Details of the Researcher

PHOTO

Fanyan Wei
Section
Institute of Development, Aging and Cancer
Job title
Professor
Degree

  • 博士（医学）（岡山大学）

  • 修士（理学）（東京都立大学）

Research History 7

  • 2019/10 - Present
    Tohoku University　Department of Modomics Biology and Medicine, IDAC　Professor

  • 2017/03 - 2019/09
    Kumamoto University

  • 2015/10 - 2019/03
    Japan Science and Technology Agency

  • 2015/05 - 2017/02
    Kumamoto University

  • 2009/04 - 2015/04
    Kumamoto University

  • 2006/04 - 2009/03
    Yale University　Department of Psychiatry　Postdoctoral Fellow

  • 2015 -
    Lecturer,Faculty of Life Sciences(Basic medicine group),Kumamoto University

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Professional Memberships 2

  • THE RNA SOCIETY OF JAPAN

  • THE PHYSIOLOGICAL SOCIETY OF JAPAN

Research Interests 6

  • Mitochondria

  • Metabolism

  • RNA Modification

  • RNA

  • 生理学

  • physiology

Research Areas 6

  • Life sciences / Metabolism and endocrinology /

  • Life sciences / Ophthalmology /

  • Life sciences / Molecular biology /

  • Life sciences / Medical biochemistry /

  • Life sciences / Clinical pharmacy /

  • Life sciences / Physiology /

Awards 8

  1. JSPS Prize

    2022/02

  2. 熊本医学会賞

    2017/03

  3. EMBO Reports Prize

    2016/09

  4. 日本生理学会奨励賞

    2016

  5. 第23回分子糖尿病シンポジウム若手研究奨励賞

    2011

  6. 第62回西日本生理学会奨励賞

    2011

  7. 岡山医学賞

    2006

  8. Human Frontier Long Term Fellowship Award

    2006

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Papers 108

  1. Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis. International-journal

    Tatsuya Morishima, Md Fakruddin, Yohei Kanamori, Takeshi Masuda, Akiko Ogawa, Yuxin Wang, Vivien A C Schoonenberg, Falk Butter, Yuichiro Arima, Takaaki Akaike, Toshiro Moroishi, Kazuhito Tomizawa, Toshio Suda, Fan-Yan Wei, Hitoshi Takizawa

    Science advances　11　(8)　eadu3011　2025/02/21

    DOI： 10.1126/sciadv.adu3011 　

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    Mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 (Mto1) is essential for the mitochondrial protein translation. Mto1 deficiency was shown to induce proteostress in embryonic stem cells. A recent finding that a patient with MTO1 gene mutation showed severe anemia led us to hypothesize that Mto1 dysfunctions may result in defective erythropoiesis. Hematopoietic-specific Mto1 conditional knockout (cKO) mice were embryonic lethal and showed niche-independent defect in erythroblast proliferation and terminal differentiation. Mechanistically, mitochondrial oxidative phosphorylation complexes were severely impaired in the Mto1 cKO fetal liver, and this was followed by cytosolic iron accumulation. Overloaded cytosolic iron promoted heme biosynthesis, which induced an unfolded protein response (UPR) in Mto1 cKO erythroblasts. An iron chelator or UPR inhibitor rescued erythroid terminal differentiation in the Mto1 cKO fetal liver in vitro. This mitochondrial regulation of iron homeostasis revealed the indispensable role of mitochondrial tRNA modification in fetal hematopoiesis.

  2. TEFM facilitates transition from RNA synthesis to DNA synthesis at H-strand replication origin of mtDNA

    Shigeru Matsuda, Masunari Nakayama, Yura Do, Takashi Ishiuchi, Mikako Yagi, Sjoerd Wanrooij, Kazuto Nakada, Fan-Yan Wei, Kenji Ichiyanagi, Hiroyuki Sasaki, Dongchon Kang, Takehiro Yasukawa

    Communications Biology　8　(1)　2025/02/08

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42003-025-07645-4 　

    eISSN： 2399-3642

  3. Chemogenetic activation of hepatic G12 signaling ameliorates hepatic steatosis and obesity. International-journal

    Kaito Arai, Yuki Ono, Natsumi Hirai, Yuki Sugiura, Keizo Kaneko, Shigeru Matsuda, Keita Iio, Keita Kajino, Tsuyoshi Saitoh, Fan-Yan Wei, Hideki Katagiri, Asuka Inoue

    Biochimica et biophysica acta. Molecular basis of disease　1871　(2)　167566-167566　2024/11/12

    DOI： 10.1016/j.bbadis.2024.167566 　

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    OBJECTIVE: Hepatic steatosis, the early stage of nonalcoholic fatty liver disease (NAFLD), currently lacks targeted pharmacological treatments. G protein-coupled receptors (GPCRs) in hepatocytes differentially regulate lipid metabolism depending on their coupling profile of G protein subtypes. Unlike Gs, Gi, and Gq signaling, the role of G12 signaling in hepatic steatosis remains elusive. The objective of this study was to investigate the effect of G12 signaling on hepatic steatosis and obesity and its mechanisms. METHODS: We generated mice expressing a G12-coupled designer GPCR in a liver-specific manner. We performed phenotypic analysis in the mice under the condition of fasting (acute hepatic steatosis model) or high-fat diet feeding (chronic hepatic steatosis model). RESULTS: In acute and chronic hepatic steatosis models, chemogenetic activation of hepatic G12 signaling suppressed the progression of hepatic steatosis. The treatment led to an increased triglyceride secretion with little effect on mitochondrial respiratory activity, fatty acid oxidation, de novo lipogenesis, and fatty acid uptake. Furthermore, in a high-fat-diet-induced obesity model, activation of the G12-coupled designer GPCR exerted anti-obesity effects with increased whole-body energy expenditure and fat oxidation. Anti-FGF21 antibody treatment showed that the anti-obesity effects of the hepatic G12D activation relied in part on the hepatokine FGF21. CONCLUSIONS: Our findings indicate that the activation of G12 signaling in the liver has the potential to prevent hepatic steatosis and obesity. This discovery provides a strong rationale for the development of drugs targeting G12-coupled GPCRs expressed in the liver.

  4. Structural insights into the agonist selectivity of the adenosine A3 receptor. International-journal

    Hidetaka S Oshima, Akiko Ogawa, Fumiya K Sano, Hiroaki Akasaka, Tomoyoshi Kawakami, Aika Iwama, Hiroyuki H Okamoto, Chisae Nagiri, Fan-Yan Wei, Wataru Shihoya, Osamu Nureki

    Nature communications　15　(1)　9294-9294　2024/11/07

    DOI： 10.1038/s41467-024-53473-1 　

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    Adenosine receptors play pivotal roles in physiological processes. Adenosine A3 receptor (A3R), the most recently identified adenosine receptor, is expressed in various tissues, exhibiting important roles in neuron, heart, and immune cells, and is often overexpressed in tumors, highlighting the therapeutic potential of A3R-selective agents. Recently, we identified RNA-derived N6-methyladenosine (m6A) as an endogenous agonist for A3R, suggesting the relationship between RNA-derived modified adenosine and A3R. Despite extensive studies on the other adenosine receptors, the selectivity mechanism of A3R, especially for A3R-selective agonists such as m6A and namodenoson, remained elusive. Here, we identify tRNA-derived N6-isopentenyl adenosine (i6A) as an A3R-selective ligand via screening of modified nucleosides against the adenosine receptors. Like m6A, i6A is found in the human body and may be an endogenous A3R ligand. Our cryo-EM analyses elucidate the A3R-Gi complexes bound to adenosine, 5'-N-ethylcarboxamidoadenosine (NECA), m6A, i6A, and namodenoson at overall resolutions of 3.27 Å (adenosine), 2.86 Å (NECA), 3.19 Å (m6A), 3.28 Å (i6A), and 3.20 Å (namodenoson), suggesting the selectivity and activation mechanism of A3R. We further conduct structure-guided engineering of m6A-insensitive A3R, which may aid future research targeting m6A and A3R, providing a molecular basis for future drug discovery.

  5. Human DUS1L catalyzes dihydrouridine modification at tRNA positions 16/17, and DUS1L overexpression perturbs translation. International-journal

    Jin Matsuura, Shinichiro Akichika, Fan-Yan Wei, Tsutomu Suzuki, Takahiro Yamamoto, Yuka Watanabe, Leoš Shivaya Valášek, Akitake Mukasa, Kazuhito Tomizawa, Takeshi Chujo

    Communications biology　7　(1)　1238-1238　2024/10/02

    DOI： 10.1038/s42003-024-06942-8 　

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    Human cytoplasmic tRNAs contain dihydrouridine modifications at positions 16 and 17 (D16/D17). The enzyme responsible for D16/D17 formation and its cellular roles remain elusive. Here, we identify DUS1L as the human tRNA D16/D17 writer. DUS1L knockout in the glioblastoma cell lines LNZ308 and U87 causes loss of D16/D17. D formation is reconstituted in vitro using recombinant DUS1L in the presence of NADPH or NADH. DUS1L knockout/overexpression in LNZ308 cells shows that DUS1L supports cell growth. Moreover, higher DUS1L expression in glioma patients is associated with poorer prognosis. Upon vector-mediated DUS1L overexpression in LNZ308 cells, 5' and 3' processing of precursor tRNATyr(GUA) is inhibited, resulting in a reduced mature tRNATyr(GUA) level, reduced translation of the tyrosine codons UAC and UAU, and reduced translational readthrough of the near-cognate stop codons UAA and UAG. Moreover, DUS1L overexpression increases the amounts of several D16/D17-containing tRNAs and total cellular translation. Our study identifies a human dihydrouridine writer, providing the foundation to study its roles in health and disease.

  6. RNA修飾 悪性神経膠腫におけるA37位tRNA修飾の重要性(RNA modification The role of tRNA modifications on the adenosine at position 37 of tRNA in glioblastoma)

    山本 隆広, 藤村 篤史, 松浦 任, 中條 岳志, 魏 范研, 篠島 直樹, 黒田 順一郎, 武笠 晃丈, 富澤 一仁

    日本癌学会総会記事　83回　S01-6　2024/09

    Publisher: (一社)日本癌学会

    ISSN： 0546-0476

  7. Accumulation of mitochondrial DNA with a point mutation in tRNALeu(UUR) gene induces brain dysfunction in mice. International-journal

    Kaori Ishikawa, Daiki Miyata, Satoko Hattori, Haruna Tani, Takayoshi Kuriyama, Fan-Yan Wei, Tsuyoshi Miyakawa, Kazuto Nakada

    Pharmacological research　208　107374-107374　2024/08/27

    DOI： 10.1016/j.phrs.2024.107374 　

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    Brain functions are mediated via the complex interplay between several complex factors, and hence, identifying the underlying cause of an abnormality within a certain brain region can be challenging. In mitochondrial disease, abnormalities in brain function are thought to be attributed to accumulation of mitochondrial DNA (mtDNA) with pathogenic mutations; however, only few previous studies have directly demonstrated that accumulation of mutant mtDNA induced abnormalities in brain function. Herein, we examined the effects of mtDNA mutations on brain function via behavioral analyses using a mouse model with an A2748G point mutation in mtDNA tRNALeu(UUR). Our results revealed that mice with a high percentage of mutant mtDNA showed a characteristic trend toward reduced prepulse inhibition and memory-dependent test performance, similar to that observed in psychiatric disorders, such as schizophrenia; however, muscle strength and motor coordination were not markedly affected. Upon examining the hippocampus and frontal lobes of the brain, mitochondrial morphology was abnormal, and the brain weight was slightly reduced. These results indicate that the predominant accumulation of a point mutation in the tRNALeu(UUR) gene may affect brain functions, particularly the coordination of sensory and motor functions and memory processes. These abnormalities probably caused by both direct effects of accumulation of the mutant mtDNA in neuronal cells and indirect effects via changes of systemic extracellular environments. Overall, these findings will lead to a better understanding of the pathogenic mechanism underlying this complex disease and facilitate the development of optimal treatment methods.

  8. TRMT10A dysfunction perturbs codon translation of initiator methionine and glutamine and impairs brain functions in mice

    Roland Tresky, Yuta Miyamoto, Yu Nagayoshi, Yasushi Yabuki, Kimi Araki, Yukie Takahashi, Yoshihiro Komohara, Huicong Ge, Kayo Nishiguchi, Takaichi Fukuda, Hitomi Kaneko, Nobuko Maeda, Jin Matsuura, Shintaro Iwasaki, Kourin Sakakida, Norifumi Shioda, Fan-Yan Wei, Kazuhito Tomizawa, Takeshi Chujo

    Nucleic Acids Research　2024/07/02

    Publisher: Oxford University Press (OUP)

    DOI： 10.1093/nar/gkae520 　

    ISSN： 0305-1048

    eISSN： 1362-4962

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    Abstract In higher eukaryotes, tRNA methyltransferase 10A (TRMT10A) is responsible for N1-methylguanosine modification at position nine of various cytoplasmic tRNAs. Pathogenic mutations in TRMT10A cause intellectual disability, microcephaly, diabetes, and short stature in humans, and generate cytotoxic tRNA fragments in cultured cells; however, it is not clear how TRMT10A supports codon translation or brain functions. Here, we generated Trmt10a null mice and showed that tRNAGln(CUG) and initiator methionine tRNA levels were universally decreased in various tissues; the same was true in a human cell line lacking TRMT10A. Ribosome profiling of mouse brain revealed that dysfunction of TRMT10A causes ribosome slowdown at the Gln(CAG) codon and increases translation of Atf4 due to higher frequency of leaky scanning of its upstream open reading frames. Broadly speaking, translation of a subset of mRNAs, especially those for neuronal structures, is perturbed in the mutant brain. Despite not showing discernable defects in the pancreas, liver, or kidney, Trmt10a null mice showed lower body weight and smaller hippocampal postsynaptic densities, which is associated with defective synaptic plasticity and memory. Taken together, our study provides mechanistic insight into the roles of TRMT10A in the brain, and exemplifies the importance of universal tRNA modification during translation of specific codons.

  9. Pathological mutations promote proteolysis of mitochondrial tRNA-specific 2-thiouridylase 1 (MTU1) via mitochondrial caseinolytic peptidase (CLPP). International-journal

    Raja Norazireen Raja Ahmad, Long-Teng Zhang, Rikuri Morita, Haruna Tani, Yong Wu, Takeshi Chujo, Akiko Ogawa, Ryuhei Harada, Yasuteru Shigeta, Kazuhito Tomizawa, Fan-Yan Wei

    Nucleic acids research　2023/12/19

    DOI： 10.1093/nar/gkad1197 　

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    MTU1 controls intramitochondrial protein synthesis by catalyzing the 2-thiouridine modification of mitochondrial transfer RNAs (mt-tRNAs). Missense mutations in the MTU1 gene are associated with life-threatening reversible infantile hepatic failure. However, the molecular pathogenesis is not well understood. Here, we investigated 17 mutations associated with this disease, and our results showed that most disease-related mutations are partial loss-of-function mutations, with three mutations being particularly severe. Mutant MTU1 is rapidly degraded by mitochondrial caseinolytic peptidase (CLPP) through a direct interaction with its chaperone protein CLPX. Notably, knockdown of CLPP significantly increased mutant MTU1 protein expression and mt-tRNA 2-thiolation, suggesting that accelerated proteolysis of mutant MTU1 plays a role in disease pathogenesis. In addition, molecular dynamics simulations demonstrated that disease-associated mutations may lead to abnormal intermolecular interactions, thereby impairing MTU1 enzyme activity. Finally, clinical data analysis underscores a significant correlation between patient prognosis and residual 2-thiolation levels, which is partially consistent with the AlphaMissense predictions. These findings provide a comprehensive understanding of MTU1-related diseases, offering prospects for modification-based diagnostics and novel therapeutic strategies centered on targeting CLPP.

  10. Supersulfide biology and translational medicine for disease control. International-journal

    Uladzimir Barayeu, Tomohiro Sawa, Motohiro Nishida, Fan-Yan Wei, Hozumi Motohashi, Takaaki Akaike

    British journal of pharmacology　2023/10/23

    DOI： 10.1111/bph.16271 　

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    For decades, the major focus of redox biology has been oxygen, the most abundant element on Earth. Molecular oxygen functions as the final electron acceptor in the mitochondrial respiratory chain, contributing to energy production in aerobic organisms. In addition, oxygen-derived reactive oxygen species including hydrogen peroxide and nitrogen free radicals, such as superoxide, hydroxyl radical and nitric oxide radical, undergo a complicated sequence of electron transfer reactions with other biomolecules, which lead to their modified physiological functions and diverse biological and pathophysiological consequences (e.g. oxidative stress). What is now evident is that oxygen accounts for only a small number of redox reactions in organisms and knowledge of biological redox reactions is still quite limited. This article reviews a new aspects of redox biology which is governed by redox-active sulfur-containing molecules-supersulfides. We define the term 'supersulfides' as sulfur species with catenated sulfur atoms. Supersulfides were determined to be abundant in all organisms, but their redox biological properties have remained largely unexplored. In fact, the unique chemical properties of supersulfides permit them to be readily ionized or radicalized, thereby allowing supersulfides to actively participate in redox reactions and antioxidant responses in cells. Accumulating evidence has demonstrated that supersulfides are indispensable for fundamental biological processes such as energy production, nucleic acid metabolism, protein translation and others. Moreover, manipulation of supersulfide levels was beneficial for pathogenesis of various diseases. Thus, supersulfide biology has opened a new era of disease control that includes potential applications to clinical diagnosis, prevention and therapeutics of diseases.

  11. Supersulphides provide airway protection in viral and chronic lung diseases. International-journal

    Tetsuro Matsunaga, Hirohito Sano, Katsuya Takita, Masanobu Morita, Shun Yamanaka, Tomohiro Ichikawa, Tadahisa Numakura, Tomoaki Ida, Minkyung Jung, Seiryo Ogata, Sunghyeon Yoon, Naoya Fujino, Yorihiko Kyogoku, Yusaku Sasaki, Akira Koarai, Tsutomu Tamada, Atsuhiko Toyama, Takakazu Nakabayashi, Lisa Kageyama, Shigeru Kyuwa, Kenji Inaba, Satoshi Watanabe, Péter Nagy, Tomohiro Sawa, Hiroyuki Oshiumi, Masakazu Ichinose, Mitsuhiro Yamada, Hisatoshi Sugiura, Fan-Yan Wei, Hozumi Motohashi, Takaaki Akaike

    Nature communications　14　(1)　4476-4476　2023/07/25

    DOI： 10.1038/s41467-023-40182-4 　

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    Supersulphides are inorganic and organic sulphides with sulphur catenation with diverse physiological functions. Their synthesis is mainly mediated by mitochondrial cysteinyl-tRNA synthetase (CARS2) that functions as a principal cysteine persulphide synthase (CPERS). Here, we identify protective functions of supersulphides in viral airway infections (influenza and COVID-19), in aged lungs and in chronic lung diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF). We develop a method for breath supersulphur-omics and demonstrate that levels of exhaled supersulphides increase in people with COVID-19 infection and in a hamster model of SARS-CoV-2 infection. Lung damage and subsequent lethality that result from oxidative stress and inflammation in mouse models of COPD, IPF, and ageing were mitigated by endogenous supersulphides production by CARS2/CPERS or exogenous administration of the supersulphide donor glutathione trisulphide. We revealed a protective role of supersulphides in airways with various viral or chronic insults and demonstrated the potential of targeting supersulphides in lung disease.

  12. Complexity and dynamics ofin organellotranslation landscape assessed by high-resolution mitochondrial ribosome profiling

    Taisei Wakigawa, Mari Mito, Haruna Yamashiro, Kotaro Tomuro, Haruna Tani, Kazuhito Tomizawa, Takeshi Chujo, Asuteka Nagao, Takeo Suzuki, Fan-Yan Wei, Yuichi Shichino, Tsutomu Suzuki, Shintaro Iwasaki

    2023/07/20

    Publisher: Cold Spring Harbor Laboratory

    DOI： 10.1101/2023.07.19.549812 　

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    Abstract Eukaryotes house an additional protein synthesis system within the mitochondria. Given that mitochondrial translation dictates OXPHOS complex abundance and ATP levels in cells, exhaustive, quantitative, and high-resolution delineation of mitoribosome traversal is needed. Here, we developed a technique for high-resolution mitochondrial ribosome profiling and unveiled the tight regulation of mammalianin organellotranslation. Our approach assessed the stoichiometry and kinetics of mitochondrial translation flux, such as the absolute numbers of mitoribosomes on a transcript and the elongation rate, initiation rate, and lifetime rounds of translation of individual transcripts. We also surveyed the impacts of modifications at anticodon stem loop in mt-tRNAs, including all possible decorations at 34th position, by deleting the corresponding enzymes and harnessing patient-derived mtDNA A3243G cells. Moreover, retapamulin-assisted profiling and disome profiling unveiled cryptic translation initiation sites at subcognate codons and programmed mitoribosome collision sites across the mitochondrial transcriptome, respectively. Our work provides a useful resource for delineating protein synthesis within this indispensable organelle.

  13. Mitochondrial alterations in the cochlea of Cdk5rap1-knockout mice with age-related hearing loss. International-journal

    Toru Miwa, Tatsuya Katsuno, Fan-Yan Wei, Kazuhito Tomizawa

    FEBS open bio　13　(7)　1365-1374　2023/07

    DOI： 10.1002/2211-5463.13655 　

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    Previous studies have revealed that age-related hearing loss (AHL) in Cdk5 regulatory subunit-associated protein 1 (Cdk5rap1)-knockout mice is associated with pathology in the cochlea. Here, we aimed to identify mitochondrial alterations in the cochlea of Cdk5rap1-knockout mice with AHL. Mitochondria in the spiral ganglion neurons (SGNs) and hair cells (HCs) were normal despite senescence; however, the mitochondria of types I, II, and IV spiral ligament fibrocytes were ballooned, damaged, and ballooned, respectively, in the stria vascularis. Our results suggest that the accumulation of dysfunctional mitochondria in the lateral wall, rather than the loss of HCs and SGNs, leads to the onset of AHL. Our results provide valuable information regarding the underlying mechanisms of AHL and the relationship between aberrant tRNA modification-induced hearing loss and mitochondrial dysfunction.

  14. Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction. International-journal

    Akiko Ogawa, Seiya Ohira, Yuri Kato, Tatsuya Ikuta, Shota Yanagida, Xinya Mi, Yukina Ishii, Yasunari Kanda, Motohiro Nishida, Asuka Inoue, Fan-Yan Wei

    Communications biology　6　(1)　511-511　2023/05/12

    DOI： 10.1038/s42003-023-04888-x 　

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    Remdesivir is an antiviral drug used for COVID-19 treatment worldwide. Cardiovascular side effects have been associated with remdesivir; however, the underlying molecular mechanism remains unknown. Here, we performed a large-scale G-protein-coupled receptor screening in combination with structural modeling and found that remdesivir is a selective, partial agonist for urotensin-II receptor (UTS2R) through the Gαi/o-dependent AKT/ERK axis. Functionally, remdesivir treatment induced prolonged field potential and APD90 in human induced pluripotent stem cell (iPS)-derived cardiomyocytes and impaired contractility in both neonatal and adult cardiomyocytes, all of which mirror the clinical pathology. Importantly, remdesivir-mediated cardiac malfunctions were effectively attenuated by antagonizing UTS2R signaling. Finally, we characterized the effect of 110 single-nucleotide variants in UTS2R gene reported in genome database and found four missense variants that show gain-of-function effects in the receptor sensitivity to remdesivir. Collectively, our study illuminates a previously unknown mechanism underlying remdesivir-related cardiovascular events and that genetic variations of UTS2R gene can be a potential risk factor for cardiovascular events during remdesivir treatment, which collectively paves the way for a therapeutic opportunity to prevent such events in the future.

  15. NSUN3-mediated mitochondrial tRNA 5-formylcytidine modification is essential for embryonic development and respiratory complexes in mice

    Yoshitaka Murakami, Fan-Yan Wei, Yoshimi Kawamura, Haruki Horiguchi, Tsuyoshi Kadomatsu, Keishi Miyata, Kyoko Miura, Yuichi Oike, Yukio Ando, Mitsuharu Ueda, Kazuhito Tomizawa, Takeshi Chujo

    Communications Biology　6　(1)　2023/03/22

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42003-023-04680-x 　

    eISSN： 2399-3642

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    Abstract In mammalian mitochondria, translation of the AUA codon is supported by 5-formylcytidine (f5C) modification in the mitochondrial methionine tRNA anticodon. The 5-formylation is initiated by NSUN3 methylase. Human NSUN3 mutations are associated with mitochondrial diseases. Here we show that Nsun3 is essential for embryonic development in mice with whole-body Nsun3 knockout embryos dying between E10.5 and E12.5. To determine the functions of NSUN3 in adult tissue, we generated heart-specific Nsun3 knockout (Nsun3HKO) mice. Nsun3HKO heart mitochondria were enlarged and contained fragmented cristae. Nsun3HKO resulted in enhanced heart contraction and age-associated mild heart enlargement. In the Nsun3HKO hearts, mitochondrial mRNAs that encode respiratory complex subunits were not down regulated, but the enzymatic activities of the respiratory complexes decreased, especially in older mice. Our study emphasizes that mitochondrial tRNA anticodon modification is essential for mammalian embryonic development and shows that tissue-specific loss of a single mitochondrial tRNA modification can induce tissue aberration that worsens in later adulthood.

  16. Epitranscriptomics in metabolic disease. International-journal

    Yoshihiro Matsumura, Fan-Yan Wei, Juro Sakai

    Nature metabolism　5　(3)　370-384　2023/03

    DOI： 10.1038/s42255-023-00764-4 　

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    While epigenetic modifications of DNA and histones play main roles in gene transcription regulation, recently discovered post-transcriptional RNA modifications, known as epitranscriptomic modifications, have been found to have a profound impact on gene expression by regulating RNA stability, localization and decoding efficiency. Importantly, genetic variations or environmental perturbations of epitranscriptome modifiers (that is, writers, erasers and readers) are associated with obesity and metabolic diseases, such as type 2 diabetes. The epitranscriptome is closely coupled to epigenetic signalling, adding complexity to our understanding of gene expression in both health and disease. Moreover, the epitranscriptome in the parental generation can affect organismal phenotypes in the next generation. In this Review, we discuss the relationship between epitranscriptomic modifications and metabolic diseases, their relationship with the epigenome and possible therapeutic strategies.

  17. CDKAL1 Drives the Maintenance of Cancer Stem-Like Cells by Assembling the eIF4F Translation Initiation Complex. International-journal

    Rongsheng Huang, Takahiro Yamamoto, Eiji Nakata, Toshifumi Ozaki, Kazuhiko Kurozumi, Fanyan Wei, Kazuhito Tomizawa, Atsushi Fujimura

    Advanced science (Weinheim, Baden-Wurttemberg, Germany)　e2206542　2023/02/14

    DOI： 10.1002/advs.202206542 　

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    Cancer stem-like cells (CSCs) have a unique translation mode, but little is understood about the process of elongation, especially the contribution of tRNA modifications to the maintenance of CSCs properties. Here, it is reported that, contrary to the initial aim, a tRNA-modifying methylthiotransferase CDKAL1 promotes CSC-factor SALL2 synthesis by assembling the eIF4F translation initiation complex. CDKAL1 expression is upregulated in patients with worse prognoses and is essential for maintaining CSCs in rhabdomyosarcoma (RMS) and common cancers. Translatome analysis reveals that a group of mRNAs whose translation is CDKAL1-dependent contains cytosine-rich sequences in the 5' untranslated region (5'UTR). Mechanistically, CDKAL1 promotes the translation of such mRNAs by organizing the eIF4F translation initiation complex. This complex formation does not require the enzyme activity of CDKAL1 but requires only the NH2 -terminus domain of CDKAL1. Furthermore, sites in CDKAL1 essential for forming the eIF4F complex are identified and discovered candidate inhibitors of CDKAL1-dependent translation.

  18. 感染症における呼気オミックス解析

    緒方 星陵, 井田 智章, 守田 匡伸, 松永 哲郎, 村上 昌平, 魏 范研, 本橋 ほづみ, 赤池 孝章

    日本細菌学雑誌　78　(1)　69-69　2023/02

    Publisher: 日本細菌学会

    ISSN： 0021-4930

    eISSN： 1882-4110

  19. RNA由来修飾核酸の代謝酵素の同定

    小川 亜希子, 渡部 聡, 稲葉 謙次, 魏 范研

    日本痛風・尿酸核酸学会総会プログラム・抄録集　56回　69-69　2023/01

    Publisher: (一社)日本痛風・尿酸核酸学会

  20. COVID-19ワクチン接種後のRNA修飾代謝物排泄の変動

    小川 亜希子, 松尾 紀孝, 齋藤 一創, 魏 范研

    痛風と尿酸・核酸　46　(2)　105-113　2022/12

    Publisher: (一社)日本痛風・尿酸核酸学会

    eISSN： 2435-0095

  21. RNA修飾由来の新しい核酸型液性因子とその生理的意義について

    小川 亜希子, 魏 范研

    痛風と尿酸・核酸　46　(2)　154-154　2022/12

    Publisher: (一社)日本痛風・尿酸核酸学会

    eISSN： 2435-0095

  22. t6A and ms2t6A Modified Nucleosides in Serum and Urine as Strong Candidate Biomarkers of COVID-19 Infection and Severity Peer-reviewed

    Yu Nagayoshi, Kayo Nishiguchi, Ryosuke Yamamura, Takeshi Chujo, Hiroyuki Oshiumi, Hiroko Nagata, Hitomi Kaneko, Keiichi Yamamoto, Hirotomo Nakata, Korin Sakakida, Akihiro Kunisawa, Masataka Adachi, Yutaka Kakizoe, Takanori Mizobe, Jun-ichi Kuratsu, Shinya Shimada, Yasushi Nakamori, Masao Matsuoka, Masashi Mukoyama, Fan-Yan Wei, Kazuhito Tomizawa

    Biomolecules　12　(9)　1233-1233　2022/09/03

    Publisher: MDPI AG

    DOI： 10.3390/biom12091233 　

    eISSN： 2218-273X

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    SARS-CoV-2 infection alters cellular RNA content. Cellular RNAs are chemically modified and eventually degraded, depositing modified nucleosides into extracellular fluids such as serum and urine. Here we searched for COVID-19-specific changes in modified nucleoside levels contained in serum and urine of 308 COVID-19 patients using liquid chromatography-mass spectrometry (LC-MS). We found that two modified nucleosides, N6-threonylcarbamoyladenosine (t6A) and 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A), were elevated in serum and urine of COVID-19 patients. Moreover, these levels were associated with symptom severity and decreased upon recovery from COVID-19. In addition, the elevation of similarly modified nucleosides was observed regardless of COVID-19 variants. These findings illuminate specific modified RNA nucleosides in the extracellular fluids as biomarkers for COVID-19 infection and severity.

  23. Aberrant RNA processing contributes to the pathogenesis of mitochondrial diseases in trans-mitochondrial mouse model carrying mitochondrial tRNALeu(UUR) with a pathogenic A2748G mutation

    Haruna Tani, Kaori Ishikawa, Hiroaki Tamashiro, Emi Ogasawara, Takehiro Yasukawa, Shigeru Matsuda, Akinori Shimizu, Dongchon Kang, Jun-Ichi Hayashi, Fan-Yan Wei, Kazuto Nakada

    Nucleic Acids Research　2022/08/24

    Publisher: Oxford University Press (OUP)

    DOI： 10.1093/nar/gkac699 　

    ISSN： 0305-1048

    eISSN： 1362-4962

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    Abstract Mitochondrial tRNAs are indispensable for the intra-mitochondrial translation of genes related to respiratory subunits, and mutations in mitochondrial tRNA genes have been identified in various disease patients. However, the molecular mechanism underlying pathogenesis remains unclear due to the lack of animal models. Here, we established a mouse model, designated ‘mito-mice tRNALeu(UUR)2748’, that carries a pathogenic A2748G mutation in the tRNALeu(UUR) gene of mitochondrial DNA (mtDNA). The A2748G mutation is orthologous to the human A3302G mutation found in patients with mitochondrial diseases and diabetes. A2748G mtDNA was maternally inherited, equally distributed among tissues in individual mice, and its abundance did not change with age. At the molecular level, A2748G mutation is associated with aberrant processing of precursor mRNA containing tRNALeu(UUR) and mt-ND1, leading to a marked decrease in the steady-levels of ND1 protein and Complex I activity in tissues. Mito-mice tRNALeu(UUR)2748 with ≥50% A2748G mtDNA exhibited age-dependent metabolic defects including hyperglycemia, insulin insensitivity, and hepatic steatosis, resembling symptoms of patients carrying the A3302G mutation. This work demonstrates a valuable mouse model with an inheritable pathological A2748G mutation in mt-tRNALeu(UUR) that shows metabolic syndrome-like phenotypes at high heteroplasmy level. Furthermore, our findings provide molecular basis for understanding A3302G mutation-mediated mitochondrial disorders.

  24. Extracellular N6-isopentenyladenosine (i6A) addition induces co-transcriptional i6A incorporation into ribosomal RNAs

    Maya Yakita, Takeshi Chujo, Fan-Yan Wei, Mayumi Hirayama, Koji Kato, Nozomu Takahashi, Kenta Naganuma, Masashi Nagata, Kenta Kawahara, Hideki Nakayama, Kazuhito Tomizawa

    RNA　rna.079176.122-rna.079176.122　2022/04/12

    Publisher: Cold Spring Harbor Laboratory

    DOI： 10.1261/rna.079176.122 　

    ISSN： 1355-8382

    eISSN： 1469-9001

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    N6-isopentenyladenosine (i6A), a modified adenosine monomer, is known to induce cell death upon its addition to the culture medium. However, the molecular fate of extracellularly added i6A has yet to be identified. Here we show that i6A addition to cell culture medium results in i6A incorporation into cellular RNA in several cell lines, including the 5-fluorouracil (5-FU)-resistant human oral squamous cell carcinoma cell line FR2-SAS and its parental 5-FU-sensitive cell line SAS. i6A was predominantly incorporated into 18S and 28S rRNAs, and i6A incorporation into total RNA was mostly suppressed by treating these cell lines with an RNA Polymerase I (Pol I) inhibitor. i6A was incorporated into RNA even upon inactivation of TRIT1, the only cellular i6A-modifying enzyme. These results indicate that upon cellular uptake of i6A, it is anabolized to be used for Pol I transcription. Interestingly, at lower i6A concentrations, the cytotoxic effect of i6A was substantially more pronounced in FR2-SAS cells than in SAS cells. Moreover, in FR2-SAS cells, i6A treatment decreased the rate of cellular protein synthesis and increased intracellular protein aggregation, and these effects were more pronounced than in SAS cells. Our work provides insights into the molecular fate of extracellularly-applied i6A in the context of intracellular nucleic acid anabolism and suggests investigation of i6A as a candidate for chemotherapy agent against 5-FU-resistant cancer cells.

  25. Subtilase cytotoxin from Shiga-toxigenic Escherichia coli impairs the inflammasome and exacerbates enteropathogenic bacterial infection

    Hiroyasu Tsutsuki, Tianli Zhang, Kinnosuke Yahiro, Katsuhiko Ono, Yukio Fujiwara, Sunao Iyoda, Fan-Yan Wei, Kazuaki Monde, Kazuko Seto, Makoto Ohnishi, Hiroyuki Oshiumi, Takaaki Akaike, Tomohiro Sawa

    iScience　25　(4)　104050-104050　2022/04

    Publisher: Elsevier BV

    DOI： 10.1016/j.isci.2022.104050 　

    ISSN： 2589-0042

  26. ミトコンドリアtRNA修飾酵素NSUN3の全身および心臓における生理的意義の解明

    村上 慶高, 中條 岳志, 魏 范研, 堀口 晴紀, 門松 毅, 尾池 雄一, 安東 由喜雄, 植田 光晴, 富澤 一仁

    日本生理学雑誌　84　(1)　18-19　2022/02

    Publisher: (一社)日本生理学会

    ISSN： 0031-9341

  27. Protocol for preparation and measurement of intracellular and extracellular modified RNA using liquid chromatography-mass spectrometry. International-journal

    Akiko Ogawa, Fan-Yan Wei

    STAR protocols　2　(4)　100848-100848　2021/12/17

    DOI： 10.1016/j.xpro.2021.100848 　

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    About 150 modifications have been identified in RNA species. Besides their regulatory roles in the intracellular gene expression, abundant modified RNA nucleosides are catabolized from RNA and released into extracellular fluids, which can impact extracellular signaling as ligands for receptors. Here, we describe a protocol to prepare samples from biological specimens, including cultured cells, extracellular fluid, and tissues, to measure both intracellular and extracellular RNA modifications using mass spectrometry. For complete details on the use and execution of this protocol, please refer to Ogawa et al. (2021).

  28. Cooperative methylation of human tRNA3Lys at positions A58 and U54 drives the early and late steps of HIV-1 replication. International-journal

    Hiroyuki Fukuda, Takeshi Chujo, Fan-Yan Wei, Sheng-Lan Shi, Mayumi Hirayama, Taku Kaitsuka, Takahiro Yamamoto, Hiroyuki Oshiumi, Kazuhito Tomizawa

    Nucleic acids research　49　(20)　11855-11867　2021/11/18

    DOI： 10.1093/nar/gkab879 　

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    Retroviral infection requires reverse transcription, and the reverse transcriptase (RT) uses cellular tRNA as its primer. In humans, the TRMT6-TRMT61A methyltransferase complex incorporates N1-methyladenosine modification at tRNA position 58 (m1A58); however, the role of m1A58 as an RT-stop site during retroviral infection has remained questionable. Here, we constructed TRMT6 mutant cells to determine the roles of m1A in HIV-1 infection. We confirmed that tRNA3Lys m1A58 was required for in vitro plus-strand strong-stop by RT. Accordingly, infectivity of VSV-G pseudotyped HIV-1 decreased when the virus contained m1A58-deficient tRNA3Lys instead of m1A58-modified tRNA3Lys. In TRMT6 mutant cells, the global protein synthesis rate was equivalent to that of wild-type cells. However, unexpectedly, plasmid-derived HIV-1 expression showed that TRMT6 mutant cells decreased accumulation of HIV-1 capsid, integrase, Tat, Gag, and GagPol proteins without reduction of HIV-1 RNAs in cells, and fewer viruses were produced. Moreover, the importance of 5,2'-O-dimethyluridine at U54 of tRNA3Lys as a second RT-stop site was supported by conservation of retroviral genome-tRNALys sequence-complementarity, and TRMT6 was required for efficient 5-methylation of U54. These findings illuminate the fundamental importance of tRNA m1A58 modification in both the early and late steps of HIV-1 replication, as well as in the cellular tRNA modification network.

  29. 緑内障術後線維化におけるRNA修飾の変動

    小川 亜希子, 井上 俊洋, 魏 范研

    日本緑内障学会抄録集　32回　76-76　2021/09

    Publisher: 日本緑内障学会

  30. Export of RNA-derived modified nucleosides by equilibrative nucleoside transporters defines the magnitude of autophagy response and Zika virus replication. International-journal

    Sheng-Lan Shi, Hiroyuki Fukuda, Takeshi Chujo, Takahisa Kouwaki, Hiroyuki Oshiumi, Kazuhito Tomizawa, Fan-Yan Wei

    RNA biology　1-18　2021/08/12

    DOI： 10.1080/15476286.2021.1960689 　

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    RNA contains a wide variety of posttranscriptional modifications covalently attached to its base or sugar group. These modified nucleosides are liberated from RNA molecules as the consequence of RNA catabolism and released into extracellular space, but the molecular mechanism of extracellular transport and its pathophysiological implications have been unclear. In the present study, we discovered that RNA-derived modified nucleosides are exported to extracellular space through equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2), with ENT1 showing higher preference for modified nucleosides than ENT2. Pharmacological inhibition or genetic deletion of ENT1 and ENT2 significantly attenuated export of modified nucleosides thereby resulting in their accumulation in cytosol. Using mutagenesis strategy, we identified an amino acid residue in ENT1 that is involved in the discrimination of unmodified and modified nucleosides. In ENTs-deficient cells, the elevated levels of intracellular modified nucleosides were closely associated with an induction of autophagy response as evidenced by increased LC3-II level. Importantly, we performed a screening of modified nucleosides capable of inducing autophagy and found that 1-methylguanosine (m1G) was sufficient to induce LC3-II levels. Pathophysiologically, defective export of modified nucleosides drastically induced Zika virus replication in an autophagy-dependent manner. In addition, we also found that pharmacological inhibition of ENTs by dilazep significantly induced Zika virus replication. Collectively, our findings highlight RNA-derived modified nucleosides as important signaling modulators that activate autophagy response and indicate that defective export of these modified nucleoside can have profound consequences for pathophysiology.

  31. Cdk5 regulatory subunit-associated protein 1 knockout mice show hearing loss phenotypically similar to age-related hearing loss. International-journal

    Toru Miwa, Fan-Yan Wei, Kazuhito Tomizawa

    Molecular brain　14　(1)　82-82　2021/05/17

    DOI： 10.1186/s13041-021-00791-w 　

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    Mitochondrial dysfunction is associated with aging and age-related hearing loss (AHL). However, the precise mechanisms underlying the pathophysiology of hearing loss remain unclear. Cdk5 regulatory subunit-associated protein 1 (CDK5RAP1) enables efficient intramitochondrial translation by catalyzing the deposition of 2-methylthio modifications on mitochondrial tRNAs. Here we investigated the effect of defective mitochondrial protein translation on hearing and AHL in a Cdk5rap1 deficiency C57BL/6 mouse model. Compared to control C57BL/6 mice, Cdk5rap1-knockout female mice displayed hearing loss phenotypically similar to AHL from an early age. The premature hearing loss in Cdk5rap1-knockout mice was associated with the degeneration of the spiral ligament and reduction of endocochlear potentials following the loss of auditory sensory cells. Furthermore, cultured primary mouse embryonic fibroblasts displayed early onset of cellular senescence associated with high oxidative stress and cell death. These results indicate that the CDK5RAP1 deficiency-induced defective mitochondrial translation might cause early hearing loss through the induction of cellular senescence and cochlear dysfunction in the inner ear. Our results suggest that the accumulation of dysfunctional mitochondria might promote AHL progression. Furthermore, our findings suggest that mitochondrial dysfunction and dysregulated mitochondrial tRNA modifications mechanistically cause AHL. Understanding the mechanisms underlying AHL will guide future clinical investigations and interventions in the attempt to mitigate the consequences of AHL.

  32. tRNA修飾と糖尿病性神経障害との関連に関する臨床研究

    井島 廣子, 榊田 光倫, 魏 范研, 陣内 秀昭, 富澤 一仁

    糖尿病　64　(3)　229-229　2021/03

    Publisher: (一社)日本糖尿病学会

    ISSN： 0021-437X

    eISSN： 1881-588X

  33. Loss of Ftsj1 perturbs codon-specific translation efficiency in the brain and is associated with X-linked intellectual disability. International-journal

    Y Nagayoshi, T Chujo, S Hirata, H Nakatsuka, C-W Chen, M Takakura, K Miyauchi, Y Ikeuchi, B C Carlyle, R R Kitchen, T Suzuki, F Katsuoka, M Yamamoto, Y Goto, M Tanaka, K Natsume, A C Nairn, T Suzuki, K Tomizawa, F-Y Wei

    Science advances　7　(13)　2021/03

    DOI： 10.1126/sciadv.abf3072 　

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    FtsJ RNA 2'-O-methyltransferase 1 (FTSJ1) gene has been implicated in X-linked intellectual disability (XLID), but the molecular pathogenesis is unknown. We show that Ftsj1 is responsible for 2'-O-methylation of 11 species of cytosolic transfer RNAs (tRNAs) at the anticodon region, and these modifications are abolished in Ftsj1 knockout (KO) mice and XLID patient-derived cells. Loss of 2'-O-methylation in Ftsj1 KO mouse selectively reduced the steady-state level of tRNAPhe in the brain, resulting in a slow decoding at Phe codons. Ribosome profiling showed that translation efficiency is significantly reduced in a subset of genes that need to be efficiently translated to support synaptic organization and functions. Ftsj1 KO mice display immature synaptic morphology and aberrant synaptic plasticity, which are associated with anxiety-like and memory deficits. The data illuminate a fundamental role of tRNA modification in the brain through regulation of translation efficiency and provide mechanistic insights into FTSJ1-related XLID.

  34. N6-methyladenosine (m6A) is an endogenous A3 adenosine receptor ligand. International-journal

    Akiko Ogawa, Chisae Nagiri, Wataru Shihoya, Asuka Inoue, Kouki Kawakami, Suzune Hiratsuka, Junken Aoki, Yasuhiro Ito, Takeo Suzuki, Tsutomu Suzuki, Toshihiro Inoue, Osamu Nureki, Hidenobu Tanihara, Kazuhito Tomizawa, Fan-Yan Wei

    Molecular cell　81　(4)　659-674　2021/02/18

    DOI： 10.1016/j.molcel.2020.12.038 　

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    About 150 post-transcriptional RNA modifications have been identified in all kingdoms of life. During RNA catabolism, most modified nucleosides are resistant to degradation and are released into the extracellular space. In this study, we explored the physiological role of these extracellular modified nucleosides and found that N6-methyladenosine (m6A), widely recognized as an epigenetic mark in RNA, acts as a ligand for the human adenosine A3 receptor, for which it has greater affinity than unmodified adenosine. We used structural modeling to define the amino acids required for specific binding of m6A to the human A3 receptor. We also demonstrated that m6A was dynamically released in response to cytotoxic stimuli and facilitated type I allergy in vivo. Our findings implicate m6A as a signaling molecule capable of activating G protein-coupled receptors (GPCRs) and triggering pathophysiological responses, a previously unreported property of RNA modifications.

  35. メタボローム解析を用いたミトコンドリア機能異常による加齢性難聴の原因解明

    三輪 徹, 蓑田 涼生, 魏 范研, 折田 頼尚, 富澤 一仁

    Otology Japan　30　(3)　191-196　2020/10

    Publisher: (一社)日本耳科学会

    ISSN： 0917-2025

    eISSN： 1884-1457

  36. Intranasal Drug Delivery into Mouse Nasal Mucosa and Brain Utilizing Arginine-Rich Cell-Penetrating Peptide-Mediated Protein Transduction

    Toru Miwa, Kyoko Tachii, Fan-Yan Wei, Taku Kaitsuka, Kazuhito Tomizawa

    International Journal of Peptide Research and Therapeutics　26　(3)　1643-1650　2020/09

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1007/s10989-019-09971-8 　

    ISSN： 1573-3149

    eISSN： 1573-3904

  37. Posttranscriptional modifications in mitochondrial tRNA and its implication in mitochondrial translation and disease. International-journal Peer-reviewed

    Tomizawa Kazuhito, Fan-Yan Wei

    Journal of biochemistry　168　(5)　435-444　2020/08/20

    DOI： 10.1093/jb/mvaa098 　

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    A fundamental aspect of mitochondria is that they possess DNA and protein translation machinery. Mitochondrial DNA encodes 22 tRNAs that translate mitochondrial mRNAs to 13 polypeptides of respiratory complexes. Various chemical modifications have been identified in mitochondrial tRNAs via complex enzymatic processes. A growing body of evidence has demonstrated that these modifications are essential for translation by regulating tRNA stability, structure, and mRNA binding, and can be dynamically regulated by the metabolic environment. Importantly, the hypomodification of mitochondrial tRNA due to pathogenic mutations in mitochondrial tRNA genes or nuclear genes encoding modifying enzymes can result in life-threatening mitochondrial diseases in humans. Thus, the mitochondrial tRNA modification is a fundamental mechanism underlying the tight regulation of mitochondrial translation and is essential for life. In this review, we focus on recent findings on the physiological roles of 5-taurinomethyl modification (herein referred as taurine modification) in mitochondrial tRNAs. We summarize the findings in human patients and animal models with a deficiency of taurine modifications and provide pathogenic links to mitochondrial diseases. We anticipate that this review will help understand the complexity of mitochondrial biology and disease.

  38. Movements of ancient human endogenous retroviruses detected in SOX2-expressing cells

    Kazuaki Monde, Yorifumi Satou, Mizuki Goto, Yoshikazu Uchiyama, Jumpei Ito, Taku Kaitsuka, Hiromi Terasawa, Shinya Yamaga, Tomoya Matsusako, Fan-Yan Wei, Ituro Inoue, Kazuhito Tomizawa, Akira Ono, Takumi Era, Tomohiro Sawa, Yosuke Maeda

    2020/07/14

    Publisher: Cold Spring Harbor Laboratory

    DOI： 10.1101/2020.07.14.202135 　

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    <title>Summary</title>Human endogenous retroviruses (HERVs) occupy approximately 8% of human genome. HERVs, which are transcribed in early embryos, are epigenetically silenced in somatic cells, except in pathological contexts. HERV-K is thought to protect the embryo from exogenous viral infection. However, uncontrollable HERV-K expression in somatic cells has been implicated in several diseases. Here, we show that SOX2, which plays a key role in maintaining pluripotency of stem cells, is critical for the transcription of HERV-K LTR5Hs. HERV-K can undergo retrotransposition within producer cells in the absence of Env expression. Furthermore, new HERV-K integration sites were identified in a long-term culture of induced pluripotent stem cells, which express SOX2. Together, these results suggest the possibility that the strict dependence of HERV-K on SOX2 have allowed contribution of HERV-K to the protection of early embryos during evolution while limiting potentially harmful effects of HERV-K retrotransposition on host genome integrity to these early embryos.

  39. GCN2 regulates pancreatic β cell mass by sensing intracellular amino acid levels. International-journal Peer-reviewed

    Ayumi Kanno, Shun-Ichiro Asahara, Ayuko Furubayashi, Katsuhisa Masuda, Risa Yoshitomi, Emi Suzuki, Tomoko Takai, Maki Kimura-Koyanagi, Tomokazu Matsuda, Alberto Bartolome, Yushi Hirota, Norihide Yokoi, Yuka Inaba, Hiroshi Inoue, Michihiro Matsumoto, Kenichi Inoue, Takaya Abe, Fan-Yan Wei, Kazuhito Tomizawa, Wataru Ogawa, Susumu Seino, Masato Kasuga, Yoshiaki Kido

    JCI insight　5　(9)　2020/05/07

    DOI： 10.1172/jci.insight.128820 　

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    EIF2AK4, which encodes the amino acid deficiency-sensing protein GCN2, has been implicated as a susceptibility gene for type 2 diabetes in the Japanese population. However, the mechanism by which GCN2 affects glucose homeostasis is unclear. Here, we show that insulin secretion is reduced in individuals harboring the risk allele of EIF2AK4 and that maintenance of GCN2-deficient mice on a high-fat diet results in a loss of pancreatic β cell mass. Our data suggest that GCN2 senses amino acid deficiency in β cells and limits signaling by mechanistic target of rapamycin complex 1 to prevent β cell failure during the consumption of a high-fat diet.

  40. FTO Demethylates Cyclin D1 mRNA and Controls Cell-Cycle Progression. International-journal Peer-reviewed

    Mayumi Hirayama, Fan-Yan Wei, Takeshi Chujo, Shinya Oki, Maya Yakita, Daiki Kobayashi, Norie Araki, Nozomu Takahashi, Ryoji Yoshida, Hideki Nakayama, Kazuhito Tomizawa

    Cell reports　31　(1)　107464-107464　2020/04/07

    DOI： 10.1016/j.celrep.2020.03.028 　

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    N6-Methyladenosine (m6A) modification is the major chemical modification in mRNA that controls fundamental biological processes, including cell proliferation. Herein, we demonstrate that fat mass and obesity-associated (FTO) demethylates m6A modification of cyclin D1, the key regulator for G1 phase progression and controls cell proliferation in vitro and in vivo. FTO depletion upregulates cyclin D1 m6A modification, which in turn accelerates the degradation of cyclin D1 mRNA, leading to the impairment of G1 progression. m6A modification of cyclin D1 oscillates in a cell-cycle-dependent manner; m6A levels are suppressed during the G1 phase and enhanced during other phases. Low m6A levels during G1 are associated with the nuclear translocation of FTO from the cytosol. Furthermore, nucleocytoplasmic shuttling of FTO is regulated by casein kinase II-mediated phosphorylation of FTO. Our results highlight the role of m6A in regulating cyclin D1 mRNA stability and add another layer of complexity to cell-cycle regulation.

  41. Impaired bile acid metabolism with defectives of mitochondrial-tRNA taurine modification and bile acid taurine conjugation in the taurine depleted cats. International-journal Peer-reviewed

    Teruo Miyazaki, Sei-Ich Sasaki, Atsushi Toyoda, Fan-Yan Wei, Mutsumi Shirai, Yukio Morishita, Tadashi Ikegami, Kazuhito Tomizawa, Akira Honda

    Scientific reports　10　(1)　4915-4915　2020/03/18

    DOI： 10.1038/s41598-020-61821-6 　

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    Taurine that conjugates with bile acid (BA) and mitochondrial-tRNA (mt-tRNA) is a conditional essential amino acid in humans, similarly to cats. To better understand the influence of acquired depletion of taurine on BA metabolism, the profiling of BAs and its intermediates, BA metabolism-enzyme expression, and taurine modified mt-tRNAs were evaluated in the taurine deficient diet-supplemented cats. In the taurine depleted cats, taurine-conjugated bile acids in bile and taurine-modified mt-tRNA in liver were significantly decreased, whereas unconjugated BA in serum was markedly increased. Impaired bile acid metabolism in the liver was induced accompanied with the decreases of mitochondrial cholesterol 27-hydroxylase expression and mitochondrial activity. Consequently, total bile acid concentration in bile was significantly decreased by the low activity of mitochondrial bile acid synthesis. These results implied that the insufficient dietary taurine intake causes impaired bile acid metabolism, and in turn, a risk for the various diseases similar to the mitochondrial diseases would be enhanced.

  42. [Corrigendum]Phosphorylation of cortactin by cyclin-dependent kinase 5 modulates actin bundling by the dynamin 1-cortactin ring-like complex and formation of filopodia and lamellipodia in NG108-15 glioma-derived cells. International-journal Peer-reviewed

    Tadashi Abe, The Mon La, Yuuzi Miyagaki, Eri Oya, Fan-Yan Wei, Kento Sumida, Kenshiro Fujise, Tetsuya Takeda, Kazuhito Tomizawa, Kohji Takei, Hiroshi Yamada

    International journal of oncology　56　(3)　859-859　2020/03

    DOI： 10.3892/ijo.2020.4962 　

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    Subsequently to the publication of the above article, the authors have realized that the second‑listed author, The Mon La, had not been properly credited as one of the co‑writers of the paper. Therefore, the Authors' Contributions of the Declarations section of the article should have read as follows: Authors' contributions HY, KTa and TML designed the research and wrote the paper. HY, TA, YM, EO and TT performed mutant protein construction, protein purification and actin bundling experiments. TA and YM performed electron microscopy. EO, TML, KS and KF performed immunofluorescent microscopy, cell migration assay and analyzed data. FYW and KTo identified phosphorylation sites by MALDI‑MS. All authors read and approved the final manuscript. The authors apologize to the readership of the Journal for the misinformation in this regard, and for any inconvenience caused. [the original article was published in International Journal of Oncology 54: 550‑558, 2019; DOI: 10.3892/ijo.2018.4663].

  43. Movement of accessible plasma membrane cholesterol by GRAMD1 lipid transfer protein complex. International-journal Peer-reviewed

    Naito T, Ercan B, Krshnan L, Triebl A, Koh DHZ, Wei FY, Tomizawa K, Torta FT, Wenk MR, Saheki Y

    eLife　8　2019/11

    DOI： 10.7554/eLife.51401 　

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    Cholesterol is a major structural component of the plasma membrane (PM). The majority of PM cholesterol forms complexes with other PM lipids, making it inaccessible for intracellular transport. Transition of PM cholesterol between accessible and inaccessible pools maintains cellular homeostasis, but how cells monitor the accessibility of PM cholesterol remains unclear. We show that endoplasmic reticulum (ER)-anchored lipid transfer proteins, the GRAMD1s, sense and transport accessible PM cholesterol to the ER. GRAMD1s bind to one another and populate ER-PM contacts by sensing a transient expansion of the accessible pool of PM cholesterol via their GRAM domains. They then facilitate the transport of this cholesterol via their StART-like domains. Cells that lack all three GRAMD1s exhibit striking expansion of the accessible pool of PM cholesterol as a result of less efficient PM to ER transport of accessible cholesterol. Thus, GRAMD1s facilitate the movement of accessible PM cholesterol to the ER in order to counteract an acute increase of PM cholesterol, thereby activating non-vesicular cholesterol transport.

  44. 2-Methylthio Conversion of N6-Isopentenyladenosine in Mitochondrial tRNAs by CDK5RAP1 Promotes the Maintenance of Glioma-Initiating Cells. Peer-reviewed

    Yamamoto T, Fujimura A, Wei FY, Shinojima N, Kuroda JI, Mukasa A, Tomizawa K

    iScience　21　42-56　2019/11

    DOI： 10.1016/j.isci.2019.10.012 　

    eISSN： 2589-0042

  45. Mitochondrial localization of PABPN1 in oculopharyngeal muscular dystrophy. International-journal Peer-reviewed

    Tsukasa Doki, Satoshi Yamashita, Fan-Yan Wei, Kentaro Hara, Takahiro Yamamoto, Ziwei Zhang, Xiao Zhang, Nozomu Tawara, Hirotake Hino, Eiichiro Uyama, Takashi Kurashige, Hirofumi Maruyama, Kazuhito Tomizawa, Yukio Ando

    Laboratory investigation; a journal of technical methods and pathology　99　(11)　1728-1740　2019/11

    DOI： 10.1038/s41374-019-0243-8 　

    ISSN： 0023-6837

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    Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by ptosis, dysphagia, and weakness of proximal limbs. OPMD is caused by the expansion of polyalanine in poly(A)-binding protein, nuclear 1 (PABPN1). Although mitochondrial abnormality has been proposed as the possible etiology, the molecular pathogenesis is still poorly understood. The aim of the study was to specify the mechanism by which expanded PABPN1 causes mitochondrial dysfunction in OPMD. We evaluated whether transgenic mouse model of OPMD, by expressing expanded PABPN1, indeed causes mitochondrial abnormality associated with muscle degeneration. We also investigated the mechanism by which expanded PABPN1 would cause mitochondrial dysfunction in the mouse and cell models of OPMD. Mitochondrial localization of PABPN1 was observed in the muscle fibers of patients with OPMD. Moreover, abnormal accumulation of PABPN1 on the inner membrane of mitochondria and reduced expression of OXPHOS complexes were detected in the muscle fibers of the transgenic mice expressing expanded human PABPN1 with a 13-alanine stretch. In cells expressing PABPN1 with a 10-alanine or 18-alanine stretch, both types of PABPN1 accumulated in the mitochondria and interacted with TIM23 mitochondrial protein import complex, but PABPN1 with 18-alanine stretch decreased the cell viability and aggresome formation. We proposed that the abnormal accumulation of expanded PABPN1 in mitochondria may be associated with mitochondrial abnormality in OPMD.

  46. Mammalian NSUN2 introduces 5-methylcytidines into mitochondrial tRNAs International-journal Peer-reviewed

    Shinoda Saori, Kitagawa Sho, Nakagawa Shinichi, Wei Fan-Yan, Tomizawa Kazuhito, Araki Kimi, Araki Masatake, Suzuki Takeo, Suzuki Tsutomu

    NUCLEIC ACIDS RESEARCH　47　(16)　8734-8745　2019/09/19

    DOI： 10.1093/nar/gkz575 　

    ISSN： 0305-1048

  47. RNA修飾による癌の上皮間葉転換の制御(RNA modification regulates epithelial-to-mesenchymal transition in cancer)

    平山 真弓, 魏 范研, 中山 秀樹, 富澤 一仁

    日本癌学会総会記事　78回　P-3053　2019/09

    Publisher: (一社)日本癌学会

    ISSN： 0546-0476

  48. tRNA修飾酵素CDK5RAP1は膠芽腫幹細胞様細胞に重要である(Detoxification of N6-isopentenyladenosine by Cdk5rap1 controls the cell fate of glioma initiating cells)

    山本 隆広, 藤村 篤史, 魏 范研, 篠島 直樹, 黒田 順一郎, 武笠 晃丈, 富澤 一仁

    日本癌学会総会記事　78回　P-3054　2019/09

    Publisher: (一社)日本癌学会

    ISSN： 0546-0476

  49. Regulation of growth hormone biosynthesis by Cdk5 regulatory subunit associated protein 1-like 1 (CDKAL1) in pituitary adenomas. Peer-reviewed

    Takesue Y, Wei FY, Fukuda H, Tanoue Y, Yamamoto T, Chujo T, Shinojima N, Yano S, Morioka M, Mukasa A, Kuratsu J, Tomizawa K

    Endocrine journal　66　(9)　807-816　2019/09

    DOI： 10.1507/endocrj.EJ18-0536 　

    ISSN： 0918-8959

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    CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1) is a tRNA-modifying enzyme that catalyzes 2-methylthiolation (ms2) and has been implicated in the development of type 2 diabetes (T2D). CDKAL1-mediated ms2 is important for efficient protein translation and regulates insulin biosynthesis in pancreatic cells. Interestingly, an association between T2D and release of growth hormone (GH) has been reported in humans. However, it is unknown whether CDKAL1 is important for hormone production in the pituitary gland. The present study investigated the role of CDKAL1 in GH-producing pituitary adenomas (GHPAs). CDKAL1 activity was suppressed in GHPAs, as evidenced by a decrease in ms2, compared with non-functioning pituitary adenomas (NFPAs), which do not produce specific hormones. Downregulation of Cdkal1 using small interfering and short hairpin RNAs increased the biosynthesis and secretion of GH in rat GH3 cells. Depletion of Cdkal1 increased the cytosolic calcium level via downregulation of DnaJ heat shock protein family (Hsp40) member C10 (Dnajc10), which is an endoplasmic reticulum protein related to calcium homeostasis. This stimulated transcription of GH via upregulation of Pit-1. Moreover, CDKAL1 activity was highly sensitive to proteostatic stress and was upregulated by suppression of this stress. Taken together, these results suggest that dysregulation of CDKAL1 is involved in the pathogenesis of GHPAs, and that modulation of the proteostatic stress response might control CDKAL1 activity and facilitate treatment of GHPAs.

  50. Noninvasive diagnosis of TRIT1-related mitochondrial disorder by measuring i(6)A37 and ms(2)i(6)A37 modifications in tRNAs from blood and urine samples Peer-reviewed

    Toshiki Takenouchi, Fan-Yan Wei, Hisato Suzuki, Tomoko Uehara, Takao Takahashi, Yasushi Okazaki, Kenjiro Kosaki, Kazuhito Tomizawa

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A　179　(8)　1609-1614　2019/08

    DOI： 10.1002/ajmg.a.61211 　

    ISSN： 1552-4825

    eISSN： 1552-4833

  51. Regulation of mitochondrial iron homeostasis by sideroflexin 2. Peer-reviewed

    Mon EE, Wei FY, Ahmad RNR, Yamamoto T, Moroishi T, Tomizawa K

    The journal of physiological sciences : JPS　69　(2)　359-373　2019/03

    DOI： 10.1007/s12576-018-0652-2 　

    ISSN： 1880-6546

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    Mitochondrial iron is indispensable for heme biosynthesis and iron-sulfur cluster assembly. Several mitochondrial transmembrane proteins have been implicated to function in the biosynthesis of heme and iron-sulfur clusters by transporting reaction intermediates. However, several mitochondrial proteins related to iron metabolism remain uncharacterized. Here, we show that human sideroflexin 2 (SFXN2), a member of the SFXN protein family, is involved in mitochondrial iron metabolism. SFXN2 is an evolutionarily conserved protein that localized to mitochondria via its transmembrane domain. SFXN2-knockout (KO) cells had an increased mitochondrial iron content, which was associated with decreases in the heme content and heme-dependent enzyme activities. By contrast, the activities of iron-sulfur cluster-dependent enzymes were unchanged in SFXN2-KO cells. Moreover, abnormal iron metabolism impaired mitochondrial respiration in SFXN2-KO cells and accelerated iron-mediated death of these cells. Our findings demonstrate that SFXN2 functions in mitochondrial iron metabolism by regulating heme biosynthesis.

  52. Phosphorylation of cortactin by cyclin-dependent kinase 5 modulates actin bundling by the dynamin 1-cortactin ring-like complex and formation of filopodia and lamellipodia in NG108-15 glioma-derived cells. International-journal Peer-reviewed

    Tadashi Abe, The Mon La, Yuuzi Miyagaki, Eri Oya, Fan-Yan Wei, Kento Sumida, Kenshiro Fujise, Tetsuya Takeda, Kazuhito Tomizawa, Kohji Takei, Hiroshi Yamada

    International journal of oncology　54　(2)　550-558　2019/02

    DOI： 10.3892/ijo.2018.4663 　

    ISSN： 1019-6439

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    Dynamin copolymerizes with cortactin to form a ring‑like complex that bundles and stabilizes actin filaments. Actin bundle formation is crucial for generation of filopodia and lamellipodia, which guide migration, invasion, and metastasis of cancer cells. However, it is unknown how the dynamin‑cortactin complex regulates actin bundle formation. The present study investigated phosphorylation of cortactin by cyclin‑dependent kinase 5 (CDK5) and its effect on actin bundle formation by the dynamin‑cortactin complex. CDK5 directly phosphorylated cortactin at T145/T219 in vitro. Phosphomimetic mutants in which one or both of these threonine residues was substituted by aspartate were used. The three phosphomimetic mutants (T145D, T219D and T145DT219D) had a decreased affinity for F‑actin. Furthermore, electron microscopy demonstrated that these phosphomimetic mutants could not form a ring‑like complex with dynamin 1. Consistently, the dynamin 1‑phosphomimetic cortactin complexes exhibited decreased actin‑bundling activity. Expression of the phosphomimetic mutants resulted in not only aberrant lamellipodia and short filopodia but also cell migration in NG108‑15 glioma‑derived cells. These results indicate that phosphorylation of cortactin by CDK5 regulates formation of lamellipodia and filopodia by modulating dynamin 1/cortactin‑dependent actin bundling. Taken together, these findings suggest that CDK5 is a potential molecular target for anticancer therapy.

  53. フェニルアラニンtRNAメチル化酵素FTSJ1の機能喪失による精神遅滞発症の分子機構の解明

    上里 美也子, 中條 岳志, 魏 范研, 高松 岳矢, 富澤 一仁, 松下 正之

    琉球医学会誌　38　(1-4)　119-119　2019

    Publisher: 琉球医学会

    ISSN： 1346-888X

  54. tRNA modifications and islet function. Peer-reviewed

    Wei FY, Tomizawa K

    Diabetes, obesity & metabolism　20 Suppl 2　20-27　2018/09

    DOI： 10.1111/dom.13405 　

    ISSN： 1462-8902

  55. Study Design of a Phase II Clinical Trial to Assess the Efficacy and Safety of Eperisone in Japanese Type 2 Diabetes Patients with Risk and Non-risk Alleles of CDKAL1. Peer-reviewed

    Sakakida K, Wei FY, Senokuchi T, Shimoda S, Kakuma T, Araki E, Tomizawa K, Eperisone for, Diabetes with, Impaired tRNA (EDIT, Study Group

    Acta medica Okayama　72　(4)　423-426　2018/08

    DOI： 10.18926/AMO/56182 　

    ISSN： 0386-300X

  56. YAP/TAZ are essential for TGF-β2–mediated conjunctival fibrosis Peer-reviewed

    Akiko Futakuchi, Toshihiro Inoue, Fan-Yan Wei, Miyuki Inoue-Mochita, Tomokazu Fujimoto, Kazuhito Tomizawa, Hidenobu Tanihara

    Investigative Ophthalmology and Visual Science　59　(7)　3069-3078　2018/06/01

    Publisher: Association for Research in Vision and Ophthalmology Inc.

    DOI： 10.1167/iovs.18-24258 　

    ISSN： 1552-5783 0146-0404

    eISSN： 1552-5783

  57. Sirtuin 7 is involved in the consolidation of fear memory in mice Peer-reviewed

    Md Safiqul Islam, Fan Yan Wei, Kunimasa Ohta, Naoki Shigematsu, Takaichi Fukuda, Kazuhito Tomizawa, Tatsuya Yoshizawa, Kazuya Yamagata

    Biochemical and Biophysical Research Communications　495　(1)　261-266　2018/01/01

    DOI： 10.1016/j.bbrc.2017.10.159 　

    ISSN： 0006-291X

    eISSN： 1090-2104

  58. Defective Mitochondrial tRNA Taurine Modification Activates Global Proteostress and Leads to Mitochondrial Disease Peer-reviewed

    Md Fakruddin, Fan-Yan Wei, Takeo Suzuki, Kana Asano, Takashi Kaieda, Akiko Omori, Ryoma Izumi, Atsushi Fujimura, Taku Kaitsuka, Keishi Miyata, Kimi Araki, Yuichi Oike, Luca Scorrano, Tsutomu Suzuki, Kazuhito Tomizawa

    Cell Reports　22　(2)　482-496　2018

    Publisher: Elsevier B.V.

    DOI： 10.1016/j.celrep.2017.12.051 　

    ISSN： 2211-1247

    eISSN： 2211-1247

  59. Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease Peer-reviewed

    Kana Asano, Takeo Suzuki, Ayaka Saito, Fan-Yan Wei, Yoshiho Ikeuchi, Tomoyuki Numata, Ryou Tanaka, Yoshihisa Yamane, Takeshi Yamamoto, Takanobu Goto, Yoshihito Kishita, Kei Murayama, Akira Ohtake, Yasushi Okazaki, Kazuhito Tomizawa, Yuriko Sakaguchi, Tsutomu Suzuki

    Nucleic Acids Research　46　(4)　1565-1583　2018/01

    Publisher: Oxford University Press ({OUP})

    DOI： 10.1093/nar/gky068 　

    ISSN： 0305-1048

  60. Cdk5rap1-mediated 2-methylthio-&ITN&IT6-isopentenyladenosine modification is absent from nuclear-derived RNA species Peer-reviewed

    Md. Fakruddin, Fan Yan Wei, Shohei Emura, Shigeru Matsuda, Takehiro Yasukawa, Dongchon Kang, Kazuhito Tomizawa

    NUCLEIC ACIDS RESEARCH　45　(20)　11954-11961　2017/11

    DOI： 10.1093/nar/gkx819 　

    ISSN： 0305-1048

    eISSN： 1362-4962

  61. Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics. International-journal Peer-reviewed

    Takaaki Akaike, Tomoaki Ida, Fan-Yan Wei, Motohiro Nishida, Yoshito Kumagai, Md Morshedul Alam, Hideshi Ihara, Tomohiro Sawa, Tetsuro Matsunaga, Shingo Kasamatsu, Akiyuki Nishimura, Masanobu Morita, Kazuhito Tomizawa, Akira Nishimura, Satoshi Watanabe, Kenji Inaba, Hiroshi Shima, Nobuhiro Tanuma, Minkyung Jung, Shigemoto Fujii, Yasuo Watanabe, Masaki Ohmuraya, Péter Nagy, Martin Feelisch, Jon M Fukuto, Hozumi Motohashi

    Nature communications　8　(1)　1177-1177　2017/10/27

    DOI： 10.1038/s41467-017-01311-y 　

    More details Close

    Cysteine hydropersulfide (CysSSH) occurs in abundant quantities in various organisms, yet little is known about its biosynthesis and physiological functions. Extensive persulfide formation is apparent in cysteine-containing proteins in Escherichia coli and mammalian cells and is believed to result from post-translational processes involving hydrogen sulfide-related chemistry. Here we demonstrate effective CysSSH synthesis from the substrate L-cysteine, a reaction catalyzed by prokaryotic and mammalian cysteinyl-tRNA synthetases (CARSs). Targeted disruption of the genes encoding mitochondrial CARSs in mice and human cells shows that CARSs have a crucial role in endogenous CysSSH production and suggests that these enzymes serve as the principal cysteine persulfide synthases in vivo. CARSs also catalyze co-translational cysteine polysulfidation and are involved in the regulation of mitochondrial biogenesis and bioenergetics. Investigating CARS-dependent persulfide production may thus clarify aberrant redox signaling in physiological and pathophysiological conditions, and suggest therapeutic targets based on oxidative stress and mitochondrial dysfunction.

  62. Tctex-1 controls ciliary resorption by regulating branched actin polymerization and endocytosis Peer-reviewed

    Masaki Saito, Wataru Otsu, Kuo-Shun Hsu, Jen-Zen Chuang, Teruyuki Yanagisawa, Vincent Shieh, Taku Kaitsuka, Fan-Yan Wei, Kazuhito Tomizawa, Ching-Hwa Sung

    EMBO REPORTS　18　(8)　1460-1472　2017/08

    DOI： 10.15252/embr.201744204 　

    ISSN： 1469-221X

    eISSN： 1469-3178

  63. Erythropoietin facilitates definitive endodermal differentiation of mouse embryonic stem cells via activation of ERK signaling Peer-reviewed

    Taku Kaitsuka, Kohei Kobayashi, Wakako Otsuka, Takuya Kubo, Farzana Hakim, Fan-Yan Wei, Nobuaki Shiraki, Shoen Kume, Kazuhito Tomizawa

    AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY　312　(5)　C573-C582　2017/05

    DOI： 10.1152/ajpcell.00071.2016 　

    ISSN： 0363-6143

    eISSN： 1522-1563

  64. Synthesis of L-cysteine derivatives containing stable sulfur isotopes and application of this synthesis to reactive sulfur metabolome Peer-reviewed

    Katsuhiko Ono, Minkyung Jung, Tianli Zhang, Hiroyasu Tsutsuki, Hiroshi Sezaki, Hideshi Ihara, Fan-Yan Wei, Kazuhito Tomizawa, Takaaki Akaike, Tomohiro Sawa

    FREE RADICAL BIOLOGY AND MEDICINE　106　69-79　2017/05

    DOI： 10.1016/j.freeradbiomed.2017.02.023 　

    ISSN： 0891-5849

    eISSN： 1873-4596

  65. Reactive sulfur species regulate tRNA methylthiolation and contribute to insulin secretion Peer-reviewed

    Nozomu Takahashi, Fan-Yan Wei, Sayaka Watanabe, Mayumi Hirayama, Yuya Ohuchi, Atsushi Fujimura, Taku Kaitsuka, Isao Ishii, Tomohiro Sawa, Hideki Nakayama, Takaaki Akaike, Kazuhito Tomizawa

    NUCLEIC ACIDS RESEARCH　45　(1)　435-445　2017/01

    DOI： 10.1093/nar/gkw745 　

    ISSN： 0305-1048

    eISSN： 1362-4962

  66. HDAC9 regulates the alternative lengthening of telomere (ALT) pathway via the formation of ALT-associated PML bodies Peer-reviewed

    Mohd. Raeed Jamiruddin, Taku Kaitsuka, Farzana Hakim, Atsushi Fujimura, Fan-Yan Wei, Hisato Saitoh, Kazuhito Tomizawa

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　481　(1-2)　25-30　2016/12

    DOI： 10.1016/j.bbrc.2016.11.026 　

    ISSN： 0006-291X

    eISSN： 1090-2104

  67. Mtu1-Mediated Thiouridine Formation of Mitochondrial tRNAs Is Required for Mitochondrial Translation and Is Involved in Reversible Infantile Liver Injury Peer-reviewed

    Wu Yong, Wei Fan-Yan, Kawarada Layla, Suzuki Takeo, Araki Kimi, Komohara Yoshihiro, Fujimura Atsushi, Kaitsuka Taku, Takeya Motohiro, Oike Yuichi, Suzuki Tsutomu, Tomizawa Kazuhito

    PLOS GENETICS　12　(9)　2016/09

    DOI： 10.1371/journal.pgen.1006355 　

    ISSN： 1553-7404

  68. Mtu1-Mediated Thiouridine Formation of Mitochondrial tRNAs Is Required for Mitochondrial Translation and Is Involved in Reversible Infantile Liver Injury Peer-reviewed

    Yong Wu, Fan-Yan Wei, Layla Kawarada, Takeo Suzuki, Kimi Araki, Yoshihiro Komohara, Atsushi Fujimura, Taku Kaitsuka, Motohiro Takeya, Yuichi Oike, Tsutomu Suzuki, Kazuhito Tomizawa

    PLoS Genetics　12　(9)　e1006355　2016/09/01

    Publisher: Public Library of Science

    DOI： 10.1371/journal.pgen.1006355 　

    ISSN： 1553-7404 1553-7390

  69. Evolving specificity of tRNA 3-methyl-cytidine-32 (m(3)C32) modification: a subset of tRNAs(Ser) requires N-6-isopentenylation of A37 Peer-reviewed

    Aneeshkumar G. Arimbasseri, James Iben, Fan-Yan Wei, Keshab Rijal, Kazuhito Tomizawa, Markus Hafner, Richard J. Maraia

    RNA　22　(9)　1400-1410　2016/09

    DOI： 10.1261/rna.056259.116 　

    ISSN： 1355-8382

    eISSN： 1469-9001

  70. Oxytocin Protects against Stress-Induced Cell Death in Murine Pancreatic beta-Cells Peer-reviewed

    Sayaka Watanabe, Fan-Yan Wei, Tomomi Matsunaga, Nanami Matsunaga, Taku Kaitsuka, Kazuhito Tomizawa

    SCIENTIFIC REPORTS　6　25185　2016/05

    DOI： 10.1038/srep25185 　

    ISSN： 2045-2322

  71. Lack of tRNA-i6A modification causes mitochondrial-like metabolic deficiency in S-pombe by limiting activity of cytosolic tRNA(Tyr), not mito-tRNA Peer-reviewed

    Tek N. Lamichhane, Aneeshkumar G. Arimbasseri, Keshab Rijal, James R. Iben, Fan Yan Wei, Kazuhito Tomizawa, Richard J. Maraia

    RNA　22　(4)　583-596　2016/04

    DOI： 10.1261/rna.054064.115 　

    ISSN： 1355-8382

    eISSN： 1469-9001

  72. Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization Peer-reviewed

    Keiichiro Hayashi, Hiroyuki Michiue, Hiroshi Yamada, Katsuyoshi Takata, Hiroki Nakayama, Fan-Yan Wei, Atsushi Fujimura, Hiroshi Tazawa, Akira Asai, Naohisa Ogo, Hiroyuki Miyachi, Tei-ichi Nishiki, Kazuhito Tomizawa, Kohji Takei, Hideki Matsui

    SCIENTIFIC REPORTS　6　23372　2016/03

    DOI： 10.1038/srep23372 　

    ISSN： 2045-2322

  73. Molecular basis of tRNA methylthiolation and the pathological implications Peer-reviewed

    Fan-Yan Wei, Kazuhito Tomizawa

    Seikagaku　88　(3)　328-334　2016

    Publisher: Japanese Biochemical Society

    DOI： 10.14952/SEIKAGAKU.2016.880328 　

    ISSN： 2189-0544 0037-1017

  74. Possible role of cortactin phosphorylation by protein kinase C in actin-bundle formation at growth cone Peer-reviewed

    Hiroshi Yamada, Tatsuya Kikuchi, Toshio Masumoto, Fan-Yan Wei, Tadashi Abe, Tetsuya Takeda, Teiichi Nishiki, Kazuhito Tomizawa, Masami Watanabe, Hideki Matsui, Kohji Takei

    BIOLOGY OF THE CELL　107　(9)　319-330　2015/09

    DOI： 10.1111/boc.201500032 　

    ISSN： 0248-4900

    eISSN： 1768-322X

  75. A cautionary tale: the non-causal association between type 2 diabetes risk SNP, rs7756992, and levels of non-coding RNA, CDKAL1-v1 Peer-reviewed

    Jonathan M. Locke, Fan-Yan Wei, Kazuhito Tomizawa, Michael N. Weedon, Lorna W. Harries

    DIABETOLOGIA　58　(4)　745-748　2015/04

    DOI： 10.1007/s00125-015-3508-9 　

    ISSN： 0012-186X

    eISSN： 1432-0428

  76. Cdk5rap1-Mediated 2-Methylthio Modification of Mitochondrial tRNAs Governs Protein Translation and Contributes to Myopathy in Mice and Humans Peer-reviewed

    Fan-Yan Wei, Bo Zhou, Takeo Suzuki, Keishi Miyata, Yoshihiro Ujihara, Haruki Horiguchi, Nozomu Takahashi, Peiyu Xie, Hiroyuki Michiue, Atsushi Fujimura, Taku Kaitsuka, Hideki Matsui, Yasutoshi Koga, Satoshi Mohri, Tsutomu Suzuki, Yuichi Oike, Kazuhito Tomizawa

    CELL METABOLISM　21　(3)　428-442　2015/03

    DOI： 10.1016/j.cmet.2015.01.019 　

    ISSN： 1550-4131

    eISSN： 1932-7420

  77. Identification of a splicing variant that regulates type 2 diabetes risk factor CDKAL1 level by a coding-independent mechanism in human Peer-reviewed

    Bo Zhou, Fan-Yan Wei, Narumi Kanai, Atsushi Fujimura, Taku Kaitsuka, Kazuhito Tomizawa

    HUMAN MOLECULAR GENETICS　23　(17)　4639-4650　2014/09

    DOI： 10.1093/hmg/ddu184 　

    ISSN： 0964-6906

    eISSN： 1460-2083

  78. Efficient Transduction of 11 Poly-arginine Peptide in an Ischemic Lesion of Mouse Brain Peer-reviewed

    Yuki Gotanda, Fan-Yan Wei, Hideki Harada, Keisuke Ohta, Kei-ichiro Nakamura, Kazuhito Tomizawa, Kazuo Ushijima

    JOURNAL OF STROKE & CEREBROVASCULAR DISEASES　23　(8)　2023-2030　2014/09

    DOI： 10.1016/j.jstrokecerebrovasdis.2014.02.027 　

    ISSN： 1052-3057

    eISSN： 1532-8511

  79. High Oxygen Condition Facilitates the Differentiation of Mouse and Human Pluripotent Stem Cells into Pancreatic Progenitors and Insulin-producing Cells* Peer-reviewed

    Farzana Hakim, Taku Kaitsuka, Jamiruddin Mohd Raeed, Fan-Yan Wei, Nobuaki Shiraki, Tadayuki Akagi, Takashi Yokota, Shoen Kume, Kazuhito Tomizawa

    JOURNAL OF BIOLOGICAL CHEMISTRY　289　(14)　9623-9638　2014/04

    DOI： 10.1074/jbc.M113.524363 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  80. Generation of Functional Insulin-Producing Cells From Mouse Embryonic Stem Cells Through 804G Cell-Derived Extracellular Matrix and Protein Transduction of Transcription Factors Peer-reviewed

    Taku Kaitsuka, Hirofumi Noguchi, Nobuaki Shiraki, Takuya Kubo, Fan-Yan Wei, Farzana Hakim, Shoen Kume, Kazuhito Tomizawa

    STEM CELLS TRANSLATIONAL MEDICINE　3　(1)　114-127　2014/01

    DOI： 10.5966/sctm.2013-0075 　

    ISSN： 2157-6564

    eISSN： 2157-6580

  81. Quantitative PCR Measurement of tRNA 2-Methylthio Modification for Assessing Type 2 Diabetes Risk Peer-reviewed

    Peiyu Xie, Fan-Yan Wei, Shoji Hirata, Taku Kaitsuka, Tsutomu Suzuki, Takeo Suzuki, Kazuhito Tomizawa

    CLINICAL CHEMISTRY　59　(11)　1604-1612　2013/11

    DOI： 10.1373/clinchem.2013.210401 　

    ISSN： 0009-9147

    eISSN： 1530-8561

  82. Cyclin G2 Promotes HypoxiaDriven Local Invasion of Glioblastoma by Orchestrating Cytoskeletal Dynamics Peer-reviewed

    Atsushi Fujimura, Hiroyuki Michiue, Yan Cheng, Atsuhito Uneda, Yasunari Tani, Tei-ichi Nishiki, Tomotsugu Ichikawa, Fan-Yan Wei, Kazuhito Tomizawa, Hideki Matsui

    NEOPLASIA　15　(11)　1272-+　2013/11

    DOI： 10.1593/neo.131440 　

    ISSN： 1522-8002

    eISSN： 1476-5586

  83. Functional characterization of Cdkal1, a risk factor of type 2 diabetes, and the translational opportunities.

    Watanabe, S, Wei, F.-Y, Tomizawa, K

    Drug Discov. Today　10　(2)　65-68　2013

    DOI： 10.1016/j.ddmod.2012.12.001 　

  84. Induction of autophagic cell death of glioma-initiating cells by cell-penetrating D-isomer peptides consisting of Pas and the p53 C-terminus Peer-reviewed

    Yutaka Ueda, Fan-Yan Wei, Taku-ichiro Hide, Hiroyuki Michiue, Kentaro Takayama, Taku Kaitsuka, Hideo Nakamura, Keishi Makino, Jun-ichi Kuratsu, Shiroh Futaki, Kazuhito Tomizawa

    BIOMATERIALS　33　(35)　9061-9069　2012/12

    DOI： 10.1016/j.biomaterials.2012.09.003 　

    ISSN： 0142-9612

    eISSN： 1878-5905

  85. Anks4b, a Novel Target of HNF4 alpha Protein, Interacts with GRP78 Protein and Regulates Endoplasmic Reticulum Stress-induced Apoptosis in Pancreatic beta-Cells Peer-reviewed

    Yoshifumi Sato, Mitsutoki Hatta, Md Fazlul Karim, Tomohiro Sawa, Fan-Yan Wei, Shoki Sato, Mark A. Magnuson, Frank J. Gonzalez, Kazuhito Tomizawa, Takaaki Akaike, Tatsuya Yoshizawa, Kazuya Yamagata

    JOURNAL OF BIOLOGICAL CHEMISTRY　287　(27)　23236-23245　2012/06

    DOI： 10.1074/jbc.M112.368779 　

    ISSN： 0021-9258

  86. RGS2 mediates the anxiolytic effect of oxytocin Peer-reviewed

    Naoki Okimoto, Oliver J. Bosch, David A. Slattery, Konstanze Pflaum, Hiroaki Matsushita, Fan-Yan Wei, Masayasu Ohmori, Tei-ichi Nishiki, Iori Ohmori, Yuji Hiramatsu, Hideki Matsui, Inga D. Neumann, Kazuhito Tomizawa

    BRAIN RESEARCH　1453　26-33　2012/05

    DOI： 10.1016/j.brainres.2012.03.012 　

    ISSN： 0006-8993

  87. Development of type 2 diabetes caused by a deficiency of a tRNA(lys) modification Peer-reviewed

    Fan-Yan Wei, Kazuhito Tomizawa

    ISLETS　4　(1)　71-73　2012/01

    DOI： 10.4161/isl.18262 　

    ISSN： 1938-2014

  88. Functional loss of Cdkal1, a novel tRNA modification enzyme, causes the development of type 2 diabetes Peer-reviewed

    Fan-Yan Wei, Kazuhito Tomizawa

    ENDOCRINE JOURNAL　58　(10)　819-825　2011/10

    DOI： 10.1507/endocrj.EJ11-0099 　

    ISSN： 0918-8959

  89. Deficit of tRNA(Lys) modification by Cdkal1 causes the development of type 2 diabetes in mice Peer-reviewed

    Fan-Yan Wei, Takeo Suzuki, Sayaka Watanabe, Satoshi Kimura, Taku Kaitsuka, Atsushi Fujimura, Hideki Matsui, Mohamed Atta, Hiroyuki Michiue, Marc Fontecave, Kazuya Yamagata, Tsutomu Suzuki, Kazuhito Tomizawa

    JOURNAL OF CLINICAL INVESTIGATION　121　(9)　3598-3608　2011/09

    DOI： 10.1172/JCI58056 　

    ISSN： 0021-9738

  90. Expression of a Constitutively Active Calcineurin Encoded by an Intron-Retaining mRNA in Follicular Keratinocytes Peer-reviewed

    Atsushi Fujimura, Hiroyuki Michiue, Tei-ichi Nishiki, Iori Ohmori, Fan-Yan Wei, Hideki Matsui, Kazuhito Tomizawa

    PLOS ONE　6　(3)　e17685　2011/03

    DOI： 10.1371/journal.pone.0017685 　

    ISSN： 1932-6203

  91. Identification of Eukaryotic and Prokaryotic Methylthiotransferase for Biosynthesis of 2-Methylthio-N-6-threonylcarbamoyladenosine in tRNA Peer-reviewed

    Simon Arragain, Samuel K. Handelman, Farhad Forouhar, Fan-Yan Wei, Kazuhito Tomizawa, John F. Hunt, Thierry Douki, Marc Fontecave, Etienne Mulliez, Mohamed Atta

    JOURNAL OF BIOLOGICAL CHEMISTRY　285　(37)　28425-28433　2010/09

    DOI： 10.1074/jbc.M110.106831 　

    ISSN： 0021-9258

  92. Cdk5 in presynapses Peer-reviewed

    Fan-Yan Wei, Kazuhito Tomizawa

    Cyclin Dependent Kinase 5 (Cdk5)　25-33　2008

    Publisher: Springer US

    DOI： 10.1007/978-0-387-78887-6_3 　

  93. Cyclin-dependent kinase 5 (Cdk5): A potential therapeutic target for the treatment of neurodegenerative diseases and diabetes mellitus Peer-reviewed

    Fan-Yan Wei, Kazuhito Tomizawa

    MINI-REVIEWS IN MEDICINAL CHEMISTRY　7　(10)　1070-1074　2007/10

    DOI： 10.2174/138955707782110114 　

    ISSN： 1389-5575

  94. Major Cdk5-dependent phosphorylation sites of amphiphysin 1 are implicated in the regulation of the membrane binding and endocytosis Peer-reviewed

    Shuang Liang, Fan-Yan Wei, Yu-Mei Wu, Kenji Tanabe, Tadashi Abe, Yoshiya Oda, Yumi Yoshida, Hiroshi Yamada, Hideki Matsui, Kazuhito Tomizawa, Kohji Takei

    JOURNAL OF NEUROCHEMISTRY　102　(5)　1466-1476　2007/09

    DOI： 10.1111/j.1471-4159.2007.04507.x 　

    ISSN： 0022-3042

  95. Enhancement of the efficiency of phosphoproteomic identification by removing phosphates after phosphopeptide enrichment Peer-reviewed

    Yasushi Ishihama, Fan-Yan Wei, Ken Aoshima, Toshitaka Sato, Junro Kuromitsu, Yoshiya Oda

    JOURNAL OF PROTEOME RESEARCH　6　(3)　1139-1144　2007/03

    DOI： 10.1021/pr060452w 　

    ISSN： 1535-3893

  96. Cdk5-dependent regulation of glucose-stimulated insulin secretion Peer-reviewed

    FY Wei, K Nagashima, T Ohshima, Y Saheki, YF Lu, M Matsushita, Y Yamada, K Mikoshiba, Y Seino, H Matsui, K Tomizawa

    NATURE MEDICINE　11　(10)　1104-1108　2005/10

    DOI： 10.1038/nm1299 　

    ISSN： 1078-8956

  97. BETA2/NeuroD protein can be transduced into cells due to an arginine- and lysine-rich sequence Peer-reviewed

    H Noguchi, S Bonner-Weir, FY Wei, M Matsushita, S Matsumoto

    DIABETES　54　(10)　2859-2866　2005/10

    DOI： 10.2337/diabetes.54.10.2859 　

    ISSN： 0012-1797

  98. A new approach to inhibiting astrocytic IP3-induced intracellular calcium increase in an astrocyte-neuron co-culture system Peer-reviewed

    Y Saheki, ST Li, M Matsushita, YM Wu, WH Cai, FY Wei, YF Lu, A Moriwaki, K Tomizawa, H Matsui

    BRAIN RESEARCH　1055　(1-2)　196-201　2005/09

    DOI： 10.1016/j.brainres.2005.06.056 　

    ISSN： 0006-8993

  99. Channel function is dissociated from the intrinsic kinase activity and autophosphorylation of TRPM7/ChaK1 Peer-reviewed

    M Matsushita, JA Kozak, Y Shimizu, DT McLachlin, H Yamaguchi, FY Wei, K Tomizawa, H Matsui, BT Chait, MD Cahalan, AC Nairn

    JOURNAL OF BIOLOGICAL CHEMISTRY　280　(21)　20793-20803　2005/05

    DOI： 10.1074/jbc.M413671200 　

    ISSN： 0021-9258

  100. Physiological function of cyclin-dependent kinase 5 in neuron Peer-reviewed

    FY Wei, K Tomizawa

    SEIKAGAKU　77　(5)　436-439　2005/05

    ISSN： 0037-1017

  101. Regulation of synaptic vesicle recycling by calcineurin in different vesicle pools Peer-reviewed

    S Kumashiro, YF Lu, K Tomizawa, M Matsushita, FY Wei, H Matsui

    NEUROSCIENCE RESEARCH　51　(4)　435-443　2005/04

    DOI： 10.1016/j.neures.2004.12.018 　

    ISSN： 0168-0102

  102. Control of cyclin-dependent kinase 5 (Cdk5) activity by glutamatergic regulation of p35 stability Peer-reviewed

    FY Wei, K Tomizawa, T Ohshima, A Asada, T Saito, C Nguyen, JA Bibb, K Ishiguro, AB Kulkarni, HC Pant, K Mikoshiba, H Matsui, S Hisanaga

    JOURNAL OF NEUROCHEMISTRY　93　(2)　502-512　2005/04

    DOI： 10.1111/j.1471-4159.2005.03058.x 　

    ISSN： 0022-3042

  103. The NH2 terminus of influenza virus hemagglutinin-2 subunit peptides enhances the antitumor potency of polyarginine-mediated p53 protein transduction Peer-reviewed

    H Michiue, K Tomizawa, FY Wei, M Matsushita, YF Lu, T Ichikawa, T Tamiya, Date, I, H Matsui

    JOURNAL OF BIOLOGICAL CHEMISTRY　280　(9)　8285-8289　2005/03

    DOI： 10.1074/jbc.M412430200 　

    ISSN： 0021-9258

  104. PDX-1 protein is internalized by lipid raft-dependent macropinocytosis Peer-reviewed

    H Noguchi, S Matsumoto, T Okitsu, Y Iwanaga, Y Yonekawa, H Nagata, M Matsushita, FY Wei, H Matsui, K Minami, S Seino, Y Masui, S Futaki, K Tanaka

    CELL TRANSPLANTATION　14　(9)　637-645　2005

    DOI： 10.3727/000000005783982648 　

    ISSN： 0963-6897

  105. Critical role of calpain-mediated cleavage of calcineurin in excitotoxic neurodegeneration Peer-reviewed

    HY Wu, K Tomizawa, Y Oda, FY Wei, YF Lu, M Matsushita, ST Li, A Moriwaki, H Matsui

    JOURNAL OF BIOLOGICAL CHEMISTRY　279　(6)　4929-4940　2004/02

    DOI： 10.1074/jbc.M309767200 　

    ISSN： 0021-9258

  106. Cophosphorylation of amphiphysin 1 and dynamin 1 by Cdk5 regulates clathrin-mediated endocytosis of synaptic vesicles Peer-reviewed

    K Tomizawa, S Sunada, YF Lu, Y Oda, M Kinuta, T Ohshima, T Saito, FY Wei, M Matsushita, ST Li, K Tsutsui, S Hisanaga, K Mikoshiba, K Takei, H Matsui

    JOURNAL OF CELL BIOLOGY　163　(4)　813-824　2003/11

    DOI： 10.1083/jcb.200308110 　

    ISSN： 0021-9525

  107. Brain-derived neurotrophic factor-induced phosphorylation of neurofilament-H subunit in primary cultures of embryo rat cortical neurons Peer-reviewed

    H Tokuoka, T Saito, H Yorifuji, FY Wei, T Kishimoto, S Hisanaga

    JOURNAL OF CELL SCIENCE　113　(6)　1059-1068　2000/03

    ISSN： 0021-9533

  108. Cell-penetrating D-isomer Peptides Consisting of Pas and the p53 C-terminus Induce Autophagic Cell Death of Glioma-initiating Cells Peer-reviewed

    Ueda, Y, Fan-Yan Wei, Hide, T, Michiue, H, Takayama, K, Kaitsuka, T, Nakamura, H, Makino, K, Kuratsu, J, Futaki, S, Tomizawa, K

    Biomaterials, in press,

Show all ︎Show first 5

Misc. 78

  1. RNA modification regulates cell cycle in cancers

    平山真弓, 魏范研, 中條岳志, 指田吾郎, 富澤一仁

    日本癌学会学術総会抄録集(Web)　83rd　2024

  2. ミトコンドリア内転写開始複合体の可視化システムの開発

    松田盛, 中村行則, 魏范研

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

  3. ミトコンドリア転写伸長因子TEFMはミトコンドリアDNAの複製と転写のバランス制御に重要な役割を果たす

    安川武宏, 安川武宏, 松田盛, 松田盛, 中山益成, 都由羅, 石内崇, 石内崇, 八木美佳子, 八木美佳子, SJOERD Wanrooij, 中田和人, 魏范研, 一柳健司, 一柳健司, 佐々木裕之, 康東天

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

  4. 炎症性腸疾患モデルのxCT阻害による抗炎症作用

    岩城 英也, 関根 弘樹, 村上 昌平, 加藤 伸史, 北村 洋, 魏 范研, 佐藤 英世, 福田 真嗣, 曽我 朋義, 角田 洋一, 正宗 淳, 本橋 ほづみ

    日本生化学会大会プログラム・講演要旨集　96回　[1T08a-238)]　2023/10

    Publisher: (公社)日本生化学会

  5. シスチン/グルタミン酸トランスポーターxCTの阻害による慢性炎症性腸疾患モデルでの抗炎症作用

    岩城 英也, 関根 弘樹, 村上 昌平, 加藤 伸史, 北村 大志, 魏 范研, 福田 真嗣, 曽我 朋義, 角田 洋一, 正宗 淳, 本橋 ほづみ

    日本生化学会大会プログラム・講演要旨集　95回　1T08a-07　2022/11

    Publisher: (公社)日本生化学会

  6. シスチン/グルタミン酸トランスポーターxCTの阻害による慢性炎症性腸疾患モデルでの抗炎症作用

    岩城 英也, 関根 弘樹, 村上 昌平, 加藤 伸史, 北村 大志, 魏 范研, 福田 真嗣, 曽我 朋義, 角田 洋一, 正宗 淳, 本橋 ほづみ

    日本生化学会大会プログラム・講演要旨集　95回　1T08a-07　2022/11

    Publisher: (公社)日本生化学会

  7. RNA修飾代謝物のN6-methyladenosine(m6A)は受容体応答を引き起こす新規液性因子である

    小川亜希子, 小川亜希子, 名切千彩恵, 志甫谷渉, 井上飛鳥, 川上耕季, 平塚寿々音, 青木淳賢, 青木淳賢, 伊藤康裕, 鈴木健夫, 鈴木勉, 井上俊洋, 濡木理, 富澤一仁, 魏范研, 魏范研

    日本生化学会大会(Web)　94th　2021

  8. tRNA修飾酵素CDK5RAP1は膠芽腫幹細胞様細胞に重要である(Detoxification of N6-isopentenyladenosine by Cdk5rap1 controls the cell fate of glioma initiating cells)

    山本 隆広, 藤村 篤史, 魏 范研, 篠島 直樹, 黒田 順一郎, 武笠 晃丈, 富澤 一仁

    日本癌学会総会記事　78回　P-3054　2019/09

    Publisher: 日本癌学会

    ISSN： 0546-0476

  9. 【ミトコンドリアと疾患・老化 細胞内代謝プラントとしての役割を知り、ミトコンドリアを標的とした創薬に挑む】(第3章)ミトコンドリア疾患の診断技術と治療戦略 バイオマーカーの同定と診断技術 ミトコンドリアtRNAのタウリン修飾によるミトコンドリア機能制御と疾患

    魏 范研, 富澤 一仁

    実験医学　37　(12)　2054-2059　2019/08

    Publisher: (株)羊土社

    ISSN： 0288-5514

  10. X染色体連鎖性精神遅滞の分子機構解明に関する研究

    永芳 友, 魏 范研, 中條 岳志, 富澤 一仁

    日本生理学雑誌　81　(1)　1-1　2019/02

    Publisher: (一社)日本生理学会

    ISSN： 0031-9341

  11. 個体老化におけるRNA修飾変動の網羅的解析

    二口亜希子, 二口亜希子, 松丸大輔, 井上俊洋, 富澤一仁, 本橋ほづみ, 魏范研

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

  12. 成長ホルモン産生性下垂体腺腫における転移RNAの転写後修飾を介した成長ホルモンの生合成の制御

    武末吉広, 魏范研, 山本隆広, 山本隆広, 篠島直樹, 矢野茂敏, 森岡基浩, 武笠晃丈, 倉津純一, 富澤一仁

    日本分子脳神経外科学会プログラム・抄録集　20th　2019

  13. ミトコンドリアtRNA修飾酵素CDK5RAP1によるチオメチル化修飾は膠芽腫細胞に重要である

    山本隆広, 山本隆広, 藤村篤史, 魏范研, 甲斐恵太郎, 竹崎達也, 大田和貴, 黒田順一郎, 篠島直樹, 富澤一仁, 武笠晃丈

    日本脳腫瘍学会プログラム・抄録集　37th　2019

  14. 下垂体腺腫におけるtRNA転写後修飾を介した成長ホルモン産生の制御

    武末吉広, 魏范研, 篠島直樹, 矢野茂敏, 武笠晃丈, 富澤一仁

    日本間脳下垂体腫瘍学会プログラム・抄録集　29th　2019

  15. ミトコンドリアtRNA修飾酵素CDK5RAP1によるチオメチル化修飾は膠芽腫細胞に重要である

    山本隆広, 山本隆広, 藤村篤史, 魏范研, 甲斐恵太郎, 竹崎達也, 大田和貴, 黒田順一郎, 篠島直樹, 富澤一仁, 武笠晃丈

    日本脳腫瘍学会プログラム・抄録集　37th　2019

  16. ミトコンドリアの鉄トランスポーターSFXN2の機能解析

    池田 愛恵, 魏 范研, 松下 正之, 富澤 一仁

    琉球医学会誌　37　(1-4)　115-115　2018/12

    Publisher: 琉球医学会

    ISSN： 1346-888X

  17. 癌における細胞周期のエピトランスクリプトミックな制御(Epitranscriptomic regulation of cell cycle in cancers)

    平山 真弓, 魏 范研, 中山 秀樹, 富澤 一仁

    日本癌学会総会記事　77回　2097-2097　2018/09

    Publisher: 日本癌学会

    ISSN： 0546-0476

  18. Cdkal1による下垂体ホルモンの産生・分泌機構

    武末 吉広, 魏 范研, 矢野 茂敏, 森岡 基浩, 富澤 一仁

    日本生理学雑誌　80　(2)　28-28　2018/05

    Publisher: (一社)日本生理学会

    ISSN： 0031-9341

  19. tRNA修飾異常による神経障害の分子機構に関する研究

    榊田 光倫, 魏 范研, 荒木 栄一, 富澤 一仁

    日本生理学雑誌　80　(2)　27-28　2018/05

    Publisher: (一社)日本生理学会

    ISSN： 0031-9341

  20. 【レドックス疾患学 酸素・窒素・硫黄活性種はどう作用するのか、どこまで健康・疾患と関わるのか?】(第2章)レドックスと疾患 RNAイオウ編集の分子機構と代謝疾患

    魏 范研, 富澤 一仁

    実験医学　36　(5)　746-752　2018/03

    Publisher: (株)羊土社

    ISSN： 0288-5514

  21. 成長ホルモン産生性下垂体腺腫における小胞体ストレスと成長ホルモン産生との関係

    武末吉広, 武末吉広, 魏范研, 篠島直樹, 秀拓一郎, 矢野茂敏, 倉津純一, 森岡基浩, 武笠晃丈, 富澤一仁

    日本間脳下垂体腫瘍学会プログラム・抄録集　28th　2018

  22. 精神遅滞関連遺伝子Ftsj1による翻訳調節機構に関する研究

    西田 ななこ, 魏 范研, 富澤 一仁, 松下 正之

    琉球医学会誌　36　(1-2)　46-46　2017/12

    Publisher: 琉球医学会

    ISSN： 1346-888X

  23. 口腔扁平上皮癌におけるtRNA修飾の網羅的解析(tRNA modomics)および機能解析

    高橋 望, 魏 范研, 平山 真弓, 廣末 晃之, 吉田 遼司, 富澤 一仁, 中山 秀樹

    日本口腔科学会雑誌　66　(2)　173-173　2017/07

    Publisher: (NPO)日本口腔科学会

    ISSN： 0029-0297

    eISSN： 2185-0461

  24. システイニルtRNA合成酵素によるミトコンドリア機能制御の解明

    松永哲郎, 井田智章, 魏范研, 澤智裕, 守田匡伸, 西村明, 笠松真吾, 田沼延公, 藤井重元, 島礼, 居原秀, 西田基宏, 西田基宏, 富澤一仁, 本橋ほづみ, 赤池孝章

    日本酸化ストレス学会学術集会プログラム・抄録集　70th　124　2017/06/28

  25. システインtRNA合成酵素によるミトコンドリア形態および機能の制御

    松永哲郎, 井田智章, 魏范研, 西村明幸, 守田匡伸, 藤井重元, 西田基宏, 西田基宏, 富澤一仁, 本橋ほづみ, 赤池孝章

    日本NO学会学術集会プログラム抄録集　17th　56　2017/05/01

  26. RNA修飾の代謝機構に関する研究

    森岡 太意気, 魏 范研, 藤村 篤史, 富澤 一仁

    日本生理学雑誌　79　(1)　32-33　2017/02

    Publisher: (一社)日本生理学会

    ISSN： 0031-9341

  27. tRNA修飾異常による糖尿病性神経障害の分子機構に関する研究

    榊田 光倫, 魏 范研, 荒木 栄一, 富澤 一仁

    日本生理学雑誌　79　(1)　30-30　2017/02

    Publisher: (一社)日本生理学会

    ISSN： 0031-9341

  28. メッセンジャーRNA(mRNA)に存在するチオメチル化修飾の探索

    江村 修平, 魏 范研, 藤村 篤史, 富澤 一仁

    日本生理学雑誌　79　(1)　30-31　2017/02

    Publisher: (一社)日本生理学会

    ISSN： 0031-9341

  29. 代謝疾患におけるRNA修飾の分子機能およびRNA修飾を標的とするオミクス研究の最前線

    魏 范研, 富澤 一仁

    基礎老化研究　41　(1)　29-36　2017/01

    Publisher: 日本基礎老化学会

    ISSN： 0912-8921

  30. 新しいシステインパースルフィド合成酵素の発見とパースルフィドによるミトコンドリア機能制御機構の解明

    井田智章, 魏范研, 松永哲郎, 西田基宏, 澤智裕, 西村明幸, 守田匡伸, 笠松真吾, 居原秀, 藤井重元, 熊谷嘉人, 本橋ほづみ, 赤池孝章

    日本酸化ストレス学会学術集会プログラム・抄録集　69th　129　2016/08/30

  31. 【代謝変化とエピジェネティクス制御】tRNAのチオメチル化修飾による翻訳制御と代謝疾患

    魏 范研, 富澤 一仁

    生化学　88　(3)　328-334　2016/06

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  32. 活性イオウシグナル伝達の新展開 RNAのイオウ修飾を標的とした創薬

    富澤 一仁, 魏 范研

    日本薬学会年会要旨集　136年会　(1)　230-230　2016/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  33. 大腸菌システインtRNA合成酵素による新規システインパースルフィド生成機構の解明

    赤司 壮一郎, 井田 智章, 居原 秀, Wei Fanyan, 富澤 一仁, 笠松 真吾, 松永 哲郎, 藤井 重元, 澤 智裕, 赤池 孝章

    日本細菌学雑誌　71　(1)　70-70　2016/02

    Publisher: 日本細菌学会

    ISSN： 0021-4930

    eISSN： 1882-4110

  34. 新しい活性パースルフィド産生系の発見

    JUNG Minkyung, 井田智章, 居原秀, 魏范研, 富澤一仁, 笠松真吾, 松永哲郎, 藤井重元, 澤智裕, 赤池孝章

    臨床フリーラジカル会議　32nd　20　2016

  35. システインtRNA合成酵素によるシステインパースルフィド生成とミトコンドリア機能制御

    井田智章, 魏范研, 富澤一仁, 守田匡伸, 居原秀, 松永哲郎, 笠松真吾, 澤智裕, 藤井重元, 赤池孝章

    日本生体防御学会学術総会講演抄録集　27th　51　2016

  36. X染色体連鎖性精神遅滞の分子機構解明に関する研究

    永芳 友, 魏 范研, 貝塚 拓, 藤村 篤史, 平田 翔児, 鈴木 健夫, 鈴木 勉, 富澤 一仁

    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　[1T18p-02(1P1278)]　2015/12

    Publisher: (公社)日本生化学会

  37. 成長円錐におけるPKCαのコルタクチンリン酸化によるアクチン制御の可能性

    山田 浩司, 菊池 達也, 増本 年男, 魏 范研, 阿部 匡史, 竹田 哲也, 西木 禎一, 富澤 一仁, 渡部 昌実, 松井 秀樹, 竹居 孝二

    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　[1P1328]-[1P1328]　2015/12

    Publisher: (公社)日本生化学会

  38. タンパク質ポリサルファ化の分子メカニズムの解明

    井田 智章, 居原 秀, 魏 范研, 富澤 一仁, 長尾 翌手可, 鈴木 勉, 熊谷 嘉人, 澤 智裕, 笠松 真吾, 本橋 ほづみ, 赤池 孝章

    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　[3T21p-03(3P0211)]　2015/12

    Publisher: (公社)日本生化学会

  39. Possible role of cortactin phosphorylation by protein kinase C in actin-bundle formation at growth cone

    Hiroshi Yamada, Tatsuya Kikuchi, Toshio Masumoto, Fan-Yan Wei, Tadashi Abe, Tetsuya Takeda, Teiichi Nishiki, Kazuhito Tomizawa, Masami Watanabe, Hideki Matsui, Kohji Takei

    BIOLOGY OF THE CELL　107　(9)　319-330　2015/09

    DOI： 10.1111/boc.201500032 　

    ISSN： 0248-4900

    eISSN： 1768-322X

  40. A cautionary tale: the non-causal association between type 2 diabetes risk SNP, rs7756992, and levels of non-coding RNA, CDKAL1-v1

    Jonathan M. Locke, Fan-Yan Wei, Kazuhito Tomizawa, Michael N. Weedon, Lorna W. Harries

    DIABETOLOGIA　58　(4)　745-748　2015/04

    DOI： 10.1007/s00125-015-3508-9 　

    ISSN： 0012-186X

    eISSN： 1432-0428

  41. Cdkal1機能異常を標的とした2型糖尿病治療薬の最適化

    渡部 佐耶加, 魏 范研, 貝塚 拓, 富澤 一仁

    日本生理学雑誌　77　(2)　39-40　2015/03

    Publisher: (一社)日本生理学会

    ISSN： 0031-9341

  42. 過硫化物によるtRNAチオル修飾の制御

    高橋 望, 魏 范研, 澤 智裕, 赤池 孝章, 富澤 一仁

    日本生理学雑誌　77　(2)　43-43　2015/03

    Publisher: (一社)日本生理学会

    ISSN： 0031-9341

  43. ミトコンドリア脳筋症関連遺伝子MTO1の機能解析

    海江田 崇史, 魏 范研, 貝塚 拓, 富澤 一仁

    日本生理学雑誌　77　(2)　44-45　2015/03

    Publisher: (一社)日本生理学会

    ISSN： 0031-9341

  44. Cdk5rap1-Mediated 2-Methylthio Modification of Mitochondrial tRNAs Governs Protein Translation and Contributes to Myopathy in Mice and Humans

    Fan-Yan Wei, Bo Zhou, Takeo Suzuki, Keishi Miyata, Yoshihiro Ujihara, Haruki Horiguchi, Nozomu Takahashi, Peiyu Xie, Hiroyuki Michiue, Atsushi Fujimura, Taku Kaitsuka, Hideki Matsui, Yasutoshi Koga, Satoshi Mohri, Tsutomu Suzuki, Yuichi Oike, Kazuhito Tomizawa

    CELL METABOLISM　21　(3)　428-442　2015/03

    DOI： 10.1016/j.cmet.2015.01.019 　

    ISSN： 1550-4131

    eISSN： 1932-7420

  45. Molecular mechanism and the physiological function of sulfur-modifications in mammalian tRNAs

    Fan-Yan Wei, Kazuhito Tomizawa

    Saiboukougaku　34　(4)　384-388　2015

  46. イオウによるtRNA編集の分子機構および生理機能

    魏范研, 富澤一仁

    細胞工学　34　(4)　384-388　2015

  47. Identification of a splicing variant that regulates type 2 diabetes risk factor CDKAL1 level by a coding-independent mechanism in human

    Bo Zhou, Fan-Yan Wei, Narumi Kanai, Atsushi Fujimura, Taku Kaitsuka, Kazuhito Tomizawa

    HUMAN MOLECULAR GENETICS　23　(17)　4639-4650　2014/09

    DOI： 10.1093/hmg/ddu184 　

    ISSN： 0964-6906

    eISSN： 1460-2083

  48. Efficient Transduction of 11 Poly-arginine Peptide in an Ischemic Lesion of Mouse Brain

    Yuki Gotanda, Fan-Yan Wei, Hideki Harada, Keisuke Ohta, Kei-ichiro Nakamura, Kazuhito Tomizawa, Kazuo Ushijima

    JOURNAL OF STROKE & CEREBROVASCULAR DISEASES　23　(8)　2023-2030　2014/09

    DOI： 10.1016/j.jstrokecerebrovasdis.2014.02.027 　

    ISSN： 1052-3057

    eISSN： 1532-8511

  49. X染色体連鎖性精神遅滞の分子機構解明に関する研究

    永芳 友, 魏 范研, 貝塚 拓, 富澤 一仁

    日本生理学雑誌　76　(3)　82-82　2014/05

    Publisher: (一社)日本生理学会

    ISSN： 0031-9341

  50. オキシトシンによる膵β細胞の保護作用

    松永 友美, 松永 奈々美, 魏 范研, 貝塚 拓, 富澤 一仁

    日本生理学雑誌　76　(3)　82-82　2014/05

    Publisher: (一社)日本生理学会

    ISSN： 0031-9341

  51. High Oxygen Condition Facilitates the Differentiation of Mouse and Human Pluripotent Stem Cells into Pancreatic Progenitors and Insulin-producing Cells*

    Farzana Hakim, Taku Kaitsuka, Jamiruddin Mohd Raeed, Fan-Yan Wei, Nobuaki Shiraki, Tadayuki Akagi, Takashi Yokota, Shoen Kume, Kazuhito Tomizawa

    JOURNAL OF BIOLOGICAL CHEMISTRY　289　(14)　9623-9638　2014/04

    DOI： 10.1074/jbc.M113.524363 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  52. ミトコンドリアtRNAのチオメチル化修飾欠損とミオパチー

    魏范研, 周波, 鈴木健夫, 貝塚拓, 古賀靖敏, 鈴木勉, 富澤一仁

    日本ミトコンドリア学会年会要旨集　14th　47　2014

  53. Generation of Functional Insulin-Producing Cells From Mouse Embryonic Stem Cells Through 804G Cell-Derived Extracellular Matrix and Protein Transduction of Transcription Factors

    Taku Kaitsuka, Hirofumi Noguchi, Nobuaki Shiraki, Takuya Kubo, Fan-Yan Wei, Farzana Hakim, Shoen Kume, Kazuhito Tomizawa

    STEM CELLS TRANSLATIONAL MEDICINE　3　(1)　114-127　2014/01

    DOI： 10.5966/sctm.2013-0075 　

    ISSN： 2157-6564

    eISSN： 2157-6580

  54. Quantitative PCR Measurement of tRNA 2-Methylthio Modification for Assessing Type 2 Diabetes Risk

    Peiyu Xie, Fan-Yan Wei, Shoji Hirata, Taku Kaitsuka, Tsutomu Suzuki, Takeo Suzuki, Kazuhito Tomizawa

    CLINICAL CHEMISTRY　59　(11)　1604-1612　2013/11

    DOI： 10.1373/clinchem.2013.210401 　

    ISSN： 0009-9147

    eISSN： 1530-8561

  55. Cyclin G2 Promotes HypoxiaDriven Local Invasion of Glioblastoma by Orchestrating Cytoskeletal Dynamics

    Atsushi Fujimura, Hiroyuki Michiue, Yan Cheng, Atsuhito Uneda, Yasunari Tani, Tei-ichi Nishiki, Tomotsugu Ichikawa, Fan-Yan Wei, Kazuhito Tomizawa, Hideki Matsui

    NEOPLASIA　15　(11)　1272-+　2013/11

    DOI： 10.1593/neo.131440 　

    ISSN： 1522-8002

    eISSN： 1476-5586

  56. Cdkal1遺伝子一塩基多型による2型糖尿病発症の分子メカニズム

    魏 范研, 渡部 佐耶加, 貝塚 拓, 山縣 和也, 富澤 一仁

    糖尿病　56　(Suppl.1)　S-117　2013/04

    Publisher: (一社)日本糖尿病学会

    ISSN： 0021-437X

    eISSN： 1881-588X

  57. Fine-tuning of protein translation by tRNA modification and its pathological relevance

    Wei Fanyan

    JOURNAL OF PHYSIOLOGICAL SCIENCES　63　S80-S80　2013

    ISSN： 1880-6546

  58. Comparison of the effect of current therapeutic agents for diabetes in Cdkal1-deficient mice

    Sayake Watanabe, Fanyan Wei, Taku Kaitsuka, Kazuhito Tomizawa

    JOURNAL OF PHYSIOLOGICAL SCIENCES　63　S249-S249　2013

    ISSN： 1880-6546

  59. Functional characterization of GWAS genes - Cdkal1, a GWAS gene, functional characterization in mice and translational opportunities (30)

    Sayaka Watanabe, Fan-Yan Wei, Tomizawa Kazuhito

    Drug Discovery Today　2013

    DOI： 10.1016/j.ddmod.2012.12.001 　

  60. Induction of autophagic cell death of glioma-initiating cells by cell-penetrating D-isomer peptides consisting of Pas and the p53 C-terminus. International-journal

    Yutaka Ueda, Fan-Yan Wei, Taku-ichiro Hide, Hiroyuki Michiue, Kentaro Takayama, Taku Kaitsuka, Hideo Nakamura, Keishi Makino, Jun-ichi Kuratsu, Shiroh Futaki, Kazuhito Tomizawa

    Biomaterials　33　(35)　9061-9　2012/12

    DOI： 10.1016/j.biomaterials.2012.09.003 　

    More details Close

    Glioblastoma multiforme (GBM) is the most aggressive and fatal brain tumor. GBM is resistant to chemotherapy and radiation. Recent studies have shown that glioma-initiating cells (GICs), which have characteristics of cancer stem cells, are responsible for the resistance to chemotherapy and radiation and regrowth. No effective therapy for GICs has been developed. Here we showed that D-isomer peptides (dPasFHV-p53C') consisting of a cell-penetrating peptide (FHV), penetration accelerating sequence (Pas) and C-terminus of p53 (p53C') induced the cell death of GICs. dPasFHV-p53C' was effectively transduced into human GICs. The peptides dose-dependently inhibited cell growth and at 3 μM completely blocked the growth of GICs but not embryonic stem cells. Autophagic cell death was observed in the GICs treated with dPasFHV-p53C' but apoptosis was not. dPasFHV without p53C' showed the same effect as dPasFHV-p53C', suggesting Pas to play a critical role in the cell death of GICs. Finally, dPasFHV-p53C' reduced tumor mass in mice transplanted with GICs. Peptide transduction therapy using dPasFHV-p53C' could be a new method for the treatment of GBM.

  61. Anks4b, a Novel Target of HNF4 alpha Protein, Interacts with GRP78 Protein and Regulates Endoplasmic Reticulum Stress-induced Apoptosis in Pancreatic beta-Cells

    Yoshifumi Sato, Mitsutoki Hatta, Md Fazlul Karim, Tomohiro Sawa, Fan-Yan Wei, Shoki Sato, Mark A. Magnuson, Frank J. Gonzalez, Kazuhito Tomizawa, Takaaki Akaike, Tatsuya Yoshizawa, Kazuya Yamagata

    JOURNAL OF BIOLOGICAL CHEMISTRY　287　(27)　23236-23245　2012/06

    DOI： 10.1074/jbc.M112.368779 　

    ISSN： 0021-9258

  62. Cdkal1機能欠損による2型糖尿病発症機序の解明

    魏 范研, 富澤 一仁

    日本生理学雑誌　74　(3)　78-78　2012/05

    Publisher: (一社)日本生理学会

    ISSN： 0031-9341

  63. オキシトシンによる膵β細胞の保護作用

    松永 奈々美, 魏 范研, 貝塚 拓, 富澤 一仁

    日本生理学雑誌　74　(3)　81-81　2012/05

    Publisher: (一社)日本生理学会

    ISSN： 0031-9341

  64. RGS2 mediates the anxiolytic effect of oxytocin

    Naoki Okimoto, Oliver J. Bosch, David A. Slattery, Konstanze Pflaum, Hiroaki Matsushita, Fan-Yan Wei, Masayasu Ohmori, Tei-ichi Nishiki, Iori Ohmori, Yuji Hiramatsu, Hideki Matsui, Inga D. Neumann, Kazuhito Tomizawa

    BRAIN RESEARCH　1453　26-33　2012/05

    DOI： 10.1016/j.brainres.2012.03.012 　

    ISSN： 0006-8993

  65. Development of type 2 diabetes caused by a deficiency of a tRNAlys modification. (50)

    Wei Fanyan, Tomizawa Kazuhito

    Islets　4　(1)　2012

  66. 2型糖尿病危険因子 Cdkall の生理機能の解明

    魏 范研

    日本生理学雜誌　73　(11)　239-239　2011/11/01

    ISSN： 0031-9341

  67. Deficit of tRNA(Lys) modification by Cdkal1 causes the development of type 2 diabetes in mice

    Fan-Yan Wei, Takeo Suzuki, Sayaka Watanabe, Satoshi Kimura, Taku Kaitsuka, Atsushi Fujimura, Hideki Matsui, Mohamed Atta, Hiroyuki Michiue, Marc Fontecave, Kazuya Yamagata, Tsutomu Suzuki, Kazuhito Tomizawa

    JOURNAL OF CLINICAL INVESTIGATION　121　(9)　3598-3608　2011/09

    DOI： 10.1172/JCI58056 　

    ISSN： 0021-9738

  68. Functional loss of Cdkal1, a novel tRNA modification enzyme, causes the development of type 2 diabetes. (50)

    Wei Fanyan, Tomizawa Kazuhito

    Endocrinology Journal　58　(10)　819-825　2011

    DOI： 10.1507/endocrj.EJ11-0099 　

  69. Induction of the differentiation of ES cells into insulin-producing cells by protein transduction

    Taku Kaitsuka, Hirofumi Noguchi, Shiraki Nobuaki, Fanyan Wei, Shoen Kume, Kazuhito Tomizawa

    JOURNAL OF PHYSIOLOGICAL SCIENCES　60　S186-S186　2010

    ISSN： 1880-6546

  70. Functional characterization of novel type 2 diabetes risk factor Cdk5 regulatory subunit association protein 1-like 1 (Cdkal1)

    Fanyan Wei, Takeo Suzuki, Taku Kaitsuka, Kazuya Yamagata, Tsutomu Suzuki, Kazuhito Tomizawa

    JOURNAL OF PHYSIOLOGICAL SCIENCES　60　S175-S175　2010

    ISSN： 1880-6546

  71. Cdk5によるインスリン分泌の制御機構

    魏 范研, 長嶋 一昭, 大島 登志男, 佐伯 恭範, 陸 雲飛, 松下 正之, 山田 祐一郎, 御子柴 克彦, 清野 裕, 松井 秀樹, 富澤 一仁

    岡山医学会雑誌　119　(1)　17-20　2007/05

    Publisher: 岡山医学会

    ISSN： 0030-1558

    eISSN： 1882-4528

  72. 蛋白導入システム"Protein Transduction System"を利用したプロテインセラピーの発展と現状について 悪性脳腫瘍に対する蛋白導入法の利用を中心に

    道上 宏之, 富澤 一仁, 魏 范研, 松下 正之, 陸 雲飛, 市川 智継, 田宮 隆, 松井 秀樹, 伊達 勲

    岡山医学会雑誌　118　(3)　205-208　2007/01

    Publisher: 岡山医学会

    ISSN： 0030-1558

    eISSN： 1882-4528

  73. オキシトシンによるProtein kinase C発現制御

    藤田 梨嘉, 魏 范研, 富澤 一仁, 松下 正之, 大守 伊織, 松井 秀樹

    日本生理学雑誌　68　(5)　183-183　2006/05

    Publisher: (一社)日本生理学会

    ISSN： 0031-9341

  74. Cdk5によるインスリン分泌制御機構

    魏 范研, 富澤 一仁, 佐伯 恭範, 松下 正之, 大守 伊織, 松井 秀樹

    日本生理学雑誌　68　(5)　185-185　2006/05

    Publisher: (一社)日本生理学会

    ISSN： 0031-9341

  75. 【プロテオーム研究を成功させる試料調製と解析法】翻訳後修飾の解析 リン酸化部位やプロテアーゼ切断部位の解析

    魏 范研, 富澤 一仁

    バイオテクノロジージャーナル　6　(2)　168-173　2006/03

    Publisher: (株)羊土社

    ISSN： 1349-7448

  76. Dynamin 2 is involved in PS-dependent formation of membrane ruffles and phagocytosis in rat sertoli cells

    H Yamada, S Li, M Watanabe, F Wei, N Kusumi, K Tomizawa, M McNiven, H Matsui, H Kumon, K Takei

    MOLECULAR BIOLOGY OF THE CELL　15　195A-196A　2004/11

    ISSN： 1059-1524

  77. エンドソームリリーシングペプチドを利用したp53蛋白質導入法による悪性腫瘍抑制効果

    道上 宏之, 富澤 一仁, 魏 范研, 松下 正之, 陸 雲飛, 市川 智継, 田宮 隆, 伊達 勲, 松井 秀樹

    日本癌学会総会記事　63回　511-511　2004/09

    Publisher: 日本癌学会

    ISSN： 0546-0476

  78. ALTERNATIVE PATHWAYS OF T-CELL ACTIVATION AND POSITIVE CLONAL SELECTION

    R PATARCA, RP SINGH, FY WEI, MV IREGUI, P SINGH, J SCHWARTZ, H CANTOR

    IMMUNOLOGICAL REVIEWS　116　85-100　1990/08

    ISSN： 0105-2896

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Books and Other Publications 1

  1. Cyclin-Dependent Kinase 5 (Cdk5) (50)

    Springer　2008

    ISBN: 9780387788869

Presentations 23

  1. tRNA修飾異常によるX染色体連鎖性精神遅滞の発症分子メカニズムの解析

    魏 范研

    第95回日本生理学会大会　2018/03/29

  2. ミトコンドリアtRNAタウリン修飾によるタンパク質恒常性ネットワークの制御

    魏 范研

    日本RNA学会年会　2017/07/20

  3. マウス個体発生におけるミトコンドリアtRNA修飾の役割 Invited

    魏 范研

    第30回モロシヌス研究会　2017/06/23

  4. tRNA 修飾異常によるX染色体連鎖性精神遅滞の発症分子メカニズムの解析

    第93回日本生理学会大会　2016

  5. tRNA 修飾異常によるX染色体連鎖性精神遅滞の発症分子メカニズムの解析

    第17回日本RNA学会年会　2015

  6. がんにおけるミトコンドリアタンパク合成関連遺伝子の解析

    第92回日本生理学会大会　2015

  7. X染色体連鎖性精神遅滞の分子機構解明に関する研究

    第92回日本生理学会大会　2015

  8. マウスES細胞から分化したインスリン産生細胞での膵島特異的な転写因子の欠如とその補充による分化効率の改善

    第92回日本生理学会大会　2015

  9. ミトコンドリア脳筋症関連遺伝子MTO1の機能解析

    第65回西日本生理学会　2014

  10. 過硫化物によるtRNA チオル修飾の制御

    第65回西日本生理学会　2014

  11. Cdkal1 機能異常を標的とした２型糖尿病治療薬の最適化

    第65回西日本生理学会　2014

  12. X染色体連鎖性精神遅滞の分子機構解明に関する研究

    第16回ブレインサイエンス研究会　2014

  13. ミトコンドリアtRNA修飾によるがんの機能制御

    第一回がんと代謝研究会　2013

  14. Cdkal1 欠損マウスにおける抗糖尿病治療薬効果の検討

    第９０回日本生理学会　2013

  15. 簡便かつ迅速に tRNA 修飾を解析する技術の開発と糖尿病診断への応用

    第９０回日本生理学会　2013

  16. 翻訳精度維持におけるtRNA修飾の役割及びその破綻による病態の解析

    第９０回日本生理学会　2013

  17. Chemical modifications of mitochondrial tRNA by Cdk5rap1 regulates mitochondrial functions through the enhancement of precise protein synthesis.

    第８９回日本生理学会　2012

  18. ２型糖尿病危険遺伝子Cdkal1の生理機能解析

    第８９回日本生理学会　2012

  19. Functional characterization of Cdkal1, a novel type 2 diabetes risk gene

    2012

  20. ２型糖尿病危険因子Cdkal1の生理機能解析

    分子糖尿病学シンポジウム　2011

  21. オキシトシンによる膵β細胞の保護作用

    第62回西日本生理学会　2011

  22. Cdk5rap1によるミトコンドリアtRNAの化学修飾とそのミトコンドリア機能制御

    第62回西日本生理学会　2011

  23. Cdkal1機能欠損による2型糖尿病発症機序の解明

    第62回西日本生理学会　2011

Show all Show first 5

Industrial Property Rights 8

  1. 2型糖尿病治療剤

    富澤 一仁, 魏 范研

    Property Type: Patent

  2. 2型糖尿病治療剤

    富澤 一仁, 魏 范研, 井上 謙吾, 大川原 正

    Property Type: Patent

  3. 2型糖尿病モデル非ヒト動物

    富澤 一仁, 魏 范研

    Property Type: Patent

  4. サイクリン依存性キナーゼ5(Cdk5)特異的ペプチド性阻害剤

    富澤 一仁, 魏 范研, 松井 秀樹

    Property Type: Patent

  5. サイクリン依存性キナーゼ5(Cdk5)特異的ペプチド性阻害剤

    富澤 一仁, 魏 范研, 松井 秀樹

    特許第4273232号

    Property Type: Patent

  6. Cdk5阻害剤を含む糖尿病治療薬

    富澤 一仁, 魏 范研, 松井 秀樹

    Property Type: Patent

  7. 糖尿病治療薬

    富澤 一仁, 魏 范研, 松井 秀樹

    Property Type: Patent

  8. ２型糖尿病モデル非ヒト動物

    富澤 一仁, 魏 范研

    特許第5804377号

    Property Type: Patent

    More details Close

    PCT/JP2010/070006

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Research Projects 22

  1. A Study on Elucidating Obesity and Lifestyle Diseases through the Epigenome-RNA Modification Axis

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

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

    Institution: Tohoku University

    2024/04/01 - 2029/03/31

  2. Molecular basis of RNA modification in immune response after transplantation and cell therapy and novel biomarkers

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

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

    Institution: Tohoku University

    2023/04/01 - 2026/03/31

  3. A synthetic metabolic network based on RNA modification for biological homeostasis

    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 - 2026/03/31

  4. ミトコンドリアにおける超硫黄分子リレーの分子基盤と生理的意義の解明

    魏 范研

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 学術変革領域研究(A)

    Institution: 東北大学

    2021/09/10 - 2026/03/31

  5. Management of international relation and facility for promotion of research on sulfur biology

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Transformative Research Areas (A)

    Institution: Tohoku University

    2021/09/10 - 2026/03/31

  6. 革新的タンパク質翻訳解析ツールによる新規ミトコンドリア病創薬への挑戦

    魏 范研, 谷 春菜

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 挑戦的研究(萌芽)

    Institution: 東北大学

    2023/06/30 - 2025/03/31

  7. RNAモドミクスを基軸とする新規核酸生理学の開拓

    魏 范研, 小川 亜希子, 松田 盛

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(B)

    Institution: 東北大学

    2021/04/01 - 2025/03/31

  8. トランスファーRNA修飾の破綻による小頭症と精神遅滞の発症機構の解明

    中條 岳志, 富澤 一仁, 魏 范研

    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: 熊本大学

    2020/04/01 - 2024/03/31

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    ウイルス増殖におけるtRNA修飾の役割を明らかにする研究として、当初計画の仮説通りの結果を得られなかったために代わりに実施したHIV-1増殖における宿主tRNA修飾の研究が、大学院生の尽力により大きく花開いた。この研究では、(1) HIV-1ゲノムRNA複製における逆転写が適切な位置で止まるためには宿主リジンtRNAの58位のm1A修飾が必要であること、(2) 状況によっては宿主リジンtRNAの54位のm5Um修飾も逆転写の適切な位置での停止に重要であること、(3) 宿主tRNAの58位のm1A修飾酵素は宿主細胞におけるHIV-1タンパク質の蓄積にも重要であること、(4) ヒトtRNAの58位のm1A修飾が54位のm5U修飾の導入に重要であることを見出した。この成果は、Nucleic Acids Research誌で公開された。 また、当初の計画とは異なるが、ジカウイルス感染における細胞内修飾ヌクレオシドの役割を所属研究室が明らかにした。この研究では、細胞内RNAが分解されて生じた修飾ヌクレオシドモノマーは、ENT1、ENT2というトランスポーターにより細胞外に積極的に排出されることと、細胞内の修飾ヌクレオシドモノマーがジカウイルスの増殖を促進することを明らかにした。これは分担者である魏教授と大学院生が主に進めた研究であり、この成果はRNA Biology誌で公開された。 さらに、あるtRNA修飾酵素の全身ノックアウトマウスが胚性致死であることと、この遺伝子の心臓特異的ノックアウトマウスでは、週齢が上がり中年になると若齢時（14週）よりも心臓の異常が進展していることを報告する論文をリバイス中である。

  9. 膠芽腫幹細胞を標的としたtRNAメチル化酵素阻害剤による制がん戦略の構築

    藤村 篤史, 石川 吉伸, 黒住 和彦, 富澤 一仁, 安藤 隆幸, 増本 年男, 中村 仁, 魏 范研

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(C)

    Category: 基盤研究(C)

    Institution: 岡山大学

    2020/04/01 - 2023/03/31

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    膠芽腫幹細胞において、特定の核酸修飾酵素が幹細胞性の維持に必須であることを細胞レベル・動物レベルで実証した。具体的には、当該酵素をコードする遺伝子に対するLoss-of-functionを行うことで、膠芽腫幹細胞株の未分化マーカーが脱落し、自己複製能が著しく減弱し、さらに造腫瘍能が低下することを確認した。当該酵素に対する阻害剤を用いることで、細胞レベルで膠芽腫幹細胞の幹細胞性が減弱することが実証できたが、担がんモデルマウスにおいては、その抗がん作用は必ずしも強力なものではなかった。このことは、当初の阻害剤の脳組織移行性が十分ではなかった点と、モデルマウスの血液中の代謝安定性が十分に高いものでなかったことに起因すると予測された。次年度以降の課題としては、上記の課題を克服できるような類縁体をデザインすることであり、同様のモデルマウスで検証を継続する。上記の課題と並行して、当初の化合物が奏功しうる膠芽腫患者と奏功が期待しがたい患者の層別化をはかる遺伝子群の解析を進めたところ、具体的に機能が未知の遺伝子を2つ同定することに成功した。それぞれの機能解析を進めたところ、一方では転写制御に関連する因子群のひとつであると推測され、もう一方では細胞内アミノ酸代謝に強く関連する因子群のひとつであることが予測された。次年度以降、これらの機能未知の遺伝子の解析を進めるとともに、特定の核酸修飾酵素とのクロストーク等を探っていくことを目指す。

  10. Modulation of mitochondrial function by reactive sulfur signaling

    Wei Fan-Yan

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

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

    Institution: Tohoku University

    2020/07/30 - 2022/03/31

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    Mitochondrial disease is a rare genetic disease characterized by the catastrophic impairment of mitochondrial metabolism caused by pathogenic mutations in mitochondrial DNA or nuclear DNA. However, there is no effective treatment for mitochondrial disease. Recently, our research has discovered that the reactive sulfur species-mediated signaling is involved in the pathogenesis of mitochondrial disease. We found that the reactive sulfur species donate sulfur atoms to mitochondrial tRNA to form tRNA thiolation. Decrease of mitochondrial tRNA thiolation is responsible for the alteration of mitochondrial protein translation and the subsequent metabolic dysfunction. In the current study, we performed a comprehensive genetic screening using shRNA library targeting genes that are related to mitochondrial functions. We identified that knockdown of several genes can lead to the recovery of mitochondrial membrane potential and cell growth in a mitochondrial disease cell model.

  11. RNA modification and autophagy

    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

    2020/04/01 - 2022/03/31

  12. Characterization of novel nucleoside signaling

    Wei Fanyan

    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)

    2018/04/01 - 2021/03/31

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    About 150 post-transcriptional RNA modifications have been identified in all kingdoms of life. During RNA catabolism, most modified nucleosides are resistant to degradation and are released into the extracellular space. In this study, we explored the physiological role of these extracellular modified nucleosides and found that N6-methyladenosine (m6A), widely recognized as an epigenetic mark in RNA, acts as a ligand for the human adenosine A3 receptor, for which it has greater affinity than unmodified adenosine. We used structural modeling to define the amino acids required for specific binding of m6A to the human A3 receptor. We also demonstrated that m6A was dynamically released in response to cytotoxic stimuli and facilitated type I allergy in vivo. Our findings implicate m6A as a signaling molecule capable of activating GPCRs and triggering pathophysiological responses, a previously unreported property of RNA modifications.

  13. 修飾ヌクレオシドを基軸とする新規ヌクレオシドシグナルの解明 Competitive

    魏 范研

    Offer Organization: 文科省科研費

    System: 基盤研究（B)

    2018/04 - 2021/03

  14. Drug development for mitochondrial disease based on sulfur metabolism

    Wei Fanyan

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

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

    2018/06/29 - 2020/03/31

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    Mitochondrial disease is a devastating genetic disease, which is mainly caused by the pathogenic mutations in mitochondrial DNA. Currently, there is no effective treatment that can cure the disease. This study is aimed to develop a functional screening system that leads to the discovery of drug target for the treatment of mitochondrial disease. In this study, we utilized a genome-wide shRNA lentiviral system and screened over 3,000 mitochondria-related genes in cell lines carrying pathogenic mitochondria DNA. We discovered a specific shRNA, which targets a gene involved in sulfur metabolism, was capable to upregulate mitochondrial reactive sulfur species as well as respiratory activity, thereby leading to an efficient energy metabolism. These results thus lay the foundation for novel and innovative drug development in near future.

  15. 硫黄代謝に基づく革新的にミトコンドリア治療薬の開発 Competitive

    魏 范研

    Offer Organization: 文科省科研費

    System: 挑戦的研究(萌芽)

    2018/04 - 2020/03

  16. Development of novel therapy for intractable pituitary adenomas focused on functional control of hormone secretion targeting insulin secretion regulatory gene in the tumor cells

    Yano Shigetoshi

    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: Kumamoto University

    2016/04/01 - 2019/03/31

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    In order to clarify the hormone secretion mechanism of pituitary tumor which causes intractable acromegaly, we tried to elucidate the function of insulin regulatory protein "CDKAL1" in pituitary tumor cells. CDKAL1 was expressed in various pituitary tumor samples removed by surgery. Expression level of mRNA and protein of CDKAL1 was significantly lower in growth hormone secreting tumors than nonfunctioning tumors. Mechanical suppression of cdkal1 gene expression caused elevation of intracellular calcium level and resulted in increased secretion of growth hormone. These results indicate that functional decline of CDKAL1 is involved in the abnormal secretion of hormones in growth hormone secreting pituitary adenomas.

  17. The role of Cdkal1-mediated tRNA modification in peripheral neuropathy

    Kazuhito Tomizawa, ARAKI Eiichi, USUKU Koichiro, KAKUMA Tatsuyuki, WEI Fan-Yan

    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: Kumamoto University

    2015/04/01 - 2018/03/31

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    Genetic variations in CDKAL1 have been associated with the development of type 2 diabetes. CDKAL1 is a methylthiotransferase that catalyzes 2-methylthi modification of tRNALys(UUU). The ms2 modification is important for accurate decoding of Lys codon in Proinsulin. In addition to Proinsulin, Lys is also critical for the processing of various neurotropic factors. We hypothesized that the dysregulation of CDKAL1 might cause aberrant translation of neurotropic factors, and lead to the development of neuropathy. To test this hypothesis, we investigated the sensory functions of peripheral nerves in Cdkal1-knockout mice. Cdkal1-deficiency induced peripheral neuropathy independent of glucose intolerance. Cdkal1-deficient mice exhibited loss of CGRP- and IB4-positive neurons in DRG. Cdkal1-deficient mice exhibited loss of nerve fibers in footpad. BDNF were reduced in DRG of Cdkal1KO mice.These results suggest that dysfunction of Cdkal1 may critical for development of diabetic neuropathy.

  18. Physiological role of mitochondrial tRNA modification

    Wei Fan-Yan, Mohri Satoshi

    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: Kumamoto University

    2015/04/01 - 2018/03/31

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    In this study, we report that Cdk5 regulatory subunit-associated protein 1 (Cdk5rap1) is responsible for 2-methylthio (ms2) modifications of mammalian mt-tRNAs for Ser(UCN), Phe, Tyr and Trp codons. Deficiency in ms2 modification markedly impaired mitochondrial protein synthesis, which resulted in respiratory defects in Cdk5rap1 knockout (KO) mice. The KO mice were highly susceptive to stress-induced mitochondrial remodelling and exhibited accelerated myopathy and cardiac dysfunction under stressed conditions. Furthermore, we demonstrate that the ms2 modifications of mt-tRNAs were sensitive to oxidative stress and were reduced in patients with mitochondrial disease. These findings highlight the fundamental role of ms2 modifications of mt-tRNAs in mitochondrial protein synthesis and their pathological consequences in mitochondrial disease.

  19. ミトコンドリアtRNA修飾の分子基盤及び生理機能解析 Competitive

    魏 范研

    Offer Organization: 文科省科研費

    System: 基盤研究（C）

    2015/04 - 2018/03

  20. Molecular mechanism of Cdkal1 single nucleotide polymorphism-dependent type 2 diabetes

    WEI Fan-Yan

    Offer Organization: Japan Society for the Promotion of Science

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

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Kumamoto University

    2013/04/01 - 2015/03/31

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    SNPs in CDKAL1 is one of the most reliable risk factors for type 2 diabetes (T2D). However, the molecular mechanism by which the intronic single nucleotide polymorphisms (SNPs) contribute to T2D has been unclear. This study revealed the SNPs as actively involved in the regulation of cellular CDKAL1 levels through a unique post-transcriptional mechanism. A specific splicing variant of CDKAL1 (CDKAL1-v1) was drastically decreased in individuals carrying the risk SNPs in CDKAL1. CDKAL1-v1 is a non-coding transcript, which regulates Cdkal1 level by the competitive binding of a CDKAL1-targeting microRNA. By direct editing of genome in human cell lines, this study further shows that the nucleotides around the SNPs regions are critical for the alternative splicing of CDKAL1-v1. These findings demonstrate that the T2D-associated SNPs in CDKAL1 directly contribute to the decrease in CDKAL1-v1 by impairing splicing, which in turn induces microRNA-mediated suppression of cellular CDKAL1 level.

  21. Characterization of Cdkal1, a novel type 2 diabetes risk gene

    WEI Fanyan

    Offer Organization: Japan Society for the Promotion of Science

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

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Kumamoto University

    2010 - 2011

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    Genetic variations in cdkal1(Cdk5 regulatory subunit associated protein 1-like 1) have been identified as a risk for type 2 diabetes. Despite the accumulating clinical evidence, the molecular characterization of Cdkal1 is completely unknown. To investigate the physiological role of Cdkal1, pancreatic b-cell-specific Cdkal1 knockout(Cdkal1 KO) mice were generated. Cdkal1 KO mice showed glucose intolerance and impaired insulin secretion. We have identified that Cdkal1 is a mammalian methylthiotranferase, which specifically modifies tRNA^<Lys>(UUU) at position 37 by catalyzing the biosynthesis of N6-threonylcabamoyladenosine(t6A) to 2-methylthio-N6-threonylcabamoyladenosine(ms2t6A) in both bacteria and mammalian cells. Modification of tRNA^<Lys>(UUU) by Cdkal1 is critical for the accurate decoding of Lys codon. In Cdkal1 KO b-cells, deficiency of modification in tRNA^<Lys>(UUU) caused mistranslation of proinsulin and thus triggered endoplasmic reticulum(ER) stress response. Furthermore, Cdkal1 KO mice fed with a high fat diet developed severe glucose intolerance and ER stress response. From these results, we concluded that modification of tRNA by Cdkal1 in b-cells is critical to maintaining translation fidelity, which contributes to the homeostasis of b-cells.

  22. 哺乳動物におけるリボヌクレオーム研究の確立

    富澤 一仁, 魏 范研

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 挑戦的萌芽研究

    Category: 挑戦的萌芽研究

    Institution: 熊本大学

    2009 - 2011

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    近年,細菌おいて転移RNA(tRNA)もDNA同様様々な化学修飾を受けることが明らかになった。しかし,哺乳動物ではtRNA修酵素の存在すら明らかでなく,tRNA修飾の生理機能は不明である。本研究では,哺乳動物における転移RNA (tRNA)の化学修飾酵素を網羅的に同定し,同修飾の生理機能,またtRNA化学修飾の破綻が蛋白質翻訳異常,延いては糖尿病などの疾患を引き起こす危険因子になっていることを明らかにすることを目的として行った。今年度は下記のことを明らかにした。 (1)哺乳動物tRNAの化学修飾の同定 マウス肝臓からtRNAを精製後、tRNAをリボヌクレアーゼで処理し、モノヌクレオチドを単離した。単離したモノヌクレオチドの化学修飾について質量分析法を用いて解析した。その結果、リジンtRNAのイソペンテニルチオメチル化修飾ならびにスレオニノカルボニルチオメチル化修飾を同定することができた。 (2)CDKAL1ノックアウトマウスの解析 CDKAL1欠損マウスでは、リジンに対応するtRNAの37番目のアデニンの修飾が欠損しているか検討した。CDKAL1欠損マウスならびに野生型マウスから肝臓を摘出し、tRNA精製後リジンtRNAの化学修飾について質量分析法を用いて解析した。その結果、野生型マウスでは、チオメチル化修飾が同定されたが、CDKAL1欠損マウスではスレオニノカルボニル修飾はされていたが、チオメチル化修飾は検出されなかった。さらに、枯草菌のMiaBおよびYqeV欠損株に、ヒトCDKAL1遺伝子を形質転換した。その後tRNAを精製し、質量分析法にてチオメチル化修飾の有無について解析した。MiaB欠損株にCdkal1遺伝子を形質転換しても、tRNAのチオメチル化修飾は認められなかった。一方、YqeV欠損株では、Cdkal1遺伝子を形質転換することにより、tRNAにチオメチル化修飾が付加された。以上の結果より、Cdkal1はリジンに対応するtRNAの37番目のスレオニノカルボニル化アデニンをチオメチル化する酵素であることが明らかになった。

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Works 8

  1. RNAモドミクスの確立及び神経・精神疾患への応用

    2015 - 2019

  2. ミトコンドリアtRNA修飾の分子基盤及び生理機能解析

    2015 - 2018

  3. Cdkal1リスクアレル保有２型糖尿病患者に対する治療薬ならびにコンパニオン診断技術の開発

    2014 - 2017

  4. Cdkal1リスクアレル保有者およびアジア型2型糖尿病を標的とした経口糖尿病薬の研 究開発

    2014 - 2015

  5. ゲノムワイド関連研究成果に基づく新規２型糖尿病治療薬の開発

    2012 - 2013

  6. アジア型２型糖尿病をターゲットにした新規抗糖尿病治療薬を開発するためのスクリーニングシステムの構築

    2011 - 2012

  7. Cdkal1遺伝子の一塩基多型変異による２型糖尿病発症の分子メカニズムの解析

    2012 -

  8. 一塩基多型による２型糖尿病発症メカニズムの研究

    2011 -

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