-2960

  64. A polycomb group protein, PHF1, is involved in the response to DNA double-strand breaks in human cell 査読有り

    Zehui Hong, Jie Jiang, Li Lan, Satoshi Nakajima, Shin-ichiro Kanno, Haruhiko Koseki, Akira Yasui

    NUCLEIC ACIDS RESEARCH　36　(9)　2939-2947　2008年5月

    DOI： 10.1093/nar/gkn146 　

    ISSN：0305-1048

  65. HMGB1 is a cofactor in mammalian base excision repair 査読有り

    Rajendra Prasad, Yuan Liu, Leesa J. Deterding, Vladimir P. Poltoratsky, Padmini S. Kedar, Julie K. Horton, Shin-Ichiro Kanno, Kenjiro Asagoshi, Esther W. Hou, Svetlana N. Khodyreva, Olga I. Lavrik, Kenneth B. Tomer, Akira Yasui, Samuel H. Wilson

    MOLECULAR CELL　27　(5)　829-841　2007年9月

    DOI： 10.1016/j.molcel.2007.06.029 　

    ISSN：1097-2765

  66. A novel human AP endonuclease with conserved zinc-finger-like motifs involved in DNA strand break responses 査読有り

    Shin-ichiro Kanno, Hiroyuki Kuzuoka, Shigeru Sasao, Zehui Hong, Li Lan, Satoshi Nakajima, Akira Yasui

    EMBO JOURNAL　26　(8)　2094-2103　2007年4月

    DOI： 10.1038/sj.emboj.7601663 　

    ISSN：0261-4189

  67. Replication-dependent and -independent responses of RAD18 to DNA damage in human cells 査読有り

    Satoshi Nakajima, Li Lan, Shin-ichiro Kanno, Noriko Usami, Katsumi Kobayashi, Masahiko Mori, Tadahiro Shiomi, Akira Yasui

    JOURNAL OF BIOLOGICAL CHEMISTRY　281　(45)　34687-34695　2006年11月

    DOI： 10.1074/jbc.M605545200 　

    ISSN：0021-9258

  68. Light-induced DNA damage and tolerance for the survival of nucleotide excision repair-deficient human cells 査読有り

    S Nakajima, L Lan, S Kanno, M Takao, K Yamamoto, APM Eker, A Yasui

    JOURNAL OF BIOLOGICAL CHEMISTRY　279　(45)　46674-46677　2004年11月

    DOI： 10.1074/jbc.M406070200 　

    ISSN：0021-9258

  69. Functional and physical interactions between ERCC1 and MSH2 complexes for resistance to cis-diamminedichloroplatinum(II) in mammalian cells 査読有り

    L Lan, T Hayashi, RM Rabeya, S Nakajima, S Kanno, M Takao, T Matsunaga, M Yoshino, M Ichikawa, HT Riele, S Tsuchiya, K Tanaka, A Yasui

    DNA REPAIR　3　(2)　135-143　2004年2月

    DOI： 10.1016/j.dnarep.2003.10.005 　

    ISSN：1568-7864

  70. Dna damage, repair and aging 査読有り

    Akira Yasui, Shin-Ichiro Kanno, Masashi Takao

    Japanese Journal of Geriatrics　40　(6)　593-595　2003年

    DOI： 10.3143/geriatrics.40.593 　

    ISSN：0300-9173

  71. A back-up glycosylase in Nth1 knock-out mice is a functional Nei (endonuclease VIII) homologue 査読有り

    M Takao, S Kanno, K Kobayashi, QM Zhang, S Yonei, GTJ van der Horst, A Yasui

    JOURNAL OF BIOLOGICAL CHEMISTRY　277　(44)　42205-42213　2002年11月

    DOI： 10.1074/jbc.M206884200 　

    ISSN：0021-9258

  72. Novel nuclear and mitochondrial glycosylases revealed by disruption of the mouse Nth1 gene encoding an endonuclease III homolog for repair of thymine glycols 査読有り

    M Takao, S Kanno, T Shiromoto, R Hasegawa, H Ide, S Ikeda, AH Sarker, S Seki, JZ Xing, XC Le, M Weinfeld, K Kobayashi, J Miyazaki, M Muijtjens, JHJ Hoeijmakers, G van der Horst, A Yasui

    EMBO JOURNAL　21　(13)　3486-3493　2002年7月

    DOI： 10.1093/emboj/cdf350 　

    ISSN：0261-4189

  73. チミングリコールを切るマウスDNAグリコシラーゼ遺伝子のノックアウトの影響について

    高尾雅, 菅野新一郎, 安井明

    加齢医学研究所雑誌　53　(1〜2)　14-14　2002年2月

  74. Activation of c-Jun amino-terminal kinase is required for retinoic acid-induced neural differentiation of P19 embryonal carcinoma cells 査読有り

    H Wang, S Ikeda, S Kanno, LM Guang, M Ohnishi, M Sasaki, T Kobayashi, S Tamura

    FEBS LETTERS　503　(1)　91-96　2001年8月

    DOI： 10.1016/S0014-5793(01)02699-0 　

    ISSN：0014-5793

  75. Cellular responses and repair of single-strand breaks introduced by UV damage endonuclease in mammalian cells 査読有り

    S Okano, S Kanno, S Nakajima, A Yasui

    JOURNAL OF BIOLOGICAL CHEMISTRY　275　(42)　32635-32641　2000年10月

    DOI： 10.1074/jbc.M004085200 　

    ISSN：0021-9258

  76. Repair of apurinic/apyrimidinic sites by UV damage endonuclease; a repair protein for UV and oxidative damage 査読有り

    S Kanno, S Iwai, M Takao, A Yasui

    NUCLEIC ACIDS RESEARCH　27　(15)　3096-3103　1999年8月

    DOI： 10.1093/nar/27.15.3096 　

    ISSN：0305-1048

  77. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms 査読有り

    GTJ van der Horst, M Muijtjens, K Kobayashi, R Takano, S Kanno, M Takao, J de Wit, A Verkerk, APM Eker, D van Leenen, R Buijs, D Bootsma, JHJ Hoeijmakers, A Yasui

    NATURE　398　(6728)　627-630　1999年4月

    DOI： 10.1038/19323 　

    ISSN：0028-0836

  78. マウス光回復酵素ホモローグの機能解析

    菅野新一郎, 岡野聡, 小林久美子, 高野りや, 高尾雅, 安井明, 大畠慶子, HorstBert van der

    加齢医学研究所雑誌　50　(3-4)　114-115　1999年

  79. A putative blue-light receptor from Drosophila melanogaster 査読有り

    S Okano, S Kanno, M Takao, APM Eker, K Isono, Y Tsukahara, A Yasui

    PHOTOCHEMISTRY AND PHOTOBIOLOGY　69　(1)　108-113　1999年1月

    DOI： 10.1562/0031-8655(1999)069<0108:APBLRF>2.3.CO;2 　

    ISSN：0031-8655

    eISSN：1751-1097

  80. CPD及び64光回復酵素遺伝子のヒト細胞への導入と発現による紫外線細胞死への影響

    中嶋敏, 高野りや, 菅野新一郎, 高尾雅, 山本和生, 安井明

    日本放射線影響学会大会講演要旨集　41回　141-141　1998年11月

  81. Characterization of photolyase/blue-light receptor homologs in mouse and human cells 査読有り

    K Kobayashi, S Kanno, R Smit, GTJ van der Horst, M Takao, A Yasui

    NUCLEIC ACIDS RESEARCH　26　(22)　5086-5092　1998年11月

    DOI： 10.1093/nar/26.22.5086 　

    ISSN：0305-1048

  82. PHOSPHORYLATION OF MG2+-DEPENDENT PROTEIN PHOSPHATASE-ALPHA (TYPE-2C-ALPHA) BY CASEIN KINASE-II 査読有り

    T KOBAYASHI, S KANNO, T TERASAWA, T MURAKAMI, M OHNISHI, K OHTSUKI, A HIRAGA, S TAMURA

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　195　(1)　484-489　1993年8月

    ISSN：0006-291X

    eISSN：1090-2104

  83. グリチルリチンによる水ほう性口内炎ウイルス結合性プロテインキナーゼ活性阻害 査読有り

    菅野新一郎

    医学の歩み　148　(2)　113-114　1989年

︎全件表示 ︎最初の5件までを表示

MISC 35

  1. CK2αはDysferlinに結合しキナーゼ活性を介して骨格筋の細胞膜修復を促進する

    中村 尚子, 鈴木 直輝, 小野 洋也, 菅野 新一郎, 山中 玲, 井泉 瑠美子, 高橋 俊明, 三宅 克也, 青木 正志

    日本筋学会学術集会プログラム・抄録集　11回　99-99　2025年8月

    出版者・発行元： (一社)日本筋学会

    ISSN： 2433-975X

  2. Spasmolytic Polypeptide-Expressing Metaplasia-Like Features of Intraislet Ducts in ZincBinding Site-Mutated CRY1-Expressing Diabetic Mice

    Satoshi Okano, Akira Yasui, Shin-Ichiro Kanno, Yu Sasaki, Kennichi Satoh, Masahiko Igarashi, Osamu Nakajima

    DIABETES　74　2025年6月

    DOI： 10.2337/db25-1805-P 　

    ISSN： 0012-1797

    eISSN： 1939-327X

  3. 新規ジスフェリン結合キナーゼが骨格筋の細胞膜修復を促進する

    NAKAMURA Naoko, SUZUKI Naoki, ONO Hiroya, KANNO Shin-ichiro, YAMANAKA Rei, IZUMI Rumiko, TAKAHASHI Toshiaki, FUNAYAMA Yukino, SAITOH Saki, HARADA Ryuhei, OHNO Akiyuki, MITSUZAWA Shio, SHIJO Tomomi, IKEDA Kensuke, WARITA Hitoshi, MIYAKE Katsuya, AOKI Masashi

    日本神経学会学術大会プログラム・抄録集　65th　2024年

  4. 骨格筋の細胞膜修復を促進する新規ジスフェルリン結合タンパクの探索

    中村尚子, 鈴木直輝, 小野洋也, 菅野新一郎, 山中玲, 井泉瑠美子, 高橋俊明, 三宅克也, 青木正志

    日本分子生物学会年会プログラム・要旨集(Web)　47th　2024年

  5. RASプロテオスタシス破綻に伴うが発がん促進機構の解明

    阿部太紀, 菅野新一郎, 新堀哲也, 寺尾美穂, 高田修治, 青木洋子

    日本薬学会年会要旨集(Web)　144th　2024年

    ISSN： 0918-9823

  6. Noonan症候群原因遺伝子産物LZTR1によるRAS分解促進機構の解明

    阿部太紀, 梅木郁美, 菅野新一郎, 井上晋一, 新堀哲也, 青木洋子

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

  7. 細胞膜修復機構に着目したdysferlin異常症の病態解明と治療法開発

    小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 井泉 瑠美子, 高橋 俊明, 北嶋 康雄, 長名 シオン, 秋山 徹也, 池田 謙輔, 四條 友望, 光澤 志緒, 割田 仁, 永富 良一, 荒木 伸一, 安井 明, 林 由起子, 三宅 克也, 青木 正志

    日本筋学会学術集会プログラム・抄録集　4回　160-160　2018年8月

    出版者・発行元： 日本筋学会

    ISSN： 2433-975X

  8. 細胞膜修復機構に着目したdysferlin異常症の病態解明と治療法開発

    小野洋也, 小野洋也, 鈴木直輝, 菅野新一郎, 川原玄理, 井泉瑠美子, 高橋俊明, 北嶋康雄, 長名シオン, 秋山徹也, 池田謙輔, 四條友望, 光澤志緒, 割田仁, 永富良一, 荒木伸一, 安井明, 林由起子, 三宅克也, 三宅克也, 青木正志

    日本筋学会学術集会プログラム・抄録集　4th　160-160　2018年8月1日

    出版者・発行元： 日本筋学会

    ISSN： 2433-975X

  9. ミトコンドリア病新規治療薬MA‐5はATP合成酵素のダイマー化によりATP合成を促進させ細胞保護効果を発揮する

    松橋徹郎, 佐藤岳哉, 菅野新一郎, 鈴木健弘, 及川善嗣, 菊地晃一, 南都文香, 何欣蓉, 秋山由雅子, 鈴木千登世, 三島英換, 呉繁夫, 林謙一郎, 中田和人, 小坂仁, 阿部高明

    日本ミトコンドリア学会年会要旨集　17th　54　2017年11月6日

  10. 筋ジストロフィー治療研究の最前線

    青木 正志, 井泉 瑠美子, 高橋 俊明, 小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 北嶋 康雄, 長名 シオン, 秋山 哲也, 池田 謙輔, 四條 友望, 光澤 志緒, 割田 仁, 永富 良一, 荒木 伸一, 安井 明, 林 由起子, 三宅 克也, 武田 篤

    筋ジストロフィー医療研究　4　18-18　2017年10月

    出版者・発行元： 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  11. 細胞膜修復機構に着目したジスフェルリン異常症の病態解明と治療法開発

    小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 井泉 瑠美子, 高橋 俊明, 北嶋 康雄, 長名 シオン, 秋山 徹也, 池田 謙輔, 四條 友望, 光澤 志緒, 割田 仁, 永富 良一, 荒木 伸一, 安井 明, 林 由起子, 三宅 克也, 青木 正志

    筋ジストロフィー医療研究　4　87-87　2017年10月

    出版者・発行元： 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  12. 細胞膜修復機構に着目したDysferlinopathyの病態解明と治療法開発

    小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 井泉 瑠美子, 高橋 俊明, 北嶋 康雄, 長名 シオン, 秋山 徹也, 池田 謙輔, 四條 友望, 光澤 志緒, 割田 仁, 永富 良一, 荒木 伸一, 安井 明, 林 由起子, 三宅 克也, 青木 正志

    日本筋学会学術集会プログラム・抄録集　3回　141-141　2017年7月

    出版者・発行元： 日本筋学会

    ISSN： 2433-975X

  13. 細胞膜修復機構に着目したDysferlinopathyの病態解明と治療法開発

    小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 井泉 瑠美子, 高橋 俊明, 北嶋 康雄, 長名 シオン, 秋山 徹也, 池田 謙輔, 四條 友望, 光澤 志緒, 割田 仁, 永富 良一, 荒木 伸一, 安井 明, 林 由起子, 三宅 克也, 青木 正志

    日本筋学会学術集会プログラム・抄録集　3回　141-141　2017年7月

    出版者・発行元： 日本筋学会

    ISSN： 2433-975X

  14. Reduced Expression of KPAN2 and Dysfunction of beta-Cells in C414A-CRY1 Transgenic Mice

    Satoshi Okano, Akira Yasui, Shinichiro Kanno, Kiyoshi Hayasaka, Masahiko Igarashi, Osamu Nakajima

    DIABETES　66　A572-A572　2017年6月

    ISSN： 0012-1797

    eISSN： 1939-327X

  15. 筋ジストロフィー関連疾患の基盤的診断・治療開発研究 Dysferlinopathyおよび類似疾患の次世代シークエンサーを用いた診断および結合蛋白に注目した病態研究

    青木正志, 小野洋也, 井泉瑠美子, 鈴木直輝, 菅野新一郎, 高橋俊明, 割田仁, 加藤昌昭, 西山亜由美, 島倉奈緒子, 舟山亮, 中山啓子, 新堀哲也, 青木洋子, 三宅克也, 三宅克也

    筋ジストロフィー関連疾患の基盤的診断・治療開発研究 平成26-28年度 総括研究報告書　18‐20　2017年

  16. Research for the pathogenesis and therapy of dysferlinopathy using proteomics approach

    H. Ono, N. Suzuki, S. Kanno, K. Miyake, Y. Kitajima, R. Izumi, T. Takahashi, H. Warita, A. Yasui, M. Aoki

    NEUROMUSCULAR DISORDERS　26　S151-S152　2016年10月

    DOI： 10.1016/j.nmd.2016.06.240 　

    ISSN： 0960-8966

    eISSN： 1873-2364

  17. Anomalous Ductal Structure in the Islet of Diabetic Cysteine414-Alanine-mCRY1 Transgenic Mice

    Satoshi Okano, Akira Yasui, Shin-Ichiro Kanno, Kiyoshi Hayasaka, Masahiko Igarashi, Osamu Nakajima

    DIABETES　65　A530-A530　2016年6月

    ISSN： 0012-1797

    eISSN： 1939-327X

  18. 新規BRCA1/BARD1結合分子OLA1は中心体複製機構に関与する

    千葉奈津子, 菅野新一郎, 藤田拡樹, 安井明, 石岡千加史, 松澤綾子

    日本分子生物学会年会プログラム・要旨集(Web)　37th　3W10-9(3P-0408) (WEB ONLY)　2014年

  19. 染色体分配における核膜孔複合体構成団子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年8月25日

    出版者・発行元： (公社)日本生化学会

    ISSN： 0037-1017

  20. Furryによるチューブリン脱アセチル化酵素SIRT2の活性制御と分裂期紡錘体微小管のアセチル化に対する役割

    永井友朗, 池田真教, 千葉秀平, 菅野新一郎, 水野健作

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

  21. Furry is a positive regulator of microtubule acetylation in mitotic spindle

    T. Nagai, S. Chiba, M. Ikeda, S-I. Kanno, A. Yasui, K. Ohashi, K. Mizuno

    MOLECULAR BIOLOGY OF THE CELL　23　2012年

    ISSN： 1059-1524

    eISSN： 1939-4586

  22. NDR is required for ciliogenesis through the phosphorylation of Rabin8

    S. Chiba, Y. Amagai, S. Kanno, A. Yasui, M. Fukuda, K. Mizuno

    MOLECULAR BIOLOGY OF THE CELL　22　2011年

    ISSN： 1059-1524

  23. DNA損傷に続くBRCA1/BARD1発現レベルの制御メカニズム(Regulatory mechanism of the level of BRCA1/BARD1 expression following DNA damage)

    柵木 絵美子, 菅野 新一郎, 松澤 綾子, 柏木 梨佐, 柴田 峻, 古川 裕美子, 魏 雷震, 石岡 千加史, 安井 明, 千葉 奈津子

    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　83回・33回　2P-0462　2010年12月

    出版者・発行元： (公社)日本生化学会

  24. Rabin8のリン酸化制御と一次繊毛形成における機能解析

    天貝佑太, 千葉秀平, 菅野祐哉, 菅野新一郎, 安井明, 福田光則, 水野健作

    生化学　2010年

    ISSN： 0037-1017

  25. 新規亜鉛フィンガーモチーフCYRドメインの構造機能解析

    磯貝信, 有吉眞理子, 杤尾豪人, 菅野新一郎, 池上貴久, 伊藤隆, 安井明, 白川昌宏

    生化学　4T4-5　2008年

    ISSN： 0037-1017

  26. 新規亜鉛フィンガーモチーフCYRドメインの構造機能解析

    磯貝信, 有吉眞理子, 杤尾豪人, 池上貴久, 伊藤隆, 菅野新一郎, 安井明, 白川昌宏

    Abstr Annu Meet NMR Soc Jpn　46th　202-203　2007年9月11日

  27. DNA損傷・修復と老化 (日本老年医学会雑誌)

    安井明, 菅野新一郎, 高尾雅

    日本老年医学会雑誌　40　(6)　593-595　2003年11月

  28. Novel nuclear and mitochondrial glycosylases revealed by disruption of the mouse Nth1 gene encoding an endonuclease III homolog for repair of thymine glycols (vol 21, pg 3486, 2002)

    M Takao, S Kanno, T Shiromoto, R Hasegawa, H Ide, S Ikeda, AH Sarker, S Seki, JZ Xing, XC Le, M Weinfeld, K Kobayashi, J Miyazaki, M Muijtjens, JHJ Hoeijmakers, G van der Horst, A Yasui

    EMBO JOURNAL　21　(16)　4391-4391　2002年8月

    ISSN： 0261-4189

  29. 寿命と老化を決める遺伝子 活性酸素によるDNA損傷と修復欠損 (基礎老化研究)

    安井明, 菅野新一郎, 高尾雅

    基礎老化研究　26　(1)　13-13　2002年4月

  30. Cellular responses and repair of single-strand breaks introduced by UV damage endonuclease in mammalian cells :

    OKANO Satoshi, KANNO Shin-ichiro, NAKAJIMA Satoshi, YASUI Akira

    Journal of radiation research　41　(4)　462-462　2000年

    出版者・発行元： the Japan Radiation Research Society

    ISSN： 0449-3060

  31. Alternative Splicing of Human DNA Glycosylases and IR Response :

    TAKAO Masashi, KANNO Shin-ichiro, YASUI Akira

    Journal of radiation research　41　(4)　393-393　2000年

    出版者・発行元： the Japan Radiation Research Society

    ISSN： 0449-3060

  32. マウスCRY蛋白質の機能解析

    菅野 新一郎, 小林 久美子, 高尾 雅, 岸上 明生, 岡野 聡, 岡村 均, VAN DER HORST Gijsbertus T. J., 安井 明

    日本時間生物学会会誌: Journal of Chronobiology　5　(2)　43-43　1999年10月1日

    ISSN： 1344-9389

  33. Expression of CPD and 64 photolyase Genes in Human Cells :

    NAKAJIMA Satoshi, TAKANO Riya, KANNO Shin-ichiro, TAKAO Masashi, YAMAMOTO Kazuo, YASUI Akira

    Journal of radiation research　39　(4)　365-365　1998年

    出版者・発行元： the Japan Radiation Research Society

    ISSN： 0449-3060

  34. Cloning and characterization of photolyase homolog from mouse : Cloning and characterization of photolyase homolog from mouse

    KOBAYASHI Kumiko, KANNO Shinichiro, YASUHIRA Shinji, TAKAO Masashi, YASUI Akira

    Journal of radiation research　37　(4)　340-340　1996年

    出版者・発行元： the Japan Radiation Research Society

    ISSN： 0449-3060

  35. BIOCHEMICAL-CHARACTERIZATION OF THE MEMBRANE-ASSOCIATED PHOSPHORYLATING PROTEINS INVOLVED IN THE ANTIPROLIFERATIVE EFFECT OF HUMAN RECOMBINANT INTERFERON-ALPHA-2A (RIFN-ALPHA-2A) IN DAUDI CELLS

    M YOKOYAMA, K KOIKE, SI KANNO, K OHTSUKI

    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE　160　(4)　343-359　1990年4月

    ISSN： 0040-8727

    eISSN： 1349-3329

︎全件表示 ︎最初の5件までを表示

共同研究・競争的資金等の研究課題 13

  1. 内皮-平滑筋相互作用におけるRNF213の役割ともやもや病発症機序解明

    新妻 邦泰, Rashad Sherif, 菅野 新一郎, 森戸 大介, 豊原 敬文, 阿部 高明, 坂田 洋之

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (A)

    研究機関：Tohoku University

    2023年4月1日 ～ 2026年3月31日

  2. 時計蛋白質CRY1の変異が惹起する膵β細胞の老化様変化と膵島機能異常の解明

    岡野 聡, 中島 修, 安井 明, 佐藤 賢一, 早坂 清, 菅野 新一郎, 五十嵐 雅彦

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (C)

    研究機関：Yamagata University

    2015年4月1日 ～ 2018年3月31日

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    代表者は、時計蛋白質CRY1の亜鉛結合部位変異体を過剰発現させることで 新しいMODY様の糖尿病モデルマウスを確立し、 CRYの研究グループを組織し、その膵β細胞機能障害の主要な分子機序を明らかにしてきた。 本研究では、 当該マウスでは加齢と共に繊維化を伴う膵構造変化が進行すこと、及び膵島内にムチン産生性の膵管異型細胞が生成されることを新たに示した。 膵β細胞の細胞老化様の性質が、それらの加齢依存的な異常の進展の本質であると考えられる。KPNA2タンパク質に着目した実験も実施し、 KPNA2は特にアダルト期のマウス膵島に於いて、膵β細胞の機能維持に重要な役割を果たすことを示す結果を得た。

  3. 効率的な染色体整列による染色体安定性の維持機構の解明

    田中 耕三, 池田 真教, 安井 明, 菅野 新一郎

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (B)

    研究機関：Tohoku University

    2015年4月1日 ～ 2018年3月31日

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    本研究では、染色体が紡錘体上で整列して正確に分配されるしくみについて研究を行った。染色体整列の課程では、染色体上の動原体が紡錘体を形成する微小管の側面に結合する状態(側面結合)を経て、末端に結合する状態(末端結合)に移行する。そこで側面結合に関与する分子の探索を行い、モーター分子であるダイニンやCENP-Eの関与を明らかにした。また側面結合と末端結合が協調的にはたらくことで、染色体が整列して正確に分配されることがわかった（Sci Rep, 2018）。さらに染色体安定性維持に重要な紡錘体チェックポイントに、分裂期キナーゼであるPlk1が関与することを明らかにした（Sci Rep, 2017）。

  4. 新規APエンドヌクレアーゼAPNXのアセチル基転移活性とTip60活性化の解明

    菅野 新一郎

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (C)

    研究機関：Tohoku University

    2014年4月1日 ～ 2017年3月31日

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    我々はDNA修復機構であるNHEJに関わる新規DNA修復酵素PALFの発見からCYR domainを発見した。このCYR domainをもつ遺伝子を調べたところショウジョウバエで未知タンパク質を発見し、そのヒトオルソログ(APNX)を発見した。ショウジョウバエとヒトオルソログタンパク質がDNA修復酵素である可能性を前提にこれらのタンパク質の活性を調べた。その結果AP endonucleaseの活性をつこと、また、アセチル基転移酵素活性の二つの活性をもつ稀なdual fanction enzymeであることがわかった。

  5. 新規癌抑制分子の細胞分裂制御能の解析による癌抑制能の解明と癌治療法の開発

    千葉 奈津子, 渡邊 利雄, 菅野 新一郎, 杉本 亜砂子

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (B)

    研究機関：Tohoku University

    2012年4月1日 ～ 2016年3月31日

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    家族性乳がん原因遺伝子BRCA1は、変異により乳がん、卵巣がんを引き起こすがん抑制遺伝子である。我々は、BRCA1に結合する新規分子Obg-like ATPase 1 (OLA1)を同定し、その機能を解析したところ、OLA1がBRCA1や中心体の主要な構成因子と直接結合し、中心体の複製を制御することを明らかにした。また、OLA1の乳がん細胞株由来の変異体ではBRCA1との結合能が消失して中心体の制御能が障害され、BRCA1の家族性乳がん由来の点突然変異で、OLA1との直接結合能が著しく低下し、中心体制御能に異常を来すことが明らかになった。

  6. 新規分子ＣＡＭＰを中心とした染色体安定性システムの解明

    田中 耕三, 伊藤 剛, 広田 亨, 安井 明, 菅野 新一郎

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (B)

    研究機関：Tohoku University

    2012年4月1日 ～ 2015年3月31日

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    本研究では、染色体の均等な分配を保証する機構（染色体安定性システム）について以下の成果を得た。1) 新規分子CAMPは、HP1, REV7, POGZと複合体を形成して機能し、またCAMPノックアウトマウスは出生直後に死亡することがわかった。2) 核膜複合体構成因子の1つであるNup188が、NuMAを紡錘体極に局在させることにより染色体分配に関与することが明らかになった。3) 微小管結合因子CLIP-170が、Plk1の動原体への局在などにより染色体分配を制御していることが判明した。4) KidとCENP-Eという2つのモーター分子が、紡錘体上での染色体整列に機能していることがわかった。

  7. 細胞分裂期に作用する抗がん剤に対する耐性克服のための基礎的研究

    田中 耕三, 伊藤 剛, 広田 亨, 安井 明, 菅野 新一郎

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Challenging Exploratory Research

    研究機関：Tohoku University

    2012年4月1日 ～ 2014年3月31日

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    本研究では、抗がん剤により細胞周期停止が持続した後に起こる細胞死に関与する分子を同定することを目的とした。我々が発見した新規分子CAMPをノックダウンした細胞を微小管阻害剤で処理したところ、がん細胞特異的に細胞周期停止持続後の細胞死の促進が観察された。がん細胞株ではCAMPの発現が高い傾向が見られ、がん細胞の生存がCAMPに依存している可能性が考えられた。またCAMPをノックダウンした細胞ではアポトーシスを抑制する機能をもつBcl-2ファミリー分子であるMcl-1およびBcl-xLの発現が低下していることがわかり、CAMPが抗がん剤治療のターゲットとなる可能性が考えられた。

  8. ２つの新規ヒトＡＰエンドヌクレアーゼと新規ポリＡＤＰリボシル化酵素の機能

    菅野 新一郎

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (C)

    研究機関：Tohoku University

    2011年 ～ 2013年

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    ゲノムの安定性はDNA修復機構とチェックポイント機構に支えられ維持されている。私たちは新規のDNA修復酵素と考えられるショウジョウバエCG1218とそのヒト遺伝子C4orf27を見いだした。これらのタンパク質をクローニングしその性質を調べた結果、これらのタンパク質はレーザーで作った核ないのDNA 損傷部位に集積すること、また、AP endonucleaseの活性があること、C4orf27を免疫沈降したところ、PARP1とヘテロダイマーを形成していることがわかった。また、siRNAでノックダウンした細胞は酸化ストレスに感受性を示すことから新規DNA修復酵素であることがわかった。

  9. DNA 修復遺伝子発現制御機構の解明:新規因子 CXXC5 に着目した制御複合体の解析

    有田 通恒, 菅野 新一郎

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (C)

    研究機関：Toho University

    2010年 ～ 2012年

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    CXXC5 タンパクは DNA に直接結合し DNA 修復遺伝子 MLH1 の転写を正に制御する因子であることが明らかとなった.また,CXXC5 は他のタンパク性因子 SYF2 や HNRNPH1 と相互作用し,協同して MLH1 の転写制御に関与することも示唆された.低酸素下ではこれら 3 因子のタンパク量はいずれも低下するが,強制的な発現によりこれら因子の低下を補完すると低酸素性 MLH1発現抑制が緩和された.従って,これら 3 因子が介在する MLH1 の低酸素性低下の新たな経路が明らかとなった.

  10. 新たな乳癌治療のための家族性乳癌原因遺伝子の新規関連分子の機能解析

    千葉 奈津子, 菅野 新一郎

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (C)

    研究機関：Tohoku University

    2009年 ～ 2011年

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    家族性乳癌原因遺伝子BRCA1は、変異により乳癌、卵巣癌を引き起こす癌抑制遺伝子で、近年は散発性乳癌との関わりも注目されている。BRCA1は、BARD1とヘテロダイマーを形成し、DNA修復や中心体制御に関与する。我々はBARD1に結合する新規分子BARD1-interacting protein(BIP)を同定し、その機能を解析した。その結果、BIPがBRCA1、BARD1とともに中心体制御や細胞質分裂で重要な機能を担うことを明らかにした。

  11. 染色体安定性システムを構成する分子ネットワークの解明

    田中 耕三, 安井 明, 伊藤 剛, 菅野 新一郎, 田中 智之

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (C)

    研究機関：Tohoku University

    2009年 ～ 2011年

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    本研究では、染色体の安定な維持に関与する分子の探索を行い、新規分子CAMP(chromosome alignment-maintaining phosphoprotein ; C13orf8, ZNF828)を同定した。CAMPはキネトコアと微小管の結合を維持することにより染色体分配に寄与するものと考えられた。またCAMPの変異とがん化との関連が示唆された。

  12. 新規ヒトAPエンドヌクレアーゼの機能

    菅野 新一郎

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (C)

    研究機関：Tohoku University

    2008年 ～ 2010年

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    DUF2228 familyは線虫からヒトまでの真核生物(酵母やカビを除く)に分布し、よく保存された配列を持つタンパク質で、機能が未知のprotein familyである。昆虫や線虫の一部では保存された配列以外にアミノ酸配列N端側にCYR motif (C2H2 zinc finger motif)を持っている。CYR motifは初めDNA修復酵素のPALF(APLF)で我々が同定したモチーフで、アミノ酸配列N 端あるいはC端に単独であるCYR motifはDNA damageによって活性化されたPARP1によって作られるpoly(ADP-ribose)鎖(PAR)に結合する性質を持っている。我々は、このfamilyメンバーのうちアミノ酸配列N端側にCYR motifをもつショウジョウバエのCG1218-PAとCYR motifを欠いたタイプのヒトのC4orf27(APNX)をクローニングしその機能を解析した。その結果、1)GFP-CG1218-PAはPAR依存性に核内のDNA損傷部位に集積するがヒトGFP-APNXはPAR非依存性に損傷に集積する。2)APNXはヒト細胞内でPARP1とヘテロダイマーを形成し、PARP1依存的に損傷に集積する。3)CG1218-PAおよびAPNXは脱塩基部位(APサイト)の5' 側に3'-OHのニックを入れるAP-endo/exonuclease活性をもつ酵素であること。などが明らかになった。さらにAPNXのノックダウンでヒト細胞がアルキル化剤MMSに感受性になることからこのタンパク質は塩基除去修復やDNA単鎖切断修復に関わる新規のDNA修復酵素であることが明らかになった。

  13. 蛋白のポリADPリボシル化により制御される新しいDNA損傷応答機構

    安井 明, 中嶋 敏, 菅野 新一郎, 田中 耕三, 高尾 雅

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research

    研究種目：Grant-in-Aid for Scientific Research (A)

    研究機関：Tohoku University

    2008年 ～ 2010年

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    最も発生頻度の高いDNA単鎖切断と最も深刻なDNA二重鎖切断がヒト細胞内でどのように修復されるかを解明した。単鎖切断ではポリADPリボースポリメラーゼ1(PARP1)がDNAのニック(単鎖切断)を見つけて結合する。PARP1に結合してDNAのニックをギャップに変換する二種類の酵素をヒト細胞で発見した。それらの欠損が細胞を単鎖切断や二重鎖切断に感受性にする事が分った。二重鎖切断では、ATP依存的なクロマチンリモデリング因子のACF1がKU70と結合しており、その結合が二重鎖切断で更に強くなり、CHRAC複合体を形成してKU770/80複合体を二重鎖切断にロードして修復を開始させる事が分った。これらの発見はクロマチンリモデリングがDNA鎖切断の修復に必須な機構である事を示した。

︎全件表示 ︎最初の5件までを表示