Updated on 2024/06/12

写真a

 
MORIYA Hisao
 
Organization
Faculty of Environmental, Life, Natural Science and Technology Professor
Position
Professor
External link

Degree

  • 博士(理学)

Research Interests

  • 量感受性遺伝子

  • 遺伝子ネットワーク

  • 遺伝子

  • 量的均衡遺伝子

  • 学習と知識獲得

  • タンパク質ネットワーク

  • 仮説枚挙

  • ゲノム

  • 遺伝子量不均衡

  • 蛋白質

  • 酵母

  • フィードバック

  • 過剰発現

Research Areas

  • Life Science / System genome science

Education

  • Kobe University   大学院自然科学研究科  

    1995.4 - 1998.3

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  • Kobe University   大学院理学研究科  

    1993.4 - 1995.3

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  • Kobe University   理学部   生物学科

    1989.4 - 1993.3

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Research History

  • Okayama University   Faculty of Environmental, Life, Natural Science and Technology   Professor

    2023.4

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    Country:Japan

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  • Okayama University   Research Core for Interdisciplinary Sciences   Associate Professor

    2013.4 - 2023.3

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  • Okayama University   Research Core for Interdisciplinary Sciences   Designated Associate Professor

    2011.4 - 2013.3

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  • Okayama University   Research Core for Interdisciplinary Sciences   Designated Assistant Professor

    2009.2 - 2011.3

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  • Japan Science and Technology Agency   Presto Researcher

    2006.10 - 2009.1

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  • Japan Science and Technology Agency   ERATO-SORST北野共生システムプロジェクト   Researcher

    2004.4 - 2006.10

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  • Washington University   School of Medicine   Research Associate

    2001.4 - 2004.3

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  • 三菱化学生命科学研究所   特別研究員

    1998.4 - 2001.3

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Professional Memberships

Committee Memberships

  • 科学技術振興機構 創発的支援事業   創発アドバイザー  

    2023   

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  • 日本学術振興会 科学研究費助成事業   審査委員  

    2021 - 2022   

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  • 日本学術振興会 科学研究費助成事業   審査委員  

    2017 - 2019   

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  • 日本学術振興会 科学研究費助成事業   第1段審査(書面審査)委員  

    2014 - 2015   

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  • 酵母遺伝学フォーラム   運営委員(広報担当)  

       

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    Committee type:Academic society

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Papers

  • Toxicity of the model protein 3×GFP arises from degradation overload, not from aggregate formation. International journal

    Shotaro Namba, Hisao Moriya

    Journal of cell science   2024.5

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    Language:English   Publishing type:Research paper (scientific journal)  

    While protein aggregation can cause cytotoxicity, it also forms to mitigate cytotoxicity from misfolded proteins, though the nature of these contrasting aggregates remains unclear. We previously found that overproduction (op) of a three green fluorescent protein linked protein (3×GFP) induces giant aggregates, and is detrimental to growth. Here, we investigated the mechanism of growth inhibition by 3×GFP-op using non-aggregative 3×MOX-op as a control. The 3×GFP aggregates were induced by misfolding, and 3×GFP-op had higher cytotoxicity than 3×MOX-op because it perturbs the ubiquitin-proteasome system. Static aggregates formed by 3×GFP-op dynamically trapped Hsp70, causing the heat shock response. Systematic analysis of mutants deficient in the protein quality control suggested that 3×GFP-op did not cause critical Hsp70 depletion and aggregation functioned in the direction of mitigating toxicity. Artificial trapping of essential cell cycle regulators into 3×GFP aggregates caused abnormalities in the cell cycle. In conclusion, the formation of the giant 3×GFP aggregates itself is not cytotoxic, as it does not entrap and deplete essential proteins. Rather, it is productive, inducing the heat shock response while preventing an overload to the degradation system.

    DOI: 10.1242/jcs.261977

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  • Demonstration of iodide-dependent UVA-triggered growth inhibition in Saccharomyces cerevisiae cells and identification of its suppressive molecules Reviewed

    Ryota Ono, Nozomu Saeki, Keiichi Kojima, Hisao Moriya, Yuki Sudo

    Biochemical and Biophysical Research Communications   677   1 - 5   2023.10

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    Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.bbrc.2023.07.048

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  • Overexpression profiling reveals cellular requirements in the context of genetic backgrounds and environments Reviewed

    Nozomu Saeki, Chie Yamamoto, Yuichi Eguchi, Takayuki Sekito, Shuji Shigenobu, Mami Yoshimura, Yoko Yashiroda, Charles Boone, Hisao Moriya

    PLOS Genetics   19 ( 4 )   e1010732 - e1010732   2023.4

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    Authorship:Last author, Corresponding author   Publishing type:Research paper (scientific journal)   Publisher:Public Library of Science (PLoS)  

    Overexpression can help life adapt to stressful environments, making an examination of overexpressed genes valuable for understanding stress tolerance mechanisms. However, a systematic study of genes whose overexpression is functionally adaptive (GOFAs) under stress has yet to be conducted. We developed a new overexpression profiling method and systematically identified GOFAs in Saccharomyces cerevisiae under stress (heat, salt, and oxidative). Our results show that adaptive overexpression compensates for deficiencies and increases fitness under stress, like calcium under salt stress. We also investigated the impact of different genetic backgrounds on GOFAs, which varied among three S. cerevisiae strains reflecting differing calcium and potassium requirements for salt stress tolerance. Our study of a knockout collection also suggested that calcium prevents mitochondrial outbursts under salt stress. Mitochondria-enhancing GOFAs were only adaptive when adequate calcium was available and non-adaptive when calcium was deficient, supporting this idea. Our findings indicate that adaptive overexpression meets the cell’s needs for maximizing the organism’s adaptive capacity in the given environment and genetic context.

    DOI: 10.1371/journal.pgen.1010732

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  • Massive expression of cysteine-containing proteins causes abnormal elongation of yeast cells by perturbing the proteasome Reviewed

    Shotaro Namba, Hisaaki Kato, Shuji Shigenobu, Takashi Makino, Hisao Moriya

    G3 Genes|Genomes|Genetics   2022.4

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    Authorship:Last author   Publishing type:Research paper (scientific journal)   Publisher:Oxford University Press (OUP)  

    Abstract

    The enhanced green fluorescent protein (EGFP) is considered to be a harmless protein because the critical expression level that causes growth defects is higher than that of other proteins. Here, we found that overexpression of EGFP, but not a glycolytic protein Gpm1, triggered the cell elongation phenotype in the budding yeast Saccharomyces cerevisiae. By the morphological analysis of the cell overexpressing fluorescent protein and glycolytic enzyme variants, we revealed that cysteine content was associated with the cell elongation phenotype. The abnormal cell morphology triggered by overexpression of EGFP was also observed in the fission yeast Schizosaccharomyces pombe. Overexpression of cysteine-containing protein was toxic, especially at high-temperature, while the toxicity could be modulated by additional protein characteristics. Investigation of protein aggregate formation, morphological abnormalities in mutants, and transcriptomic changes that occur upon overexpression of EGFP variants suggested that perturbation of the proteasome by the exposed cysteine of the overexpressed protein causes cell elongation. Overexpression of proteins with relatively low folding properties, such as EGFP, was also found to promote the formation of SHOTA (Seventy kDa Heat shock protein-containing, Overexpression-Triggered Aggregates), an intracellular aggregate that incorporates Hsp70/Ssa1, which induces a heat shock response, while it was unrelated to cell elongation. Evolutionary analysis of duplicated genes showed that cysteine toxicity may be an evolutionary bias to exclude cysteine from highly expressed proteins. The overexpression of cysteine-less moxGFP, the least toxic protein revealed in this study, would be a good model system to understand the physiological state of protein burden triggered by ultimate overexpression of harmless proteins.

    DOI: 10.1093/g3journal/jkac106

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  • Identification of uncharacterized proteins potentially localized to mitochondria (UPMs) in S. cerevisiae using a fluorescent protein unstable in the cytoplasm International journal

    Satoshi Horiuchi, Shotaro Namba, Nozomu Saeki, Ayano Satoh, Hisao Moriya

    Yeast   39 ( 5 )   303 - 311   2021.12

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    Eukaryotic cells are composed of organelles, and each organelle contains proteins that play a role in its function. Therefore, the localization of a protein, especially to organelles, is a clue to infer the function of that protein. In this study, we attempted to identify novel mitochondrially localized proteins in the budding yeast Saccharomyces cerevisiae using a fluorescent protein (GFPdeg) that is rapidly degraded in the cytoplasm. Of the budding yeast proteins predicted to localize to mitochondria by the prediction tool Deeploc-1.0, those with known mitochondrial localization or functional relevance were eliminated, and 95 proteins of unknown function were selected as candidates for analysis. By forced expression of GFPdeg fusion proteins with these proteins and observation of their localization, we identified 35 uncharacterized proteins potentially localized to mitochondria (UPMs) including 8 previously identified proteins that localize to mitochondria. Most of these had no N-terminal mitochondrial localization signal and were evolutionarily young "emerging genes" that exist only in S. cerevisiae. Some of these genes were found to be upregulated during the postdiauxic shift phase when mitochondria are being developed, suggesting that they are actually involved in some mitochondrial function.

    DOI: 10.1002/yea.3685

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  • Genetic profiling of protein burden and nuclear export overload Reviewed International journal

    Reiko Kintaka, Koji Makanae, Shotaro Namba, Hisaaki Kato, Keiji Kito, Shinsuke Ohnuki, Yoshikazu Ohya, Brenda J Andrews, Charles Boone, Hisao Moriya

    eLife   9   2020.11

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:eLife Sciences Publications, Ltd  

    Overproduction (op) of proteins triggers cellular defects. One of the consequences of overproduction is the protein burden/cost, which is produced by an overloading of the protein synthesis process. However, the physiology of cells under a protein burden is not well characterized. We performed genetic profiling of protein burden by systematic analysis of genetic interactions between GFP-op, surveying both deletion and temperature-sensitive mutants in budding yeast. We also performed genetic profiling in cells with overproduction of triple-GFP (tGFP), and the nuclear export signal-containing tGFP (NES-tGFP). The mutants specifically interacted with GFP-op were suggestive of unexpected connections between actin-related processes like polarization and the protein burden, which was supported by morphological analysis. The tGFP-op interactions suggested that this protein probe overloads the proteasome, whereas those that interacted with NES-tGFP involved genes encoding components of the nuclear export process, providing a resource for further analysis of the protein burden and nuclear export overload.

    DOI: 10.7554/elife.54080

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    Other Link: https://cdn.elifesciences.org/articles/54080/elife-54080-v1.xml

  • Exploring the Complexity of Protein-Level Dosage Compensation that Fine-Tunes Stoichiometry of Multiprotein Complexes Reviewed

    Koji Ishikawa, Akari Ishihara, Hisao Moriya

    PLOS Genetics   16 ( 10 )   e1009091 - e1009091   2020.10

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    Authorship:Last author   Publishing type:Research paper (scientific journal)   Publisher:Public Library of Science (PLoS)  

    DOI: 10.1371/journal.pgen.1009091

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  • N-terminal deletion of Swi3 created by the deletion of a dubious ORF YJL175W mitigates protein burden effect in S. cerevisiae. Reviewed International journal

    Nozomu Saeki, Yuichi Eguchi, Reiko Kintaka, Koji Makanae, Yuichi Shichino, Shintaro Iwasaki, Manabu Kanno, Nobutada Kimura, Hisao Moriya

    Scientific reports   10 ( 1 )   9500 - 9500   2020.6

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    Extreme overproduction of gratuitous proteins can overload cellular protein production resources, leading to growth defects, a phenomenon known as the protein burden/cost effect. Genetic screening in the budding yeast Saccharomyces cerevisiae has isolated several dubious ORFs whose deletions mitigated the protein burden effect, but individual characterization thereof has yet to be delineated. We found that deletion of the YJL175W ORF yielded an N-terminal deletion of Swi3, a subunit of the SWI/SNF chromatin remodeling complex, and partial loss of function of Swi3. The deletion mutant showed a reduction in transcription of genes encoding highly expressed, secreted proteins and an overall reduction in translation. Mutations in the chromatin remodeling complex could thus mitigate the protein burden effect, likely by reallocating residual cellular resources used to overproduce proteins. This cellular state might also be related to cancer cells, as they frequently harbor mutations in the SWI/SNF complex.

    DOI: 10.1038/s41598-020-66307-z

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  • Comparative Gene Analysis Focused on Silica Cell Wall Formation: Identification of Diatom-Specific SET Domain Protein Methyltransferases Reviewed

    Michiko Nemoto, Sayako Iwaki, Hisao Moriya, Yuki Monden, Takashi Tamura, Kenji Inagaki, Shigeki Mayama, Kiori Obuse

    Marine Biotechnology   22 ( 4 )   551 - 563   2020.6

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    Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    DOI: 10.1007/s10126-020-09976-1

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    Other Link: https://link.springer.com/article/10.1007/s10126-020-09976-1/fulltext.html

  • Development of an experimental method of systematically estimating protein expression limits in HEK293 cells. Reviewed International journal

    Yoshihiro Mori, Yuki Yoshida, Ayano Satoh, Hisao Moriya

    Scientific reports   10 ( 1 )   4798 - 4798   2020.3

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    Protein overexpression sometimes causes cellular defects, although the underlying mechanism is still unknown. A protein's expression limit, which triggers cellular defects, is a useful indication of the underlying mechanism. In this study, we developed an experimental method of estimating the expression limits of target proteins in the human embryonic kidney cell line HEK293 by measuring the proteins' expression levels in cells that survived after the high-copy introduction of plasmid DNA by which the proteins were expressed under a strong cytomegalovirus promoter. The expression limits of nonfluorescent target proteins were indirectly estimated by measuring the levels of green fluorescent protein (GFP) connected to the target proteins with the self-cleaving sequence P2A. The expression limit of a model GFP was ~5.0% of the total protein, and sustained GFP overexpression caused cell death. The expression limits of GFPs with mitochondria-targeting signals and endoplasmic reticulum localization signals were 1.6% and 0.38%, respectively. The expression limits of four proteins involved in vesicular trafficking were far lower compared to a red fluorescent protein. The protein expression limit estimation method developed will be valuable for defining toxic proteins and consequences of protein overexpression.

    DOI: 10.1038/s41598-020-61646-3

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  • Yeast screening system reveals the inhibitory mechanism of cancer cell proliferation by benzyl isothiocyanate through down-regulation of Mis12. Reviewed International journal

    Naomi Abe-Kanoh, Narumi Kunisue, Takumi Myojin, Ayako Chino, Shintaro Munemasa, Yoshiyuki Murata, Ayano Satoh, Hisao Moriya, Yoshimasa Nakamura

    Scientific reports   9 ( 1 )   8866 - 8866   2019.6

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    Benzyl isothiocyanate (BITC) is a naturally-occurring isothiocyanate derived from cruciferous vegetables. BITC has been reported to inhibit the proliferation of various cancer cells, which is believed to be important for the inhibition of tumorigenesis. However, the detailed mechanisms of action remain unclear. In this study, we employed a budding yeast Saccharomyces cerevisiae as a model organism for screening. Twelve genes including MTW1 were identified as the overexpression suppressors for the antiproliferative effect of BITC using the genome-wide multi-copy plasmid collection for S. cerevisiae. Overexpression of the kinetochore protein Mtw1 counteracts the antiproliferative effect of BITC in yeast. The inhibitory effect of BITC on the proliferation of human colon cancer HCT-116 cells was consistently suppressed by the overexpression of Mis12, a human orthologue of Mtw1, and enhanced by the knockdown of Mis12. We also found that BITC increased the phosphorylated and ubiquitinated Mis12 level with consequent reduction of Mis12, suggesting that BITC degrades Mis12 through an ubiquitin-proteasome system. Furthermore, cell cycle analysis showed that the change in the Mis12 level affected the cell cycle distribution and the sensitivity to the BITC-induced apoptosis. These results provide evidence that BITC suppresses cell proliferation through the post-transcriptional regulation of the kinetochore protein Mis12.

    DOI: 10.1038/s41598-019-45248-2

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  • Estimating the protein burden limit of yeast cells by measuring the expression limits of glycolytic proteins. Reviewed International journal

    Yuichi Eguchi, Koji Makanae, Tomohisa Hasunuma, Yuko Ishibashi, Keiji Kito, Hisao Moriya

    eLife   7   2018.8

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    The ultimate overexpression of a protein could cause growth defects, which are known as the protein burden. However, the expression limit at which the protein-burden effect is triggered is still unclear. To estimate this limit, we systematically measured the overexpression limits of glycolytic proteins in Saccharomyces cerevisiae. The limits of some glycolytic proteins were up to 15% of the total cellular protein. These limits were independent of the proteins' catalytic activities, a finding that was supported by an in silico analysis. Some proteins had low expression limits that were explained by their localization and metabolic perturbations. The codon usage should be highly optimized to trigger the protein-burden effect, even under strong transcriptional induction. The S-S-bond-connected aggregation mediated by the cysteine residues of a protein might affect its expression limit. Theoretically, only non-harmful proteins could be expressed up to the protein-burden limit. Therefore, we established a framework to distinguish proteins that are harmful and non-harmful upon overexpression.

    DOI: 10.7554/eLife.34595

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    Other Link: http://orcid.org/0000-0001-7638-3640

  • Genetic Analysis of Signal Generation by the Rgt2 Glucose Sensor of Saccharomyces cerevisiae. Reviewed International journal

    Peter Scharff-Poulsen, Hisao Moriya, Mark Johnston

    G3 (Bethesda, Md.)   8 ( 8 )   2685 - 2696   2018.7

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    The yeast S. cerevisiae senses glucose through Snf3 and Rgt2, transmembrane proteins that generate an intracellular signal in response to glucose that leads to inhibition of the Rgt1 transcriptional repressor and consequently to derepression of HXT genes encoding glucose transporters. Snf3 and Rgt2 are thought to be glucose receptors because they are similar to glucose transporters. In contrast to glucose transporters, they have unusually long C-terminal tails that bind to Mth1 and Std1, paralogous proteins that regulate function of the Rgt1 transcription factor. We show that the C-terminal tail of Rgt2 is not responsible for its inability to transport glucose. To gain insight into how the glucose sensors generate an intracellular signal, we identified RGT2 mutations that cause constitutive signal generation. Most of the mutations alter evolutionarily-conserved amino acids in the transmembrane spanning regions of Rgt2 that are predicted to be involved in maintaining an outward-facing conformation or to be in the substrate binding site. Our analysis of these mutations suggests they cause Rgt2 to adopt inward-facing or occluded conformations that generate the glucose signal. These results support the idea that Rgt2 and Snf3 are glucose receptors that signal in response to binding of extracellular glucose and inform the basis of their signaling.

    DOI: 10.1534/g3.118.200338

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  • Assessing phagotrophy in the mixotrophic ciliate Paramecium bursaria using GFP-expressing yeast cells. Reviewed International journal

    Takashi Miura, Hisao Moriya, Sosuke Iwai

    FEMS microbiology letters   364 ( 12 )   2017.7

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:OXFORD UNIV PRESS  

    We used cells of the yeast Saccharomyces cerevisiae expressing green fluorescent protein (GFP) as fluorescently labelled prey to assess the phagocytic activities of the mixotrophic ciliate Paramecium bursaria, which harbours symbiotic Chlorella-like algae. Because of different fluorescence spectra of GFP and algal chlorophyll, ingested GFP-expressing yeast cells can be distinguished from endosymbiotic algal cells and directly counted in individual P. bursaria cells using fluorescence microscopy. By using GFP-expressing yeast cells, we found that P. bursaria altered ingestion activities under different physiological conditions, such as different growth phases or the presence/absence of endosymbionts. Use of GFP-expressing yeast cells allowed us to estimate the digestion rates of live prey of the ciliate. In contrast to the ingestion activities, the digestion rate within food vacuoles was not affected by the presence of endosymbionts, consistent with previous findings that food and perialgal vacuoles are spatially and functionally separated in P. bursaria. Thus, GFP-expressing yeast may provide a valuable tool to assess both ingestion and digestion activities of ciliates that feed on eukaryotic organisms.

    DOI: 10.1093/femsle/fnx117

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  • Post-Translational Dosage Compensation Buffers Genetic Perturbations to Stoichiometry of Protein Complexes Reviewed

    Koji Ishikawa, Koji Makanae, Shintaro Iwasaki, Nicholas T. Ingolia, Hisao Moriya

    PLOS GENETICS   13 ( 1 )   e1006554   2017.1

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:PUBLIC LIBRARY SCIENCE  

    Understanding buffering mechanisms for various perturbations is essential for understanding robustness in cellular systems. Protein-level dosage compensation, which arises when changes in gene copy number do not translate linearly into protein level, is one mechanism for buffering against genetic perturbations. Here, we present an approach to identify genes with dosage compensation by increasing the copy number of individual genes using the genetic tug-of-war technique. Our screen of chromosome I suggests that dosage-compensated genes constitute approximately 10% of the genome and consist predominantly of sub-units of multi-protein complexes. Importantly, because subunit levels are regulated in a stoichiometry-dependent manner, dosage compensation plays a crucial role in maintaining subunit stoichiometries. Indeed, we observed changes in the levels of a complex when its subunit stoichiometries were perturbed. We further analyzed compensation mechanisms using a proteasome-defective mutant as well as ribosome profiling, which provided strong evidence for compensation by ubiquitin-dependent degradation but not reduced translational efficiency. Thus, our study provides a systematic understanding of dosage compensation and highlights that this post-translational regulation is a critical aspect of robustness in cellular systems.

    DOI: 10.1371/journal.pgen.1006554

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    Other Link: http://orcid.org/0000-0001-7638-3640

  • Cellular growth defects triggered by an overload of protein localization processes. Reviewed International journal

    Reiko Kintaka, Koji Makanae, Hisao Moriya

    Scientific reports   6   31774 - 31774   2016.8

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:NATURE PUBLISHING GROUP  

    High-level expression of a protein localized to an intracellular compartment is expected to cause cellular defects because it overloads localization processes. However, overloads of localization processes have never been studied systematically. Here, we show that the expression levels of green fluorescent proteins (GFPs) with localization signals were limited to the same degree as a toxic misfolded GFP in budding yeast cells, and that their high-level expression caused cellular defects associated with localization processes. We further show that limitation of the exportin Crm1 determined the expression limit of GFP with a nuclear export signal. Although misfolding of GFP with a vesicle-mediated transport signal triggered endoplasmic reticulum stress, it was not the primary determinant of its expression limit. The precursor of GFP with a mitochondrial targeting signal caused a cellular defect. Finally, we estimated the residual capacities of localization processes. High-level expression of a localized protein thus causes cellular defects by overloading the capacities of localization processes.

    DOI: 10.1038/srep31774

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  • Quantitative nature of overexpression experiments. Reviewed International journal

    Hisao Moriya

    Molecular biology of the cell   26 ( 22 )   3932 - 9   2015.11

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    Overexpression experiments are sometimes considered as qualitative experiments designed to identify novel proteins and study their function. However, in order to draw conclusions regarding protein overexpression through association analyses using large-scale biological data sets, we need to recognize the quantitative nature of overexpression experiments. Here I discuss the quantitative features of two different types of overexpression experiment: absolute and relative. I also introduce the four primary mechanisms involved in growth defects caused by protein overexpression: resource overload, stoichiometric imbalance, promiscuous interactions, and pathway modulation associated with the degree of overexpression.

    DOI: 10.1091/mbc.E15-07-0512

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  • Aneuploid proliferation defects in yeast are not driven by copy number changes of a few dosage-sensitive genes. Reviewed International journal

    Megan E Bonney, Hisao Moriya, Angelika Amon

    Genes & development   29 ( 9 )   898 - 903   2015.5

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    Aneuploidy-the gain or loss of one or more whole chromosome-typically has an adverse impact on organismal fitness, manifest in conditions such as Down syndrome. A central question is whether aneuploid phenotypes are the consequence of copy number changes of a few especially harmful genes that may be present on the extra chromosome or are caused by copy number alterations of many genes that confer no observable phenotype when varied individually. We used the proliferation defect exhibited by budding yeast strains carrying single additional chromosomes (disomes) to distinguish between the "few critical genes" hypothesis and the "mass action of genes" hypothesis. Our results indicate that subtle changes in gene dosage across a chromosome can have significant phenotypic consequences. We conclude that phenotypic thresholds can be crossed by mass action of copy number changes that, on their own, are benign.

    DOI: 10.1101/gad.261743.115

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    Other Link: http://orcid.org/0000-0001-7638-3640

  • Small toxic protein encoded on chromosome VII of Saccharomyces cerevisiae. Reviewed International journal

    Koji Makanae, Reiko Kintaka, Koji Ishikawa, Hisao Moriya

    PloS one   10 ( 3 )   e0120678   2015

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    In a previous study, we found an unknown element that caused growth inhibition after its copy number increased in the 3' region of DIE2 in Saccharomyces cerevisiae. In this study, we further identified this element and observed that overexpression of a small protein (sORF2) of 57 amino acids encoded in this region caused growth inhibition. The transcriptional response and multicopy suppression of the growth inhibition caused by sORF2 overexpression suggest that sORF2 overexpression inhibits the ergosterol biosynthetic pathway. sORF2 was not required in the normal growth of S. cerevisiae, and not conserved in related yeast species including S. paradoxus. Thus, sORF2 (designated as OTO1) is an orphan ORF that determines the specificity of this species.

    DOI: 10.1371/journal.pone.0120678

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  • Distinct mechanisms for spiro-carbon formation reveal biosynthetic pathway crosstalk in spirotryprostatins biosynthesis Reviewed

    Tsunematsu Yuta, Ishikawa Noriyasu, Moriya Hisao, Noguchi Hiroshi, Watanabe Kenji

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   247   2014.3

  • Evaluation of the lower protein limit in the budding yeast Saccharomyces cerevisiae using TIPI-gTOW. Reviewed International journal

    Masataka Sasabe, Sayumi Shintani, Reiko Kintaka, Kazunari Kaizu, Koji Makanae, Hisao Moriya

    BMC systems biology   8 ( 1 )   2 - 2   2014.1

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:BIOMED CENTRAL LTD  

    BACKGROUND: Identifying permissible limits of intracellular parameters such as protein expression provides important information for examining robustness. In this study, we used the TEV protease-mediated induction of protein instability (TIPI) in combination with the genetic Tug-of-War (gTOW) to develop a method to measure the lower limit of protein level. We first tested the feasibility of this method using ADE2 as a marker and then analyzed some cell cycle regulators to reveal genetic interactions. RESULTS: Using TIPI-gTOW, we successfully constructed a strain in which GFP-(TDegF)Ade2 was expressed at the lower limit, just sufficient to support cellular growth under the -Ade condition by accelerating degradation by TEV protease. We also succeeded in constructing a strain in which the minimal level of GFP-(TDegF)Cdc20 was expressed by TIPI-gTOW. Using this strain, we studied genetic interactions between cell cycle regulators and CDC20, and the result was highly consistent with the previously identified interactions. Comparison of the experimental data with predictions of a mathematical model revealed some interactions that were not implemented into the current model. CONCLUSIONS: TIPI-gTOW is useful for estimating changes in the lower limit of a protein under different conditions, such as different genetic backgrounds and environments. TIPI-gTOW is also useful for analyzing genetic interactions of essential genes whose deletion mutants cannot be obtained.

    DOI: 10.1186/1752-0509-8-2

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  • Completing SBGN-AF networks by logic-based hypothesis finding Reviewed

    Yoshitaka Yamamoto, Adrien Rougny, Hidetomo Nabeshima, Katsumi Inoue, Hisao Moriya, Christine Froidevaux, Koji Iwanuma

    Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)   8738   165 - 179   2014

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    Language:English   Publishing type:Research paper (international conference proceedings)   Publisher:Springer Verlag  

    This study considers formal methods for finding unknown interactions of incomplete molecular networks using microarray profiles. In systems biology, a challenging problem lies in the growing scale and complexity of molecular networks. Along with high-throughput experimental tools, it is not straightforward to reconstruct huge and complicated networks using observed data by hand. Thus, we address the completion problem of our target networks represented by a standard markup language, called SBGN (in particular, Activity Flow). Our proposed method is based on logic-based hypothesis finding techniques
    given an input SBGN network and its profile data, missing interactions can be logically generated as hypotheses by the proposed method. In this paper, we also show empirical results that demonstrate how the proposed method works with a real network involved in the glucose repression of S. cerevisiae. © Springer International Publishing Switzerland 2014.

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  • Distinct mechanisms for spiro-carbon formation reveal biosynthetic pathway crosstalk. Reviewed

    Tsunematsu Y, Ishikawa N, Wakana D, Goda Y, Noguchi H, Moriya H, Hotta K, Watanabe K

    Nature chemical biology   9 ( 12 )   818 - 825   2013.12

  • A genome-wide activity assessment of terminator regions in Saccharomyces cerevisiae provides a ″terminatome″ toolbox. Reviewed International journal

    Mamoru Yamanishi, Yoichiro Ito, Reiko Kintaka, Chie Imamura, Satoshi Katahira, Akinori Ikeuchi, Hisao Moriya, Takashi Matsuyama

    ACS synthetic biology   2 ( 6 )   337 - 47   2013.6

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    The terminator regions of eukaryotes encode functional elements in the 3' untranslated region (3'-UTR) that influence the 3'-end processing of mRNA, mRNA stability, and translational efficiency, which can modulate protein production. However, the contribution of these terminator regions to gene expression remains unclear, and therefore their utilization in metabolic engineering or synthetic genetic circuits has been limited. Here, we comprehensively evaluated the activity of 5302 terminator regions from a total of 5880 genes in the budding yeast Saccharomyces cerevisiae by inserting each terminator region downstream of the P TDH3 - green fluorescent protein (GFP) reporter gene and measuring the fluorescent intensity of GFP. Terminator region activities relative to that of the PGK1 standard terminator ranged from 0.036 to 2.52, with a mean of 0.87. We thus could isolate the most and least active terminator regions. The activities of the terminator regions showed a positive correlation with mRNA abundance, indicating that the terminator region is a determinant of mRNA abundance. The least active terminator regions tended to encode longer 3'-UTRs, suggesting the existence of active degradation mechanisms for those mRNAs. The terminator regions of ribosomal protein genes tended to be the most active, suggesting the existence of a common regulator of those genes. The ″terminatome″ (the genome-wide set of terminator regions) thus not only provides valuable information to understand the modulatory roles of terminator regions on gene expression but also serves as a useful toolbox for the development of metabolically and genetically engineered yeast.

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  • Identification of dosage-sensitive genes in Saccharomyces cerevisiae using the genetic tug-of-war method. Reviewed International journal

    Koji Makanae, Reiko Kintaka, Takashi Makino, Hiroaki Kitano, Hisao Moriya

    Genome research   23 ( 2 )   300 - 11   2013.2

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    Gene overexpression beyond a permissible limit causes defects in cellular functions. However, the permissible limits of most genes are unclear. Previously, we developed a genetic method designated genetic tug-of-war (gTOW) to measure the copy number limit of overexpression of a target gene. In the current study, we applied gTOW to the analysis of all protein-coding genes in the budding yeast Saccharomyces cerevisiae. We showed that the yeast cellular system was robust against an increase in the copy number by up to 100 copies in >80% of the genes. After frameshift and segmentation analyses, we isolated 115 dosage-sensitive genes (DSGs) with copy number limits of 10 or less. DSGs contained a significant number of genes involved in cytoskeletal organization and intracellular transport. DSGs tended to be highly expressed and to encode protein complex members. We demonstrated that the protein burden caused the dosage sensitivity of highly expressed genes using a gTOW experiment in which the open reading frame was replaced with GFP. Dosage sensitivities of some DSGs were rescued by the simultaneous increase in the copy numbers of partner genes, indicating that stoichiometric imbalances among complexes cause dosage sensitivity. The results obtained in this study will provide basic knowledge about the physiology of chromosomal abnormalities and the evolution of chromosomal composition.

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  • Relationships between cell cycle regulator gene copy numbers and protein expression levels in Schizosaccharomyces pombe. Reviewed International journal

    Ayako Chino, Koji Makanae, Hisao Moriya

    PloS one   8 ( 9 )   e73319   2013

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    We previously determined the copy number limits of overexpression for cell division cycle (cdc) regulatory genes in the fission yeast Schizosaccharomyces pombe using the "genetic tug-of-war" (gTOW) method. In this study, we measured the levels of tandem affinity purification (TAP)-tagged target proteins when their copy numbers are increased in gTOW. Twenty analyzed genes showed roughly linear correlations between increased protein levels and gene copy numbers, which suggested a general lack of compensation for gene dosage in S. pombe. Cdc16 and Sid2 protein levels but not their mRNA levels were much lower than that expected by their copy numbers, which suggested the existence of a post-transcriptional down regulation of these genes. The cyclin Cig1 protein level and its mRNA level were much higher than that expected by its copy numbers, which suggested a positive feedback mechanism for its expression. A higher Cdc10 protein level and its mRNA level, probably due to cloning its gene into a plasmid, indicated that Cdc10 regulation was more robust than that previously predicted.

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  • Parallel real-time PCR on a chip for genetic tug-of-war (gTOW) method. Reviewed

    Toyohiro Naito, Ai Yatsuhashi, Noritada Kaji, Taeko Ando, Kazuo Sato, Hisao Moriya, Hiroaki Kitano, Takao Yasui, Manabu Tokeshi, Yoshinobu Baba

    Analytical sciences : the international journal of the Japan Society for Analytical Chemistry   29 ( 3 )   367 - 71   2013

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    A microchip-based real-time polymerase chain reaction (PCR) device has been developed for the genetic tug-of-war (gTOW) method that provides quantitative data for research on biorobustness and systems biology. The device was constructed of a silicon glass chip, a temperature controlling Peltier element, and a microscope. A parallel real-time amplification process of target genes on the plasmids and the housekeeping genes in a model eukaryote Saccharomyces cerevisiae were detected simultaneously, and the copy number of the target genes were estimated. The device provides unique quantitative data that can be used to augment understanding of the system-level properties of living cells.

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  • Robustness analysis of cellular systems using the genetic tug-of-war method. Reviewed International journal

    Hisao Moriya, Koji Makanae, Kenji Watanabe, Ayako Chino, Yuki Shimizu-Yoshida

    Molecular bioSystems   8 ( 10 )   2513 - 22   2012.10

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    Robustness is one of the principles of design inherent to biological systems. Cellular robustness can be measured as limits of intracellular parameters such as gene expression levels. We have recently developed an experimental approach coined as genetic Tug-Of-War (gTOW), which we used to perform robustness analysis in yeast. Using gTOW, we were able to measure the upper limit of expression of gene targets. In this review, we first elaborate on how the gTOW method compares to current mathematical simulation models prevalently used in the determination of robustness. We then explain the experimental principles underlying gTOW and its associated tools, and we provide concrete examples of robustness analysis using gTOW, i.e. cell cycle and HOG pathway gene expression analysis. Finally, we list a series of Q&As related to the experimental utilization of gTOW and we describe the potential impact of gTOW and its relevance to the understanding of biological systems.

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  • Establishing a new methodology for genome mining and biosynthesis of polyketides and peptides through yeast molecular genetics. Reviewed International journal

    Kan'ichiro Ishiuchi, Takehito Nakazawa, Takashi Ookuma, Satoru Sugimoto, Michio Sato, Yuta Tsunematsu, Noriyasu Ishikawa, Hiroshi Noguchi, Kinya Hotta, Hisao Moriya, Kenji Watanabe

    Chembiochem : a European journal of chemical biology   13 ( 6 )   846 - 54   2012.4

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    Fungal genome sequencing has revealed many genes coding for biosynthetic enzymes, including polyketide synthases and nonribosomal peptide synthetases. However, characterizing these enzymes and identifying the compounds they synthesize remains a challenge, whether the genes are expressed in their original hosts or in more tractable heterologous hosts, such as yeast. Here, we developed a streamlined method for isolating biosynthetic genes from fungal sources and producing bioactive molecules in an engineered Saccharomyces cerevisiae host strain. We used overlap extension PCR and yeast homologous recombination to clone desired fungal polyketide synthase or a nonribosomal peptide synthetase genes (5-20 kb) into a yeast expression vector quickly and efficiently. This approach was used successfully to clone five polyketide synthases and one nonribosomal peptide synthetase, from various fungal species. Subsequent detailed chemical characterizations of the resulting natural products identified six polyketide and two nonribosomal peptide products, one of which was a new compound. Our system should facilitate investigating uncharacterized fungal biosynthetic genes, identifying novel natural products, and rationally engineering biosynthetic pathways for the production of enzyme analogues possessing modified bioactivity.

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  • Overexpression limits of fission yeast cell-cycle regulators in vivo and in silico. Reviewed International journal

    Hisao Moriya, Ayako Chino, Orsolya Kapuy, Attila Csikász-Nagy, Béla Novák

    Molecular systems biology   7   556 - 556   2011.12

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    Cellular systems are generally robust against fluctuations of intracellular parameters such as gene expression level. However, little is known about expression limits of genes required to halt cellular systems. In this study, using the fission yeast Schizosaccharomyces pombe, we developed a genetic 'tug-of-war' (gTOW) method to assess the overexpression limit of certain genes. Using gTOW, we determined copy number limits for 31 cell-cycle regulators; the limits varied from 1 to >100. Comparison with orthologs of the budding yeast Saccharomyces cerevisiae suggested the presence of a conserved fragile core in the eukaryotic cell cycle. Robustness profiles of networks regulating cytokinesis in both yeasts (septation-initiation network (SIN) and mitotic exit network (MEN)) were quite different, probably reflecting differences in their physiologic functions. Fragility in the regulation of GTPase spg1 was due to dosage imbalance against GTPase-activating protein (GAP) byr4. Using the gTOW data, we modified a mathematical model and successfully reproduced the robustness of the S. pombe cell cycle with the model.

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  • A comprehensive molecular interaction map of the budding yeast cell cycle. Reviewed International journal

    Kazunari Kaizu, Samik Ghosh, Yukiko Matsuoka, Hisao Moriya, Yuki Shimizu-Yoshida, Hiroaki Kitano

    Molecular systems biology   6   415 - 415   2010.9

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    With the accumulation of data on complex molecular machineries coordinating cell-cycle dynamics, coupled with its central function in disease patho-physiologies, it is becoming increasingly important to collate the disparate knowledge sources into a comprehensive molecular network amenable to systems-level analyses. In this work, we present a comprehensive map of the budding yeast cell-cycle, curating reactions from ∼600 original papers. Toward leveraging the map as a framework to explore the underlying network architecture, we abstract the molecular components into three planes--signaling, cell-cycle core and structural planes. The planar view together with topological analyses facilitates network-centric identification of functions and control mechanisms. Further, we perform a comparative motif analysis to identify around 194 motifs including feed-forward, mutual inhibitory and feedback mechanisms contributing to cell-cycle robustness. We envisage the open access, comprehensive cell-cycle map to open roads toward community-based deeper understanding of cell-cycle dynamics.

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  • Fragilities Caused by Dosage Imbalance in Regulation of the Budding Yeast Cell Cycle Reviewed

    Kazunari Kaizu, Hisao Moriya, Hiroaki Kitano

    PLOS GENETICS   6 ( 4 )   2010.4

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    Cells can maintain their functions despite fluctuations in intracellular parameters, such as protein activities and gene expression levels. This commonly observed biological property of cells is called robustness. On the other hand, these parameters have different limitations, each reflecting the property of the subsystem containing the parameter. The budding yeast cell cycle is quite fragile upon overexpression of CDC14, but is robust upon overexpression of ESP1. The gene products of both CDC14 and ESP1 are regulated by 1: 1 binding with their inhibitors (Net1 and Pds1), and a mathematical model predicts the extreme fragility of the cell cycle upon overexpression of CDC14 and ESP1 caused by dosage imbalance between these genes. However, it has not been experimentally shown that dosage imbalance causes fragility of the cell cycle. In this study, we measured the quantitative genetic interactions of these genes by performing combinatorial "genetic tug-of-war'' experiments. We first showed experimental evidence that dosage imbalance between CDC14 and NET1 causes fragility. We also showed that fragility arising from dosage imbalance between ESP1 and PDS1 is masked by CDH1 and CLB2. The masking function of CLB2 was stabilization of Pds1 by its phosphorylation. We finally modified Chen's model according to our findings. We thus propose that dosage imbalance causes fragility in biological systems.

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  • Plasmid Construction Using Recombination Activity in the Fission Yeast Schizosaccharomyces pombe Reviewed

    Ayako Chino, Kenji Watanabe, Hisao Moriya

    PLOS ONE   5 ( 3 )   2010.3

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    Background: Construction of plasmids is crucial in modern genetic manipulation. As of now, the common method for constructing plasmids is to digest specific DNA sequences with restriction enzymes and to ligate the resulting DNA fragments with DNA ligase. Another potent method to construct plasmids, known as gap-repair cloning (GRC), is commonly used in the budding yeast Saccharomyces cerevisiae. GRC makes use of the homologous recombination activity that occurs within the yeast cells. Due to its flexible design and efficiency, GRC has been frequently used for constructing plasmids with complex structures as well as genome-wide plasmid collections. Although there have been reports indicating GRC feasibility in the fission yeast Schizosaccharomyces pombe, this species is not commonly used for GRC as systematic studies of reporting GRC efficiency in S. pombe have not been performed till date.
    Methodology/Principal Findings: We investigated GRC efficiency in S. pombe in this study. We first showed that GRC was feasible in S. pombe by constructing a plasmid that contained the LEU2 auxotrophic marker gene in vivo and showed sufficient efficiency with short homology sequences (>25 bp). No preference was shown for the sequence length from the cut site in the vector plasmid. We next showed that plasmids could be constructed in a proper way using 3 DNA fragments with 70% efficiency without any specific selections being made. The GRC efficiency with 3 DNA fragments was dramatically increased >95% in lig4 Delta mutant cell, where non-homologous end joining is deficient. Following this approach, we successfully constructed plasmid vectors with leu1+, ade6+, his5+, and lys1+ markers with the low-copy stable plasmid pDblet as a backbone by applying GRC in S. pombe.
    Conclusions/Significance: We concluded that GRC was sufficiently feasible in S. pombe for genome-wide gene functional analysis as well as for regular plasmid construction. Plasmids with different markers constructed in this research are available from NBRP-yeast (http://yeast.lab.nig.ac.jp/).

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  • On-chip real-time PCR for genetic tug-of-war (g-TOW) experiment Reviewed

    Toyohiro Naito, Ai Yatsuhashi, Noritada Kaji, Taeko Ando, Kazuo Sato, Hisao Moriya, Hiroaki Kitano, Yukihiro Okamoto, Manabu Tokeshi, Yosinobu Baba

    Proceedings of Conference, MicroTAS 2009 - The 13th International Conference on Miniaturized Systems for Chemistry and Life Sciences   627 - 629   2009

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    A micro-chip based real-time PCR device has been developed for biorobustness research and systems biology. The device is constructed of a silicon-glass chip, a Peltier element and a microscopy. With the device, amplification of target gene on a plasmid and housekeeping gene were detected simultaneously, and the copy number of the plasmid could be estimated. We had optimized the device, and achieved detection of fluorescent intensity increase in reaction channels. © 2009 CBMS.

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  • In vivo robustness analysis of cell division cycle genes in Saccharomyces cerevisiae Reviewed

    Hisao Moriya, Yuki Shimizu-Yoshida, Hiroaki Kitano

    PLOS GENETICS   2 ( 7 )   1034 - 1045   2006.7

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    Intracellular biochemical parameters, such as the expression level of gene products, are considered to be optimized so that a biological system, including the parameters, works effectively. Those parameters should have some permissible range so that the systems have robustness against perturbations, such as noise in gene expression. However, little is known about the permissible range in real cells because there has been no experimental technique to test it. In this study, we developed a genetic screening method, named "genetic tug-of-war'' (gTOW) that evaluates upper limit copy numbers of genes in a model eukaryote Saccharomyces cerevisiae, and we applied it for 30 cell-cycle related genes (CDC genes). The experiment provided unique quantitative data that could be used to argue the system-level properties of the cell cycle such as robustness and fragility. The data were used to evaluate the current computational model, and refinements to the model were suggested.

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  • Integration of transcriptional and posttranslational regulation in a glucose signal transduction pathway in Saccharomyces cerevisiae Reviewed

    JH Kim, Brachet, V, H Moriya, M Johnston

    EUKARYOTIC CELL   5 ( 1 )   167 - 173   2006.1

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    Expression of the HXT genes encoding glucose transporters in the budding yeast Saccharomyces cerevisiae is regulated by two interconnected glucose-signaling pathways: the Snf3/Rgt2-Rgt1 glucose induction pathway and the Snf1-Mig1 glucose repression pathway. The Snf3 and Rgt2 glucose sensors in the membrane generate a signal in the presence of glucose that inhibits the functions of Std1 and Mth1, paralogous proteins that regulate the function of the Rgt1 transcription factor, which binds to the HXT promoters. It is well established that glucose induces degradation of Mth1, but the fate of its paralogue Std1 has been less clear. We present evidence that glucose-induced degradation of Std1 via the SCFGrr1 ubiquitin-protein ligase and the 26S proteasome is obscured by feedback regulation of STD1 expression. Disappearance of Stdl in response to glucose is accelerated when glucose induction of STD1 expression due to feedback regulation by Rgt1 is prevented. The consequence of relieving feedback regulation of STD1 expression is that reestablishment of repression of HXT1 expression upon removal of glucose is delayed. In contrast, degradation of Mth1 is reinforced by glucose repression of MTH1 expression: disappearance of Mth1 is slowed when glucose repression of MTH1 expression is prevented, and this results in a delay in induction of HXT3 expression in response to glucose. Thus, the cellular levels of Std1 and Mth1, and, as a consequence, the kinetics of induction and repression of HXT gene expression, are closely regulated by interwoven transcriptional and posttranslational controls mediated by two different glucose-sensing pathways.

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  • A robustness analysis of eukaryotic cell cycle concerning Cdc25 and weel proteins Reviewed

    Takehito Azuma, Hisao Moriya, Hayato Matsumuro, Hiroaki Kitano

    PROCEEDINGS OF THE 2006 IEEE INTERNATIONAL CONFERENCE ON CONTROL APPLICATIONS, VOLS 1-4   1058 - 1063   2006

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    This paper discusses a robustness analysis of eukaryotic cell cycle and focuses on understanding functions of Cdc25 and Wee1 proteins. The robustness of the eukaryotic cell cycle is analyzed based on the sensitivity analysis for a mathematical model. From the first analysis result, it was shown that Cdc2 and Cyclin proteins have main roles for eukaryotic cell cycle in this model but the robustness is not high against perturbation on its parameters. By introducing Cdc25 and Weel proteins to the mathematical model, it was verified by the sensitivity analysis that the modified has higher level of robustnesses; than the original model does. Numerical examples are shown to demonstrate the original model and the modified model have almost identical cell cycle behaviors leaving robustness as a salient difference.

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  • Inhibition of nuclear factor kappa B by I kappa B superrepressor gene transfer ameliorates ischemia-reperfusion injury after experimental lung transplantation Reviewed

    T Ishiyama, S Dharmarajan, M Hayama, H Moriya, K Grapperhaus, GA Patterson

    JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY   130 ( 1 )   194 - 201   2005.7

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    Objectives: Ischemia-reperfusion injury after lung transplantation is associated with significant morbidity and mortality. The activation of the transcription factor nuclear factor kappa B is central to the 2 important pathways that characterize ischemia-reperfusion injury, namely the inflammatory response and apoptosis. The purpose of this study was to determine the effects of nuclear factor kappa B inhibition on experimental lung transplant ischemia-reperfusion injury with gene transfer of the nuclear factor kappa B inhibitor I kappa B in a superrepressor form (I kappa BSR).
    Methods: An orthotopic left lung transplant model in isogeneic rats was used, with 18 hours of prolonged cold storage of donor lung grafts used to create severe ischemia-reperfusion injury. Donor rats underwent endobronchial gene transfection with saline alone or adenovirus encoding either beta-galactosidase control or I kappa BSR 48 hours before harvest. The function of transplanted lung grafts was assessed on the basis of isolated graft oxygenation, wet/dry lung weight ratio, and myeloperoxidase activity. Nuclear factor kappa B activation was assessed by means of enzyme-linked immunosorbent assay. Apoptotic cell death was assessed by evaluating the levels of histone-associated DNA fragments and caspase-3 activity.
    Results: Treatment of donor lung grafts with I kappa BSR resulted in significantly improved oxygenation compared with that seen in control tissue 24 hours after transplantation. I kappa BSR-treated lungs also demonstrated less pulmonary edema and reduced neutrophil infiltration 24 hours after reperfusion. Nuclear factor kappa B activation and apoptotic cell death induction 2 hours after transplantation was significantly reduced in I kappa BSR-treated lungs compared with in control lungs.
    Conclusions: Inhibition of nuclear factor kappa B activation by I kappa BSR gene transfer improves transplanted lung graft oxygenation, decreases pulmonary edema and neutrophil sequestration, and reduces apoptotic cell death after experimental lung transplantation.

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  • Glucose sensing and signaling in Saccharomyces cerevisiae through the Rgt2 glucose sensor and casein kinase I Reviewed

    H Moriya, M Johnston

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   101 ( 6 )   1572 - 1577   2004.2

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    The yeast Saccharomyces cerevisiae senses glucose through two transmembrane glucose sensors, Snf3 and Rgt2. Extracellular glucose causes these sensors to generate an intracellular signal that induces expression of HXTgenes encoding glucose transporters by inhibiting the function of Rgt1, a transcriptional repressor of HXT genes. We present the following evidence that suggests that the glucose sensors are coupled to the membrane-associated protein kinase casein kinase I (Yck1). (i) Overexpression of Yck1 leads to constitutive HXT1 expression; (ii) Yck1 (or its paralogue Yck2) is required for glucose induction of HXT1 expression; (iii) Yck1 interacts with the Rgt2 glucose sensor; and (iv) attaching the C-terminal cytoplasmic tail of Rgt2 to Yck1 results in a constitutive glucose signal. The likely targets of Yck1 in this signal transduction pathway are Mth1 and Std1, which bind to and regulate function of the Rgt1 transcription factor and bind to the C-terminal cytoplasmic domain of glucose sensors. Potential casein kinase I phosphorylation sites in Mth1 and Std1 are required for normal glucose regulation of HXT1 expression, and Yck1 catalyzes phosphorylation of Mth1 and Std1 in vitro. These results support a model of glucose signaling in which glucose binding to the glucose sensors causes them to activate Yckl in the cell membrane, which then phosphorylates Mthl and Stdl bound to the cytoplasmic face of the glucose sensors, triggering their degradation and leading to the derepression of HXT gene expression. Our results add nutrient sensing to the growing list of processes in which casein kinase I is involved.

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  • Yak1p, a DYRK family kinase, translocates to the nucleus and phosphorylates yeast Pop2p in response to a glucose signal Reviewed

    H Moriya, Y Shimizu-Yoshida, A Omori, S Iwashita, M Katoh, A Sakai

    GENES & DEVELOPMENT   15 ( 10 )   1217 - 1228   2001.5

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    POP2 protein of Saccharomyces cerevisiae is a component of a protein complex that regulates the transcription of many genes. We found that the 97th threonine residue (Thr 97) of Pop2p was phosphorylated upon glucose limitation. The Thr 97 phosphorylation occurred within 2 min after removing glucose and was reversed within 1 min after the readdition of glucose. The effects of hexokinase mutations and glucose analogs indicate that this phosphorylation is dependent on glucose phosphorylating activity. We purified a protein kinase that phosphorylates a peptide containing Thr 97 of Pop2p and identified it as Yak1p, a DYRK family kinase. Phosphorylation of Pop2p was barfly detectable in a yak1 Delta strain. We found that Yak1p interacted with Bmh1p and Bmh2p only in the presence of glucose. A GFP-Yak1p fusion protein shuttled rapidly between the nucleus and the cytoplasm in response to glucose. A strain with alanine substituted for Thr 97 in Pop2p showed overgrowth in the postdiauxic transition and failed to stop the cell cycle at G(1) phase in response to glucose deprivation. Thus, Yak1p and Pop2p are part of a novel glucose-sensing system in yeast that is involved in growth control in response to glucose availability.

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  • Analysis of genetic interactions between DHH1, SSD1 and ELM1 indicates their involvement in cellular morphology determination in Saccharomyces cerevisiae Reviewed

    H Moriya, K Isono

    YEAST   15 ( 6 )   481 - 496   1999.4

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    The DHH1 gene of Saccharomyces cerevisiae belongs to a family of genes that encode highly conserved DEAD-box proteins commonly present in various eukaryotic organisms. Its precise function in yeast has not yet been well documented. To investigate its role in vivo, we constructed a DHH1 disruptant, characterized it genetically and searched for genes the mutations in which would cause synthetic lethality in combination with the DHH1 disruption. CDC28, ELM1 and SSD1 were thus found to be such candidates and we subsequently analysed their interactions. Mutations in ELM1 were previously reported to result in the elongation of cells. We confirmed this phenotype and observed in addition elongated bud formation in an Elm1p overproducing strain. Also, Elm1p fused with the green fluorescent protein (GFP) was found to be localized at the bud neck. These and other observations seem to suggest that Elm1p plays a role during cytokinesis in S. cerevisiae. The phenotypes of strains harbouring either Delta dhh1 Delta elm1 or ssd1-d Delta elm1 were very similar to each other, showing abnormal cellular morphology and defects in cytokinesis and mitosis. Furthermore, DHH1 and SSD1 could functionally complement each other in the ade2 red colour pigment formation, hypersensitivity to SDS, growth on synthetic media and at high temperature. A triple mutant, Delta dhh1 ssd1-d Delta elm1, apparently had very fragile cell walls and could grow only in a medium supplemented with 1 M sorbitol. Copyright (C) 1999 John Wiley & Sons, Ltd.

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  • CLONING AND CHARACTERIZATION OF THE HRPA GENE IN THE TERC REGION OF ESCHERICHIA-COLI THAT IS HIGHLY SIMILAR TO THE DEAH FAMILY RNA HELICASE GENES OF SACCHAROMYCES-CEREVISIAE Reviewed

    H MORIYA, H KASAI, K ISONO

    NUCLEIC ACIDS RESEARCH   23 ( 4 )   595 - 598   1995.2

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    During the course of systematic nucleotide sequence analysis of the terC region of E.coli K-12 by using the ordered lambda phage clones, we found the presence of a gene, termed hrpA, that showed a high degree of sequence similarity to the PRP2, PRP16 and PRP22 genes of Saccharomyces cerevisiae, The products of these yeast genes are known to play their roles in mRNA splicing, and belong to a group of proteins collectively called the DEAH family, The hrpA gene is the first example of a DEAR family gene in prokaryotes, The N-terminal region of the protein it encodes contains conserved sequence stretches characteristic of an RNA helicase, Its molecular mass is calculated to be 146 kDa, Previously, a 135 kDa protein was identified by Moir at al, [J. Bacteriol, (1992) 174, 2102-2110] in this region which is most likely identical to that encoded by hrpA. The C-terminal region of the hrpA gene product seems to contain an RNA binding motif weakly resembling that of ribosomal protein S1 of E.coli, Disruption of the hrpA gene suggested that it is not essential for the growth of E.coli.

    DOI: 10.1093/nar/23.4.595

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MISC

  • たくさんつくれるタンパク質に隠された秘密 Invited

    現代化学   608   34 - 39   2021.11

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  • Constraints of expression levels of intracellular proteins

    守屋 央朗

    生体の科学   69 ( 1 )   83 - 87   2018.1

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    Language:Japanese   Publisher:金原一郎記念医学医療振興財団 ; 1949-  

    DOI: 10.11477/mf.2425200762

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  • My experience of Great Hanshin-Awaji Earthquake

    守屋 央朗

    生物科学   69 ( 1 )   4 - 11   2017.8

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  • Resource Allocation and Capacity of Protein Expression in a Yeast Cell

    MORIYA Hisao

    KAGAKU TO SEIBUTSU   54 ( 8 )   555 - 561   2016

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    Language:Japanese   Publisher:Japan Society for Bioscience, Biotechnology, and Agrochemistry  

    細胞の機能は数千種類のタンパク質が協調的に働くことで達成される.それぞれのタンパク質の発現量はどのように決まっているのだろうか,またその量が変化したときに何が起きるのだろうか? 本稿では,主に酵母を対象として,近年のオーミックスデータや筆者らのタンパク質発現限界のシステマティックな測定結果などを通じて,細胞がタンパク質発現リソースをどのように配分しているのか,細胞がどれくらいのタンパク質発現のキャパシティをもっているのかという視点で細胞を眺めてみたい.なお,本稿のデータや図の一部は,最近筆者が執筆した文献1から引用している.詳細な内容についてはそれも合わせて参照していただきたい.

    DOI: 10.1271/kagakutoseibutsu.54.555

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  • Analysis of the mechanism of cell death triggered by gene overexpression, and its application toward the material production

    1 - 5   2015

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  • What are determinants for the expression limits of proteins?

    Moriya Hisao, Makanae Koji, Kintaka Reiko, Ishikawa Kouji

    Abstracts for Annual Meeting of Japanese Proteomics Society   2014 ( 0 )   32 - 32   2014

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    Language:Japanese   Publisher:Japanese Proteomics Society (Japan Human Proteome Organisation)  

    DOI: 10.14889/jhupo.2014.0.32.0

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  • Measuring Robustness of The Cellular System against Changes in Protein Expression

    守屋 央朗

    細胞工学   33 ( 1 )   19 - 25   2014

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    Language:Japanese   Publisher:学研メディカル秀潤社 ; 1982-  

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  • OVERVIEW (特集 生命システムのロバストネスとは何か?)

    守屋 央朗

    細胞工学   33 ( 1 )   10 - 12   2014

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    Language:Japanese   Publisher:学研メディカル秀潤社 ; 1982-  

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  • Measuring the Copy Number Limits of All Genes in Yeast

    MORIYA Hisao

    Seibutsu Butsuri   53 ( 6 )   323 - 325   2013.11

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    Language:Japanese   Publisher:The Biophysical Society of Japan General Incorporated Association  

    DOI: 10.2142/biophys.53.323

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  • 微量天然物spirotryprostatin類生物全合成によるスピロ環形成機構の解明

    恒松雄太, 石川格靖, 若菜大悟, 合田幸広, 野口博司, 守屋央朗, 堀田欣也, 渡辺賢二

    日本生薬学会年会講演要旨集   60th   101   2013.8

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  • 研コミュ白書 第1回 酵母コロキアム 21世紀酵母生物学のオンラインフォーラム

    谷内江望, 吉田知史, 大西雅之, 丑丸敬史, 守屋央朗

    細胞工学   31 ( 5 )   604 - 607   2012.4

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  • Engineered Biosynthesis of Natural Products in Saccharomyces cerevisiae

    TSUNEMATSU Yuta, MORIYA Hisao, WATANABE Kenji

    KAGAKU TO SEIBUTSU   50 ( 3 )   163 - 174   2012.3

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    Language:Japanese   Publisher:日本農芸化学会  

    近年,天然物の生合成遺伝子の情報をもとに,有用天然物を獲得する取り組みが行なわれるようになってきた.中でも植物および真菌といった真核生物から単離された生物活性物質の生物合成に関する報告がなされてきた.ここでは,特に真核生物由来の天然物生合成遺伝子を出芽酵母の異種発現系を用いて発現させ,有用物質の生産に挑戦する取り組みについて解説する.

    DOI: 10.1271/kagakutoseibutsu.50.163

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  • 生命システムのロバストネスを探る : 出芽酵母の研究を中心として

    守屋 央朗

    化学と生物   47 ( 4 )   269 - 274   2009.4

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    Language:Japanese   Publisher:社団法人 日本農芸化学会  

    DOI: 10.1271/kagakutoseibutsu.47.269

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  • 細胞がつくるシステムのロバストネスを測る--細胞の頑健性とアキレス腱

    守屋 央朗

    現代化学   ( 456 )   26 - 32   2009.3

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    Language:Japanese   Publisher:東京化学同人  

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  • In vivo robustness analysis of cell division cycle in Saccharomyces cerevisiae (vol 2, pg 7, 2006)

    Hisao Moriya, Yuki Shimizu-Yoshida, Hiroaki Kitano

    PLOS GENETICS   2 ( 12 )   2176 - 2176   2006.12

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    Language:English   Publisher:PUBLIC LIBRARY SCIENCE  

    DOI: 10.1371/journal.pgen.0020218

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  • Understanding of Basic Systems for Eukaryotic Cell Cycle(<Special Issue>Life as Systems)

    AZUMA Takehito, MORIYA Hisao, KITANO Hiroaki

    Systems, control and information   50 ( 8 )   309 - 314   2006.8

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    Language:Japanese   Publisher:システム制御情報学会  

    DOI: 10.11509/isciesci.50.8_309

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  • Glucose sensing system of the budding yeast Saccharomyces cerevisiae

    MORIYA Hisao

    Bioscience & industry   63 ( 6 )   390 - 393   2005.6

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    Language:Japanese   Publisher:バイオインダストリー協会  

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Industrial property rights

  • カビ類ポリケチド合成遺伝子の酵母での異種発現

    渡辺 賢二, 守屋 央朗

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    Applicant:静岡県公立大学法人, 国立大学法人 岡山大学

    Application no:JP2011004566  Date applied:2011.8.11

    Announcement no:WO2012-020574  Date announced:2012.2.16

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  • サッカロミセス属微生物用プラスミドベクター

    守屋 央朗, 北野 宏明, 吉田 由紀

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    Applicant:独立行政法人科学技術振興機構, 特定非営利活動法人システム・バイオロジー研究機構

    Application no:特願2007-290659  Date applied:2007.11.8

    Announcement no:特開2009-112271  Date announced:2009.5.28

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  • シゾサッカロミセス属微生物用プラスミドベクター

    守屋 央朗, 北野 宏明

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    Applicant:独立行政法人科学技術振興機構, 特定非営利活動法人システム・バイオロジー研究機構

    Application no:特願2007-290660  Date applied:2007.11.8

    Announcement no:特開2009-112272  Date announced:2009.5.28

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Awards

  • 長瀬研究振興賞

    2023.4   長瀬科学技術振興財団  

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  • 酵母コンソーシアムフェロー

    2020.10   大隅基礎科学創成財団  

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Research Projects

  • 連続するアミノ酸(PolyX)が生み出す細胞毒性のメカニズム

    Grant number:22K19294  2022.06 - 2024.03

    日本学術振興会  科学研究費助成事業 挑戦的研究(萌芽)  挑戦的研究(萌芽)

    守屋 央朗, 牧野 能士, 紀藤 圭治

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    Grant amount:\6500000 ( Direct expense: \5000000 、 Indirect expense:\1500000 )

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  • Cellar differentiation on the electronic semiconductor device induced by the electric stimulation

    Grant number:22K18976  2022.06 - 2024.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)  Grant-in-Aid for Challenging Research (Exploratory)

    狩野 旬, 山本 泰生, 竹田 哲也, 守屋 央朗

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    Grant amount:\6500000 ( Direct expense: \5000000 、 Indirect expense:\1500000 )

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  • ヒザラガイの磁鉄鉱歯特異的な歯舌マトリックスタンパク質の機能解明

    Grant number:21K05781  2021.04 - 2025.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    根本 理子, 守屋 央朗

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    Grant amount:\4290000 ( Direct expense: \3300000 、 Indirect expense:\990000 )

    本研究では、ヒザラガイの歯冠部特異的タンパク質である歯舌マトリックスタンパク質1(RTMP1)について、遺伝子ノックダウンおよび組換えタンパク質を用いた機能解析を行ない、歯冠部への酸化鉄沈着におけるRTMP1の役割を明らかにすることを目的とする。
    2021年度は、まず、オオバンヒザラガイの遺伝子ノックダウンシステムの確立を目指して実験を行った。実験には、北海道大学の厚岸臨海実験所のご協力の下、採取したオオバンヒザラガイ個体を用いた。使用する個体重量、飼育条件、dsRNA注入量およびノックダウン後、表現型解析を行なうまでの時間を検討し、各条件について最適化した。その結果、RTMP1遺伝子をターゲットとするdsRNAを注入した個体において、陰性対照と比較して有意にRTMP1遺伝子発現量が低下することが確認された。顕微鏡観察から、遺伝子発現量が低下した個体において、歯の沈着鉄量の減少を示唆する結果が得られた。
    また、in vitro機能解析に向けて、酵母でRTMP1を組換え発現させ、その精製を行った。RTMP1遺伝子全長及びシグナル配列をコードする領域を除いたRTMP1遺伝子(RTMP1-delta-ss)をGST融合発現用ベクターpEG(KT)に組み込み酵母に発現させた。研究分担者の守屋とともに、プロモーター、可溶化タグ、コドンの最適化による発現量の増加を試みた結果、RTMP1-delta-ssの発現を確認することができた。また、発現が確認されたRTMP1-delta-ssについて、グルタチオンビーズを用いた粗精製に成功した。

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  • Mechanism of growth inhibition by overexpression explored from the expression level of the limiting mutant protein

    Grant number:20H03242  2020.04 - 2024.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    守屋 央朗

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    Grant amount:\17550000 ( Direct expense: \13500000 、 Indirect expense:\4050000 )

    本研究では、酵母細胞をモデルとして過剰発現により細胞機能に悪影響を及ぼすタンパク質が、どのようなメカニズムで細胞機能に悪影響を及ぼすのかを、変異をもとに探ることを目的としている。
    本年度はモデルタンパク質や解糖系のタンパク質による増殖阻害のメカニズムについて変異導入により探った。その1つの結果として、システインを含有するタンパク質の過剰発現が酵母細胞の細胞伸長を引き起こすことを見いだし、システインの改変によりこの細胞伸長が起きなくなることを見いだした。システインを含有するタンパク質の過剰発現は細胞伸長だけでなく細胞の増殖も阻害する、すなわち細胞機能に悪影響を与える事も分かった。この原因を酵母の様々な変異体での過剰発現実験により探ったところ、システインを含有するタンパク質の過剰発現はプロテアソームの機能を傷害することで増殖阻害を引き起こしていることが示唆された。別の実験として、モデルタンパク質に特定のアミノ酸を複数付加するという変異を導入し、過剰発現した際の増殖への悪影響についても調査した。その結果、特定のアミノ酸を付加したモデルタンパク質は酵母の増殖を著しく阻害することを見いだし、現在そのメカニズムの解明を行っている。

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  • 発現量揺らぎ-適応系により探索する発現変動の適応-進化への影響

    Grant number:20H04870  2020.04 - 2022.03

    日本学術振興会  科学研究費助成事業  新学術領域研究(研究領域提案型)

    守屋 央朗

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    Grant amount:\10270000 ( Direct expense: \7900000 、 Indirect expense:\2370000 )

    背景と目的: 細胞内のタンパク質には、発現量の変動が適応度に強い影響を与える(強い制約を受けている)ものと、発現量を多少変動させても適応度に影響を与えない(制約を受けていない)ものがある。私たちは、出芽酵母(S. cerevisiae)のほとんどの種類のタンパク質について、それぞれの発現量がどれくらい制約を受けているのかを、独自の発現量揺らぎ-適応系(gTOW法)により調べてきた。その結果、大半のタンパク質の発現量は制約を受けていない一方、2%程度のタンパク質の発現量のみが強い制約を受けている事を明らかにした。本研究では、発現量揺らぎ-適応をハイスループット化させた実験系(ADOPT法)により、課題1:発現量の制約は環境により変わるのか、課題2:発現量揺らぎは適応-進化に寄与するのか、課題3:発現変動による適応はどのようなメカニズムにより達成されるのかを追求する。
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    研究実績: 本年度はADOPT法により高塩ストレスで適応的な遺伝子群について調査した。その結果、高塩ストレスに関してカルシウム応答性遺伝子群の過剰が適応的になること、それ以外に新興遺伝子の過剰が適応的になることが見いだされた。これらの結果から、(過剰による)適応は、環境要因の補完、および新規メカニズムの外挿により達成できることが示唆された。

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  • Cell processing capacity explored by expression limits of proteins

    Grant number:18K19300  2018.06 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

    Moriya Hisao

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    Grant amount:\6240000 ( Direct expense: \4800000 、 Indirect expense:\1440000 )

    In the process of expressing their functions, proteins undergo various processes such as synthesis, folding, transport, and degradation. These processes are thought to have different processing capacities, depending on the amount of resources devoted to them. However, the processing capacity of intracellular processes has never been investigated before. In this study, we identified the proteins that are processed by specific processes in budding yeast with the highest critical expression levels by using the genetic tug-of-war method, which measures the critical expression level of proteins, and protein quantification. By using these proteins as indicator proteins, the ability to process intracellular processes, especially protein synthesis and transport processes, was clarified.

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  • 発現量揺らぎー適応系により探るプロテオームの制約条件とその適応ー進化への影響

    Grant number:18H04824  2018.04 - 2020.03

    日本学術振興会  科学研究費助成事業  新学術領域研究(研究領域提案型)

    守屋 央朗

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    Grant amount:\11180000 ( Direct expense: \8600000 、 Indirect expense:\2580000 )

    背景と目的 細胞内のタンパク質には、その発現量の変動が適応度に強い影響を与える―強い制約を受けているものと、発現量を多少変動させても適応度に影響を与えない―制約を受けていないものがある。申請者らは、出芽酵母(Saccharomyces cerevisiae)のほぼすべての種類のタンパク質を対象として、それぞれの発現量がどれくらい制約を受けているのかを、独自に開発した発現量揺らぎ-適応系(gTOW法)により調べてきた。その結果、大半のタンパク質の発現量は制約を受けていない一方、2%程度のタンパク質の発現量のみが強い制約を受けている事を明らかにした。本研究では、先行研究で構築されたこの発現量揺らぎ-適応系をハイスループット化することで、課題1:発現量の制約は環境により変わるのか、課題2:発現量揺らぎは適応-進化に寄与するのかを追求する。
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    研究方法 研究目的の2つの課題を追求するために、従来の発現量揺らぎ-適応系をハイスループット化し、様々な環境における発現量の制約と発現上昇による適応を並列に評価する実験系の構築を行う。実験系は、以下の3つのステップから成る。1)S. cerevisiaeの5,800種類の各遺伝子を2ミクロンプラスミドに連結し、それぞれを酵母に導入する(すべての遺伝子を発現量揺らぎ-適応系に乗せる)、2)この5,800種類の株を混合し様々な環境下で培養する(コピー数適応を一斉に行わせる)、3)混合培養後の細胞集団からプラスミドを回収し、各プラスミドのコピー数を次世代シーケンサーによるインサートの出現頻度により解析する(コピー数の制約と適応的コピー数を測る)。
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    研究実績 2年間の研究機関で上記の新規実験系の構築を完了した。この実験系を用いて、高温条件、高塩条件など複数の条件での適応実験を行い、これらの条件で高発現が適応的な遺伝子を複数同定した。

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  • Systematic analysis of proteins that cause overload of transport resources due to overexpression

    Grant number:17H03618  2017.04 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Moriya Hisao

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    Grant amount:\17160000 ( Direct expense: \13200000 、 Indirect expense:\3960000 )

    Overexpression of certain proteins inhibits cell proliferation. However, the mechanism of this is largely unknown. Our previous studies have shown that the depletion of essential factors due to an overload of proteins transported in the cell--transportation overload--may explain most of the growth inhibition caused by overexpression. In this study, we aimed to elucidate the mechanism of growth inhibition by transport overload through the identification of proteins that cause transport overload and restriction factors that are targets of overload. As a result, we identified several candidate limiting factors for nuclear transport in particular.

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  • Identification and characterization of phytochemical-targeted genes using a genome wide yeast screening system

    Grant number:17H03818  2017.04 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Nakamura Yoshimasa

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    Grant amount:\17680000 ( Direct expense: \13600000 、 Indirect expense:\4080000 )

    We identified 12 resistance genes against benzyl isothiocyanate (BITC) from total 6000 yeast genes using a new evaluation model system, the budding yeast gene tug-of-war method (gTOW method). A human cancer cell line stably overexpressing the human homologue (Mis12) of BITC resistance gene MTW1 was established, which showed high resistance to BITC. Mis12 knockdown conversely increased sensitivity. It was also suggested that the expression of Mis12 is down-regulated by BITC via post-translational modification, which contributes to suppressive effect of BITC on colon cancer cell proliferation by enhancing the sensitivity to apoptosis in a cell cycle-dependent manner.

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  • Analysis of mechanisms avoiding stoichometry imbalance(Fostering Joint International Research)

    Grant number:15KK0258  2016.04 - 2018.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Fund for the Promotion of Joint International Research (Fostering Joint International Research)

    Moriya Hisao, Boone Charles, Knop Michael

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    Authorship:Principal investigator  Grant type:Competitive

    It is known that expression levels of intracellular proteins are highly regulated. Disturbance of those levels, by overexpression, sometimes cause defects in cellular functions. However, little is known about the mechanisms. In this study, we tried to reveal mechanisms of overexpression- triggered cellular defects with large-scale genetic profilings performed in international collaborations. As a result, we obtained groups of genes exacerbate and mitigates the growth defects. We also established an experimental method to isolate genes whose overexpression positively function for cellular growth in specific conditions.

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  • Analysis of mechanisms to avoid stoichiometry imbalance

    Grant number:26290069  2014.04 - 2017.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Moriya Hisao

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    Grant amount:\17420000 ( Direct expense: \13400000 、 Indirect expense:\4020000 )

    About one third of proteins function as protein complexes. Imbalances in the stoichiometry of subunits constituting protein complexes sometimes cause harmful effects on cellular functions. In this study, using budding yeast, we revealed a mechanism to avoid stoichiometry imbalances in protein complexes. We identified several proteins whose expressions were not increased as expected when their gene copy numbers were artificially increased. The buffering of protein expression was performed through active degradation of excess proteins by the ubiquitin-proteasome system.

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  • Experimental verification of gene loss patterns in yeast genome after whole genome duplication

    Grant number:26650130  2014.04 - 2016.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    Makino Takashi, Moriya Hisao, Kawata Masakado

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    Grant amount:\3900000 ( Direct expense: \3000000 、 Indirect expense:\900000 )

    The purpose of this study is to establish an artificial evolutionary experiment approach for tetraploid yeast, and examine the pattern of gene function losses. We cultured tetraploid yeast for 200 days under exposure to intense ultraviolet irradiation. As a result, we observed many mutations in the genome of tetraploid yeast. In particular, deleterious mutations were enriched in genes on the same chromosome of functional gene clusters.

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  • Improving logic-based hypothesis-finding methods with inverse subsumption and its applications to systems biology

    Grant number:25730133  2013.04 - 2016.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)

    YAMAMOTO Yoshitaka, MORIYA HISAO

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    Grant amount:\4290000 ( Direct expense: \3300000 、 Indirect expense:\990000 )

    This research aims at improving logic-based hypothesis-finding methods and furthermore prompting to apply them to real problems in systems biology. First, we focus on so-called Inverse Subsumption (IS), which is a novel approach for finding hypotheses from observations with the background theory. Recently, it has been growing interests in IS to find such hypotheses that cannot be inherently obtained by the previously proposed approach. IS however has yet to achieve sufficient scalability in real problems. We consider to improve the two procedures of IS (dualization and subsumption-lattice search) in this research. Next, we focus on so-called SGBN, which is the standard markup language to describe molecular networks in systems biology. We establish an efficient way to translate SBGN into first-order logic (FOL). Together with SBGN-FOL translation, we apply hypothesis-finding methods to derive new knowledge in real SBGN-based molecular networks of cells.

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  • Analysis of the mechanisms of process burdens in yeast

    Grant number:25640115  2013.04 - 2015.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    HISAO Moriya, KITO Keiji

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3900000 ( Direct expense: \3000000 、 Indirect expense:\900000 )

    Strong expression of a protein in a cell sometimes causes cellular defects. However, it is not systematically understood the mechanisms causing the defects. In this study, we discovered that the strong expression of proteins localized to intracellular compartments caused cellular defects due to the burdens for protein localization processes themselves.

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  • 酵母の生合成キャパシティーの拡大

    Grant number:25108717  2013.04 - 2015.03

    日本学術振興会  科学研究費助成事業  新学術領域研究(研究領域提案型)

    守屋 央朗

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\7020000 ( Direct expense: \5400000 、 Indirect expense:\1620000 )

    本研究では、酵母細胞の「生合成キャパシティー」の拡大を目的としている。申請者らは遺伝子つなひき(gTOW)法という実験手法を開発し、さまざまな遺伝子(タンパク質)が、酵母の細胞内でどれくらいの量発現できるのか、という限界発現量を測ることに成功している。さらに、最近来れを発展させ、様々に局在化した異種タンパク質(GFP)の限界発現量を測ることにも成功している。本研究の目的は、これらの局在化GFPの限界発現量は、細胞内のそれぞれのプロセスにおける異種タンパク質合成マシナリーの「キャパシティー」を反映していると考え、その拡大を目指すことである。具体的には、その変異や過剰発現により、局在化GFPをより多く発現できるようになる遺伝子を取得する。さらにこれらの遺伝子を組み合わせて生合成キャパシティーの拡大した酵母株の構築をおこなう。H25年度は様々な局在化シグナルを付加したGFPならびにTEVプロテアーゼタンパク質をモデルタンパク質として、その酵母内での過剰発現の限界の測定を行った。また、光らないGFPのや活性のないTEVプロテアーゼでも同じ実験を行うことで、タンパク質の持つ活性と局在化、細胞内の過剰発現との関連についても測定を行った。さらに、タンパク質を過剰に発現している細胞の生理状態を顕微鏡観察とRNAseqにより解析した。H26年度は、過剰発現により生合成キャパシティーを拡大させる遺伝子の取得を試みた。複数の遺伝子の過剰発現により、局在化GFPの発現を上昇させることができた。現在上記のデータをまとめた論文を投稿中である。

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  • Analysis of the network constructed by dosage balanced genes in yeast

    Grant number:23310140  2011.04 - 2014.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    MORIYA Hisao, MAKINO Takashi

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\20150000 ( Direct expense: \15500000 、 Indirect expense:\4650000 )

    Dosage balanced gene (DBG) is a gene whose expression is balanced against more than two genes, and the perturbation of the balance causes cellular dysfunction. Using a genetic method designated "genetic tug-of-war", we have been trying to identify "dosage sensitive genes" whose minor overexpression cause cellular dysfunction. In this study, we proceeded this analysis, and identified 115 dosage sensitive genes in the budding yeast genome. We further identified 13 dosage-balanced interactions. This study is the first example for the systematic identification of dosage sensitive genes in a organism's genome, and for the identification of multiple dosage balanced genes at a time.

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  • 情報場への摂動を緩衝するメカニズムの解明

    Grant number:23114715  2011.04 - 2013.03

    日本学術振興会  科学研究費助成事業  新学術領域研究(研究領域提案型)

    守屋 央朗

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\10140000 ( Direct expense: \7800000 、 Indirect expense:\2340000 )

    本研究の主目的は、研究代表者が独自に開発した「遺伝子つなひき法」を用いて、遺伝子のコピー数の上昇という情報場への摂動が細胞システムによってどのように緩衝されるのかを、酵母の細胞周期制御遺伝子ならびに酵母のすべての遺伝子を対象に調査することである。またこの結果を組み込んで酵母の細胞周期の数理モデルの評価や改良を行うことも目的に含まれている。分裂酵母の細胞周期制御遺伝子のコピー数が変動した時にそれがタンパク質のレベルに反映されるのかを調査した。測定できた20の遺伝子・タンパク質のうち、1つ(Cig1)が正のフィードバックにより制御されている可能性が得られた。また2つ(Cdc16、Sid2)はタンパク質の発現上昇により自分自身の分解が加速され、遺伝子コピー数の上昇がタンパク質のレベルの上昇に結びつかないという緩衝機構があることが示唆された。また、遺伝子発現の上昇に対する緩衝機構のみならず、遺伝子発現の減少に対する緩衝機構の発見を可能にするため、遺伝子/タンパク質発現量の下限を測定する実験系を出芽酵母で開発した。具体的には、TEVプロテアーゼによる標的タンパク質の切断により分解を加速するTIPI(TEV protease-mediated induction of protein instability)と遺伝子つなひき法を組み合わせることで、いくつかの遺伝子の発現量の加減を評価する実験系を完成させることができた。

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  • Hypothesis Enumeration for Knowledge Discovery in Systems Biology

    Grant number:22700141  2010 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)

    YAMAMOTO Yoshitaka, MORIYA Hisao

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    Grant amount:\3770000 ( Direct expense: \2900000 、 Indirect expense:\870000 )

    This research project aims at studying the methodology for finding inductive hypotheses in inductive logic programming (ILP), and applying it to systems biology. We first address two problems: incompleteness and uniqueness in terms of hy

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  • 遺伝情報場へのフィードバックの同定

    Grant number:21114515  2009 - 2010

    日本学術振興会  科学研究費助成事業  新学術領域研究(研究領域提案型)

    守屋 央朗

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\10400000 ( Direct expense: \8000000 、 Indirect expense:\2400000 )

    温度やpHなど細胞外環境の変化や、変異、転写・翻訳過程のゆらぎは、核のDNAにコードされた遺伝情報が正確に機能(蛋白質)に結びつく事を妨害する。これを防ぐにため、細胞システムには、機能から情報へのフィードバックが多数存在していると考えられる。私たちが独自に開発した、「遺伝子綱引き(gTOW)法」は、遺伝子のコピー数を上げて、細胞システムの特定の要素を過剰にドライブさせることができる。このとき、遺伝子のコピー数と蛋白質の発現量の間に相関がないとすれば、核の情報の揺らぎが蛋白質の発現量に影響を与えないようにするフィードバックが、遺伝子発現のシステムに存在している事を示している。そこで、本研究では、酵母の細胞周期関連遺伝子について、gTOWによって遺伝子のコピー数を上げた時に、蛋白質の量にどのように反映されるかを調べ、フィードバックをシステマティックに同定し、その分子機構を明らかにする。最終的には、細胞周期の遺伝子発現制御に組み込まれたフィードバック機構の全容を解明し、その情報を数理モデルへと統合する。
    上記の目的のためには、遺伝子のコピー数が上がった時にそれが蛋白質量にどの程度反映するかを効率よく調べる実験系が必要となる。そのため、昨年度までに、分裂酵母内で効率よく遺伝子の改変を行なうことができる実験系の開発を行ない、分裂酵母内でGap-Rpair法によって効率の良い遺伝子改変法を開発することができ、学会発表、ならびに論文発表を行なった。さらにこのGap-Repair法を用いて約30の分裂酵母の細胞周期関連遺伝子をgTOW用プラスミドにクローニングし、コピー数の上限をはかるとともに、このデータを用いた数理モデルの評価と改良を行った。この内容は現在論文投稿中である。また、これらほとんどの遺伝子について蛋白質検出用のタグを組み込んだプラスミドの構築に成功した。このプラスミドを用いて定量的なウエスタンブロッティングを行ない、コピー数が上昇した時にそれが蛋白質にどのように反映されるかを標的としている約30の遺伝子すべてで測定することができた。

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  • 真核細胞のin vivoロバストネス解析

    2006.10 - 2010.03

    科学技術振興機構  さきがけ 

    守屋 央朗

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    Authorship:Principal investigator  Grant type:Competitive

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Academic Activities

  • 第38回 YEAST WORKSHOP

    Role(s):Planning, management, etc.

    YEAST WORKSHOP  2021.11.26

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    Type:Academic society, research group, etc. 

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