研究者紹介システム
| 中嶋 昭雄 |  |
| ナカシマ アキオ | |
| バイオシグナル総合研究センター | |
| 准教授 | |
| 生物関係 |
研究者情報
所属
【主配置】
バイオシグナル総合研究センター【配置】
農学部 資源生命科学科, 大学院農学研究科 資源生命科学専攻
学位
研究シーズ
研究シーズ紹介サイトへのリンク授業科目
- 生物学Ｃ, 国際教養教育院, 2021
- シグナル分子機構論, 大学院農学研究科, 2021
- 特定課題演習 I-1, 大学院農学研究科, 2021
- 課題開発演習, 大学院農学研究科, 2021
- 資源生命科学プレゼンテーション演習Ⅰ（オーラル・ペーパー）, 大学院農学研究科, 2021
- 特定課題演習 II-1, 大学院農学研究科, 2021
- 特定課題演習 I-2, 大学院農学研究科, 2021
- 資源生命科学プレゼンテーション演習Ⅱ（オーラル・ペーパー）, 大学院農学研究科, 2021
- 特定課題演習 II-2, 大学院農学研究科, 2021
- 動物生殖生理論, 大学院農学研究科, 2021
- Global Topics in Animal Science, 農学部, 2021
- 高度教養セミナー農学部応用動物学, 農学部, 2021
- 卒業研究, 農学部, 2021
- 応用動物学実験, 農学部, 2021
- 外国書講読 II, 農学部, 2021
- 外国書講読Ａ, 農学部, 2021
- 資源生命科学入門Ⅰ－１, 農学部, 2021
- 資源生命科学入門Ⅰ－２, 農学部, 2021
- 高度教養セミナー農学部応用動物学入門, 農学部, 2021
- 高度教養セミナー農学部応用動物学入門, 農学部, 2021
- 応用動物学各論, 農学部, 2021
- 細胞内シグナル伝達機構１, 農学部, 2021
- 細胞内シグナル伝達機構２, 農学部, 2021
ジャンル
コメントテーマ
研究活動
研究キーワード
研究分野
論文
Diacylglycerol kinase β (DGKβ) is an enzyme that converts diacylglycerol to phosphatidic acid and is mainly expressed in the cerebral cortex, hippocampus and striatum. We previously reported that DGKβ induces neurite outgrowth and spinogenesis, contributing to higher brain functions, including emotion and memory. To elucidate the mechanisms involved in neuronal development by DGKβ, we investigated the importance of DGKβ activity in the induction of neurite outgrowth using human neuroblastoma SH-SY5Y cells. Interestingly, both wild-type DGKβ and the kinase-negative (KN) mutant partially induced neurite outgrowth, and these functions shared a common pathway via the activation of mammalian target of rapamycin complex 1 (mTORC1). In addition, we found that DGKβ interacted with the small GTPase RalA and that siRNA against RalA and phospholipase D (PLD) inhibitor treatments abolished DGKβKN-induced neurite outgrowth. These results indicate that binding of RalA and activation of PLD and mTORC1 are involved in DGKβKN-induced neurite outgrowth. Taken together with our previous reports, mTORC1 is a key molecule in both kinase-dependent and kinase-independent pathways of DGKβ-mediated neurite outgrowth, which is important for higher brain functions.
2021年12月02日, Biomolecules, 11 (12), 英語, 国際誌[査読有り]
研究論文（学術雑誌）
Meiosis is a specialized cell division process that mediates genetic information transfer to the next generation. Meiotic chromosomal segregation occurs when DNA replication is completed during the pre-meiotic S phase. Here, we show that Schizosaccharomyces pombe Pef1, an orthologue of mammalian cyclin-dependent kinase 5 (CDK5), is required to promote pre-meiotic DNA replication. We examined the efficiency of meiotic initiation using pat1-114 mutants and found that, meiotic nuclear divisions did not occur in the pef1Δ pat1-114 strain. Deletion of pef1 also suppressed the expression of DNA replication factors and the phosphorylation of Cdc2 Tyr-15. The double deletion of clg1 and psl1 arrested meiotic initiation in pat1-114 mutant cells, similar to that of pef1-deficient cells. Meiotic progression was also slightly delayed in the pas1-deficient strain. Our results reveal that Pef1 regulates cyclin-coordinated meiotic progression.
2021年01月12日, Biomolecules, 11 (1), 英語, 国際誌[査読有り]
研究論文（学術雑誌）
Although senescent cells display various morphological changes including vacuole formation, it is still unclear how these processes are regulated. We have recently identified the gene, lymphocyte antigen 6 complex, locus D (LY6D), to be upregulated specifically in senescent cells. LY6D is a glycosylphosphatidylinositol-anchored cell-surface protein whose function remains unknown. Here, we analyzed the functional relationship between LY6D and the senescence processes. We found that overexpression of LY6D induced vacuole formation and knockdown of LY6D suppressed the senescence-associated vacuole formation. The LY6D-induced vacuoles were derived from macropinocytosis, a distinct form of endocytosis. Furthermore, Src family kinases and Ras were found to be recruited to membrane lipid rafts in an LY6D-dependent manner, and inhibition of their activity impaired the LY6D-induced macropinocytosis. Finally, reduction of senescent-cell survival induced by glutamine deprivation was recovered by albumin supplementation to the culture media in an LY6D-dependent manner. Because macropinocytosis acts as an amino acid supply route, these results suggest that LY6D-mediated macropinocytosis contributes to senescent-cell survival through the incorporation of extracellular nutrients.
2020年11月24日, The Journal of biological chemistry, 296, 100049 - 100049, 英語, 国際誌[査読有り]
研究論文（学術雑誌）
In Schizosaccharomyces pombe, a general strategy for survival in response to environmental changes is sexual differentiation, which is triggered by TORC1 inactivation. However, mechanisms of TORC1 regulation in fission yeast remain poorly understood. In this study, we found that Pef1, which is an ortholog of mammalian CDK5, regulates the initiation of sexual differentiation through positive regulation of TORC1 activity. Conversely, deletion of pef1 leads to activation of autophagy and subsequent excessive TORC1 reactivation during the early phases of the nitrogen starvation response. This excessive TORC1 reactivation results in the silencing of the Ste11-Mei2 pathway and mating defects. Additionally, we found that pef1 genetically interacts with tsc1 and tsc2 for TORC1 regulation, and physically interacts with three cyclins, Clg1, Pas1 and Psl1. The double deletion of clg1 and pas1 promotes activation of autophagy and TORC1 during nitrogen starvation, similar to what is seen in pef1Δ cells. Overall, our work suggests that Pef1-Clg1 and Pef1-Pas1 complexes regulate initiation of sexual differentiation through control of the TSC-TORC1 pathway and autophagy.
2020年09月09日, Journal of cell science, 133 (17), 英語, 国際誌[査読有り]
研究論文（学術雑誌）
Diacylglycerol kinase β (DGKβ) is an enzyme converting DG to phosphatidic acid (PA) and is specifically expressed in neurons, especially those in the cerebral cortex, hippocampus and striatum. We previously reported that DGKβ induces neurite outgrowth and spinogenesis, contributing to higher brain function including emotion and memory, and plasma membrane localization of DGKβ via the C1 domain and a cluster of basic amino acids at the C-terminus is necessary for its function. To clarify the mechanisms involved in neuronal development by DGKβ, we investigated whether DGKβ activity induces neurite outgrowth using human neuroblastoma SH-SY5Y cells. DGKβ induced neurite outgrowth by activation of mammalian target of rapamycin complex 1 (mTORC1) through a kinase-dependent pathway. In addition, in primary cultured cortical and hippocampal neurons, inhibition of mTORC1 abolished DGKβ induced-neurite outgrowth, branching and spinogenesis. These results indicated that DGKβ induces neurite outgrowth and spinogenesis by activating mTORC1 in a kinase-dependent pathway.
2020年03月, Neurochemistry international, 134, 104645 - 104645, 英語, 国際誌[査読有り]
Misfolded and aggregated proteins are eliminated to maintain protein homeostasis. Autophagy contributes to the removal of protein aggregates. However, if and how proteotoxic stress induces autophagy is poorly understood. Here we show that proteotoxic stress after treatment with azetidine-2-carboxylic acid (AZC), a toxic proline analog, induces autophagy in budding yeast. AZC tr
2019年04月, Biochemical and Biophysical Research Communications, 511 (2), 434 - 439, 英語[査読有り]
研究論文（学術雑誌）
- 2019年01月, Life Science Alliance, 2 (1), e201800045, 英語D-amino acid oxidase promotes cellular senescence via the production of reactive oxygen species
[査読有り]
研究論文（学術雑誌）
Cellular senescence is a complex stress response characterized by permanent loss of proliferative capacity and is implicated in agerelated disorders. Although the transcriptional activity of p53 (encoded by TP53) is known to be vital for senescence induction, the downstream effector genes critical for senescence remain unsolved. Recently, we have identified the proline dehydrogenase gene (PRODH) to be upregulated specifically in senescent cells in a p53-dependent manner, and the functional relevance of this to senescence is yet to be defined. Here, we conducted functional analyses to explore the relationship between PRODH and the senescence program. We found that genetic and pharmacological inhibition of PRODH suppressed senescent phenotypes induced by DNA damage. Furthermore, ectopic expression of wild-type PRODH, but not enzymatically inactive forms, induced senescence associated with the increase in reactive oxygen species (ROS) and the accumulation of DNA damage. Treatment with N-acetyl-L-cysteine, a ROS scavenger, prevented senescence induced by PRODH overexpression. These results indicate that PRODH plays a causative role in DNA damage-induced senescence through the enzymatic generation of ROS.
COMPANY OF BIOLOGISTS LTD, 2017年04月, JOURNAL OF CELL SCIENCE, 130 (8), 1413 - 1420, 英語[査読有り]
研究論文（学術雑誌）
ATF4 is a pro-oncogenic transcription factor whose translation is activated by eIF2 phosphorylation through delayed re-initiation involving two uORFs in the mRNA leader. However, in yeast, the effect of eIF2 phosphorylation can be mimicked by eIF5 overexpression, which turns eIF5 into translational inhibitor, thereby promoting translation of GCN4, the yeast ATF4 equivalent. Furthermore, regulatory protein termed eIF5-mimic protein (5MP) can bind eIF2 and inhibit general translation. Here, we show that 5MP1 overexpression in human cells leads to strong formation of 5MP1:eIF2 complex, nearly comparable to that of eIF5:eIF2 complex produced by eIF5 overexpression. Overexpression of eIF5, 5MP1 and 5MP2, the second human paralog, promotes ATF4 expression in certain types of human cells including fibrosarcoma. 5MP overexpression also induces ATF4 expression in Drosophila. The knockdown of 5MP1 in fibrosarcoma attenuates ATF4 expression and its tumor formation on nude mice. Since 5MP2 is overproduced in salivary mucoepidermoid carcinoma, we propose that overexpression of eIF5 and 5MP induces translation of ATF4 and potentially other genes with uORFs in their mRNA leaders through delayed re-initiation, thereby enhancing the survival of normal and cancer cells under stress conditions.
OXFORD UNIV PRESS, 2016年10月, NUCLEIC ACIDS RESEARCH, 44 (18), 8704 - 8713, 英語[査読有り]
研究論文（学術雑誌）
Cellular senescence is defined as permanent cell cycle arrest induced by various stresses. Although the p53 transcriptional activity is essential for senescence induction, the downstream genes that are crucial for senescence remain unsolved. Here, by using a developed experimental system in which cellular senescence or apoptosis is induced preferentially by altering concentration of etoposide, a DNA-damaging drug, we compared gene expression profiles of senescent and apoptotic cells by microarray analysis. Subtraction of the expression profile of apoptotic cells identified 20 genes upregulated specifically in senescent cells. Furthermore, 6 out of 20 genes showed p53-dependent upregulation by comparing gene expression between p53-proficient and -deficient cells. These 6 genes were also upregulated during replicative senescence of normal human diploid fibroblasts, suggesting that upregulation of these genes is a general phenomenon in senescence. Among these genes, 2 genes (PRODH and DAO) were found to be directly regulated by p53, and ectopic expression of 4 genes (PRODH, DAO, EPN3, and GPR172B) affected senescence phenotypes induced by etoposide treatment. Collectively, our results identified several proteins as novel downstream effectors of p53-mediated senescence and provided new clues for further research on the complex signalling networks underlying the induction and maintenance of senescence.
NATURE PUBLISHING GROUP, 2016年08月, SCIENTIFIC REPORTS, 6, 英語[査読有り]
研究論文（学術雑誌）
In mammalian cells, mTORC1 activity is regulated by Rag GTPases. It is thought that the Ragulator complex and the GATOR (GAP activity towards Rags) complex regulate RagA/B as its GDP/GTP exchange factor (GEF) and GTPase-activating protein (GAP), respectively. However, the functions of components in these complexes remain elusive. Using fission yeast as a model organism, here we found that the loss of Lam2 (SPBC1778.05c), a homo-log of a Ragulator component LAMTOR2, as well as the loss of Gtr1 or Gtr2 phenocopies the loss of Npr2 or Npr3, homologs of GATOR components Nprl2 or Nprl3, respectively. These phenotypes were rescued by TORC1 inhibition using pharmacological or genetic means, and the loss of Lam2, Gtr1, Gtr2, Npr2 or Npr3 disinhibited TORC1 activity under nitrogen depletion, as measured by Rps6 phosphorylation. Consistently, overexpression of GDP-locked Gtr1S20L or GTP-locked Gtr2Q60L, which suppress TORC1 activity in budding yeast, rescued the growth defect of.gtr1 cells or.gtr2 cells, respectively, and the loss of Lam2, Npr2 or Npr3 similarly diminished the vacuolar localization and the protein levels of Gtr1 and Gtr2. Furthermore, Lam2 physically interacted with Npr2 and Gtr1. These findings suggest that Lam2 and Npr2-Npr3 function together as a tether for GDP-bound Gtr1 to the vacuolar membrane, thereby suppressing TORC1 activity for multiple cellular functions.
PUBLIC LIBRARY SCIENCE, 2016年05月, PLOS ONE, 11 (5), 英語[査読有り]
研究論文（学術雑誌）
The CLOCK-interacting protein, Circadian (CIPC), has been identified as an additional negative-feedback regulator of the circadian clock. However, recent study on CIPC knockout mice has shown that CIPC is not critically required for basic circadian clock function, suggesting other unknown biological roles for CIPC. In this study, we focused on the cell cycle dependent nuclear-cytoplasmic shuttling function of CIPC and on identifying its binding proteins. Lys186 and 187 were identified as the essential amino acid residues within the nuclear localization signal (NLS) of CIPC. We identified CIPC-binding proteins such as the multifunctional enzyme CAD protein (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase), which is a key enzyme for de novo pyrimidine synthesis. Compared to control cells, HEK293 cells overexpressing wild-type CIPC showed suppressed cell proliferation and retardation of cell cycle. We also found that PMA-induced Erk activation was inhibited with expression of wild-type CIPC. In contrast, the NLS mutant of CIPC, which reduced the ability of CIPC to translocate into the nucleus, did not exhibit these biological effects. Since CAD and Erk have significant roles in cell proliferation and cell cycle, CIPC may work as a cell cycle regulator by interacting with these binding proteins. (C) 2015 Elsevier Inc. All rights reserved.
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2016年01月, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 469 (3), 377 - 383, 英語[査読有り]
研究論文（学術雑誌）
Background: Breast cancer is classified into three subtypes by the expression of biomarker receptors such as hormone receptors and human epidermal growth factor receptor 2. Triple-negative breast cancer (TNBC) expresses none of these receptors and has an aggressive phenotype with a poor prognosis, which is insensitive to the drugs that target the hormone receptors and human epidermal growth factor receptor 2. It is, thus, required to develop an effective therapeutic reagent to treat TNBC. Results: The study using a panel of 19 breast cancer cell lines revealed that midostaurin, a multi-target protein kinase inhibitor, suppresses preferentially the growth of TNBC cells comparing with non-TNBC cells. Clustering analysis of the drug activity data for the panel of cancer cell lines predicted that midostaurin shares the target with Aurora kinase inhibitors. Following studies indicated that midostaurin attenuates the phosphorylation reaction mediated by Aurora kinase in the cells and directly inhibits this protein kinase in vitro, and that this reagent induces apoptosis accompanying accumulation of 4N and 8N DNA cells in TNBC cells. Conclusion: Midostaurin suppresses the proliferation of TNBC cells among the breast cancer cell lines presumably through the inhibition of the Aurora kinase family. The precise study of midostaurin on cell growth will contribute to the development of the drug for the treatment of TNBC.
BIOMED CENTRAL LTD, 2015年07月, JOURNAL OF BIOMEDICAL SCIENCE, 22 (1), 英語[査読有り]
研究論文（学術雑誌）
The Tsc1-Tsc2 complex homologous to human tuberous sclerosis complex proteins governs amino acid uptake by regulating the expression and intracellular distribution of amino acid transporters in Schizosaccharomyces pombe. Here, we performed a genetic screening for molecules that are involved in amino acid uptake and found Arn1 (also known as Any1). Arn1 is homologous to ART1, an arrestin-related trafficking adaptor (ART) in Saccharomyces cerevisiae, and contains a conserved arrestin motif, a ubiquitination site, and two PY motifs. Overexpression of arn1 + confers canavanine resistance on cells, whereas its disruption causes hypersensitivity to canavanine. We also show that Arn1 regulates endocytosis of the Cat1 amino acid transporter. Furthermore, deletion of arn1 + suppresses a defect of amino acid uptake and the aberrant Cat1 localization in tsc2D. Arn1 interacts with and is ubiquitinated by the Pub1 ubiquitin ligase, which is necessary to regulate Cat1 endocytosis. Cat1 undergoes ubiquitinations on lysine residues within the N-terminus, which are mediated, in part, by Arn1 to determine Cat1 localization. Correctively, Arn1 is an ART in S. pombe and contributes to amino acid uptake through regulating Cat1 endocytosis in which Tsc2 is involved.
COMPANY OF BIOLOGISTS LTD, 2014年06月, BIOLOGY OPEN, 3 (6), 542 - 552, 英語[査読有り]
研究論文（学術雑誌）
The TSC1-TSC2-TBC1D7 complex is an important negative regulator of the mechanistic target of rapamycin complex 1 that controls cell growth in response to environmental cues. Inactivating TSC1 and TSC2 mutations cause tuberous sclerosis complex (TSC), an autosomal dominant disorder characterised by the occurrence of benign tumours in various organs and tissues, notably the brain, skin and kidneys. TBC1D7 mutations have not been reported in TSC patients but homozygous inactivation of TBC1D7 causes megaencephaly and intellectual disability. Here, using an exon-specific deletion strategy, we demonstrate that some regions of TSC1 are not necessary for the core function of the TSC1-TSC2 complex. Furthermore, we show that the TBC1D7 binding site is encoded by TSC1 exon 22 and identify amino acid residues involved in the TSC1-TBC1D7 interaction.
PUBLIC LIBRARY SCIENCE, 2014年04月, PLOS ONE, 9 (4), 英語[査読有り]
研究論文（学術雑誌）
Branched-chain amino acids (BCAAs) have been applied as an oral supplementation to patients with liver cirrhosis. BCAAs not only improve nutritional status of patients but also decrease the incidence of liver cancer. Mammalian target of rapamycin (mTOR) links cellular metabolism with growth and proliferation in response to nutrients, energy, and growth factors. BCAAs, especially leucine, have been shown to regulate protein synthesis through mTOR activities. On the other hand, cellular senescence is suggested to function as tumor suppressor mechanisms, and induced by a variety of stimuli including DNA damage-inducing drugs. However, it is not clear how BCAA supplementation prevents the incidence of liver cancer in patients with cirrhosis. Here we showed that human cancer cells, HepG2 and U2OS, cultured in medium containing BCAAs with Fischer's ratio about 3, which was shown to have highest activities to synthesize and secrete of albumin, had higher activities to induce premature senescence and elevate mTORC1 activities. Furthermore, BCAAs themselves enhanced the execution of premature senescence induced by DNA damage-inducing drugs, which was effectively prevented by rapamycin. These results strongly suggested the contribution of the mTORC1 pathway to the regulation of premature senescence. Interestingly, the protein levels of p21, a p53 target and well-known gene essential for the execution of cellular senescence, were upregulated in the presence of BCAAs. These results suggested that BCAAs possibly contribute to tumor suppression by enhancing cellular senescence mediated through the mTOR signalling pathway.
PUBLIC LIBRARY SCIENCE, 2013年11月, PLOS ONE, 8 (11), 英語[査読有り]
研究論文（学術雑誌）
Target of rapamycin complex 1 (TORC1) has a key role in cellular regulations in response to environmental conditions. In yeast, Tip41 downregulates TORC1 signaling via activation of PP2A phosphatase. We show here that overexpression of TIPRL, a mammalian Tip41, suppressed dephosphorylation of mechanistic TORC1 (mTORC1) substrates under amino acid withdrawal, and knockdown of TIPRL conversely attenuated phosphorylation of those substrates after amino acid refeeding. TIPRL associated with the catalytic subunit of PP2A (PP2Ac), which was required for the TIPRL action on mTORC1 signaling. Collectively, unlike yeast TIP41, TIPRL has a positive effect on mTORC1 signaling through the association with PP2Ac. Structured summary of protein interactions: PP2Ac physically interacts with TIPRL by anti bait coimmunoprecipitation (View Interaction: 1, 2) PR65 physically interacts with PP2Ac by anti tag coimmunoprecipitation (View interaction) TIPRL physically interacts with PP2Ac by anti tag coimmunoprecipitation (View Interaction: 1, 2) alpha 4 physically interacts with PP2Ac by anti bait coimmunoprecipitation (View interaction) PP2Ac physically interacts with PR65 and TIPRL by anti tag coimmunoprecipitation (View interaction) PP2Ac physically interacts with TIPRL by anti tag coimmunoprecipitation (View interaction) alpha 4 physically interacts with TIPRL by anti bait coimmunoprecipitation (View Interaction: 1, 2) (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.
ELSEVIER SCIENCE BV, 2013年09月, FEBS LETTERS, 587 (18), 2924 - 2929, 英語[査読有り]
研究論文（学術雑誌）
Cyclins control cell cycle progression by regulating the activity of cyclin-dependent kinases (Cdks). Cyclin I is a member of the cyclin family because of the presence of a cyclin box motif. It has been suggested that Cyclin I is involved in various biological processes, such as cell survival, angiogenesis, and cell differentiation. However, whether or not Cyclin I has a role in regulating the cell cycle similarly to other cyclins has yet to be clarified. Therefore, we investigated the role for Cyclin I in cell cycle progression. We showed that the protein level of Cyclin I oscillated during the cell cycle, and that Cyclin I was subjected to ubiquitination and degradation in cells. The interaction between Cyclin I and Cdk5 was detected in cells overexpressed with both proteins. Furthermore, depletion of Cyclin I by siRNAs prevented cell proliferation, suggesting the positive role of Cyclin I for the cell cycle progression. In addition, flow cytometric analysis revealed that cells depleted of Cyclin I were accumulated at G(2)/M phases. By using HeLa.S-Fucci (fluorescent ubiquitination-based cell cycle indicator) cells, we further confirmed that knockdown of Cyclin I induced cell cycle arrest at S/G(2)/M phases. These results strongly suggest that Cyclin I has the role in the regulation of cell cycle progression.
LANDES BIOSCIENCE, 2013年08月, CELL CYCLE, 12 (16), 2617 - 2624, 英語[査読有り]
研究論文（学術雑誌）
Background: mTOR is a genetically conserved serine/threonine protein kinase, which controls cell growth, proliferation, and survival. A multifunctional protein CAD, catalyzing the initial three steps in de novo pyrimidine synthesis, is regulated by the phosphorylation reaction with different protein kinases, but the relationship with mTOR protein kinase has not been known. Results: CAD was recovered as a binding protein with mLST8, a component of the mTOR complexes, from HEK293 cells transfected with the FLAG-mLST8 vector. Association of these two proteins was confirmed by the co-immuoprecipitaiton followed by immunoblot analysis of transfected myc-CAD and FLAG-mLST8 as well as that of the endogenous proteins in the cells. Analysis using mutant constructs suggested that CAD has more than one region for the binding with mLST8, and that mLST8 recognizes CAD and mTOR in distinct ways. The CAD enzymatic activity decreased in the cells depleted of amino acids and serum, in which the mTOR activity is suppressed. Conclusion: The results obtained indicate that mLST8 bridges between CAD and mTOR, and plays a role in the signaling mechanism where CAD is regulated in the mTOR pathway through the association with mLST8.
BIOMED CENTRAL LTD, 2013年04月, JOURNAL OF BIOMEDICAL SCIENCE, 20 (1), 英語[査読有り]
研究論文（学術雑誌）
Target of rapamycin (TOR), an evolutionarily conserved serine/threonine protein kinase, plays pivotal roles in several important cellular processes in eukaryotes. In the fission yeast Schizosaccharomyces pombe, TOR complex 1 (TORC1), which includes Tor2 as a catalytic subunit, manages the switch between cell proliferation and differentiation by sensing nutrient availability. However, little is known about the direct target of TORC1 that plays key roles in nutrient-dependent TORC1 signaling in fission yeast. Here we report that in fission yeast, three AGC kinase family members, named Psk1, Sck1 and Sck2, which exhibit high homology with human S6K1, are phosphorylated under nutrient-rich conditions and are dephosphorylated by starvation conditions. Among these, Psk1 is necessary for phosphorylation of ribosomal protein S6. Furthermore, Psk1 phosphorylation is regulated by TORC1 in nutrient-dependent and rapamycin-sensitive manners in vivo. Three conserved regulatory motifs (the activation loop, the hydrophobic and the turn motifs) in Psk1 are phosphorylated and these modifications are required for Psk1 activity. In particular, phosphorylation of the hydrophobic motif is catalyzed by TORC1 in vivo and in vitro. Ksg1, a homolog of PDK1, is also important for Psk1 phosphorylation in the activation loop and for its activity. The TORC1 components Pop3, Toc1 and Tco89, are dispensable for Psk1 regulation, but disruption of pop3(+) causes an increase in the sensitivity of TORC1 to rapamycin. Taken together, these results provide convincing evidence that TORC1/Psk1/Rps6 constitutes a nutrient-dependent signaling pathway in fission yeast.
COMPANY OF BIOLOGISTS LTD, 2012年12月, JOURNAL OF CELL SCIENCE, 125 (23), 5840 - 5849, 英語[査読有り]
研究論文（学術雑誌）
X-linked inhibitor of apoptosis protein (XIAP) is a potent antagonist of caspases, and functions as a ubiquitin-E3 ligase by itself and for caspases. Recently, NEDD8, a ubiquitin-like modifier, has been suggested to be used for modification of caspase-7 mediated by XIAP. However, it is not clear whether caspase-7 is a bona fide target for NEDD8. Here we showed that no neddylation of caspase-7 but that of XIAP itself was observed under the conditions in which caspase-7 was modified with ubiquitin. These results reveal that XIAP does not function as a NEDD8-E3 ligase for caspase-7 in vivo. Structured summary of protein interactions: NEDD8 physically interacts with Caspase-7 by pull down (View interaction) XIAP physically interacts with NEDD8 by anti-bait coimmunoprecipitation (View interaction) (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.
11, 2012年06月, FEBS letters, 586 (11), 1612 - 1616, 英語[査読有り]
研究論文（学術雑誌）
Apoptosis is induced by various stresses generated from the extracellular and intracellular environments. The fidelity of the cell cycle is monitored by surveillance mechanisms that arrest its further progression if any crucial process has not been completed or damages are sustained, and then the cells with problems undergo apoptosis. Although the molecular mechanisms involved in the regulation of the cell cycle and that of apoptosis have been elucidated, the links between them are not clear, especially that between cell cycle and death receptor-mediated apoptosis. By using the HeLa.S-Fucci (fluorescent ubiquitination-based cell cycle indicator) cells, we investigated the relationship between the cell cycle progression and apoptotic execution. To monitor apoptotic execution during cell cycle progression, we observed the cells after induction of apoptosis with time-lapse fluorescent microscopy. About 70% of Fas-mediated apoptotic cells were present at G(1) phase and about 20% of cells died immediately after cytokinesis, whereas more than 60% of etoposide-induced apoptotic cells were at S/G(2) phases in random culture of the cells. These results were confirmed by using synchronized culture of the cells. Furthermore, mitotic cells showed the resistance to Fas-mediated apoptosis. In conclusion, these findings suggest that apoptotic execution is dependent on cell cycle phase and Fas-mediated apoptosis preferentially occurs at G(1) phase. Cell Death and Disease (2012) 3, e313; doi:10.1038/cddis.2012.52; published online 24 May 2012
NATURE PUBLISHING GROUP, 2012年05月, CELL DEATH & DISEASE, 3 (5), 英語[査読有り]
研究論文（学術雑誌）
Microscopy has greatly advanced our understanding of biology. Although significant progress has recently been made in optical microscopy to break the diffraction-limit barrier, reliance of such techniques on fluorescent labeling technologies prohibits quantitative 3D imaging of the entire contents of cells. Cryoelectron microscopy can image pleomorphic structures at a resolution of 3-5 nm, but is only applicable to thin or sectioned specimens. Here, we report quantitative 3D imaging of a whole, unstained cell at a resolution of 50-60 nm by X-ray diffraction microscopy. We identified the 3D morphology and structure of cellular organelles including cell wall, vacuole, endoplasmic reticulum, mitochondria, granules, nucleus, and nucleolus inside a yeast spore cell. Furthermore, we observed a 3D structure protruding from the reconstructed yeast spore, suggesting the spore germination process. Using cryogenic technologies, a 3D resolution of 5-10 nm should be achievable by X-ray diffraction microscopy. This work hence paves a way for quantitative 3D imaging of a wide range of biological specimens at nanometer-scale resolutions that are too thick for electron microscopy.
NATL ACAD SCIENCES, 2010年06月, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 107 (25), 11234 - 11239, 英語[査読有り]
研究論文（学術雑誌）
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates a variety of cellular functions such as growth, proliferation and autophagy. In a variety of cancer cells, overactivation of mTOR has been reported. In addition, mTOR inhibitors, such as rapamycin and its derivatives, are being evaluated in clinical trials as anticancer drugs. However, no active mutants of mTOR have been identified in human cancer. Here, we report that two different point mutations, S2215Y and R2505P, identified in human cancer genome database confer constitutive activation of mTOR signaling even under nutrient starvation conditions. S2215Y was identified in large intestine adenocarcinoma whereas R2505P was identified in renal cell carcinoma. mTOR complex 1 prepared from cells expressing the mutant mTOR after nutrient starvation still retains the activity to phosphorylate 4E-BP1 in vitro. The cells expressing the mTOR mutant show increased percentage of S-phase cells and exhibit resistance to cell size decrease by amino-acid starvation. The activated mutants are still sensitive to rapamycin. However, they show increased resistance to 1-butanol. Our study points to the idea that mTOR activating mutations can be identified in a wide range of human cancer. Oncogene (2010) 29, 2746-2752; doi:10.1038/onc.2010.28; published online 1 March 2010
NATURE PUBLISHING GROUP, 2010年05月, ONCOGENE, 29 (18), 2746 - 2752, 英語研究論文（学術雑誌）
Cellular activities are regulated by environmental stimuli through protein phosphorylation. Target of rapamycin (TOR), a serine/threonine kinase, plays pivotal roles in cell proliferation and cell growth in response to nutrient status. In Schizosaccharomyces pombe, TORC1, which contains Tor2, plays crucial roles in nutrient response. Here we find a nitrogen-regulated phosphoprotein, p27, in S. pombe using the phospho-Akt substrate antibody. Response of p27 phosphorylation to nitrogen availability is mediated by TORC1 and the TSC-Rhb1 signaling, but not by TORC2 or other nutrient stress-related pathways. Database and biochemical analyses indicate that p27 is identical to ribosomal protein S6 (Rps6). Ser235 and Ser236 in Rps6 are necessary for Rps6 phosphorylation by TORC1. These Rps6 phosphorylations are dispensable for cell viability. Rps6 phosphorylation by TORC1 also responds to availability of glucose and is inhibited by osmotic and oxidative stresses. Rapamycin inhibits the ability of TORC1 to phosphorylate Rps6, owing to interaction of the rapamycin-FKBP12 complex with the FRB domain in Tor2. Rapamycin also leads to a decrease in cell size in a TORC1-dependent manner. Our findings demonstrate that the nutrient-responsive and rapamycin-sensitive TORC1-S6 signaling exists in S. pombe, and that this pathway plays a role in cell size control.
COMPANY OF BIOLOGISTS LTD, 2010年03月, JOURNAL OF CELL SCIENCE, 123 (5), 777 - 786, 英語研究論文（学術雑誌）
- [Rheb-mTOR signaling pathway involved in tumor formation].
mTORは,アミノ酸やインスリンなどの栄養・増殖因子に反応し,細胞の増殖や大きさ,オートファジー,アクチン細胞骨格の形成の制御などを行なう多機能蛋白質である.多くのがん細胞ではmTORシグナルの破綻が見受けられ,mTORシグナルの異常活性化はがん細胞の増殖などを促進していると考えられる.近年,mTORが2つの複合体を形成することがわかり,そのシグナル伝達機構や活性化機構が徐々に明らかになってきた.(著者抄録)
1, 2010年01月, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme, 55 (1), 11 - 17, 日本語[査読有り]
Rheb G-protein plays critical roles in the TSC/Rheb/mTOR signaling pathway by activating mTORC1. The activation of mTORC1 by Rheb can be faithfully reproduced in vitro by using mTORC1 immunoprecipitated by the use of anti-raptor antibody from mammalian cells starved for nutrients. The low in vitro kinase activity against 4E-BP1 of this mTORC1 preparation is dramatically increased by the addition of recombinant Rheb. On the other hand, the addition of Rheb does not activate mTORC2 immunoprecipitated from mammalian cells by the use of anti-rictor antibody. The activation of mTORC1 is specific to Rheb, because other G-proteins such as KRas, RalA/B, and Cdc42 did not activate mTORC1. Both Rheb1 and Rheb2 activate mTORC1. In addition, the activation is dependent on the presence of bound GTP. We also find that the effector domain of Rheb is required for the mTORC1 activation. FKBP38, a recently proposed mediator of Rheb action, appears not to be involved in the Rheb-dependent activation of mTORC1 in vitro, because the preparation of mTORC1 that is devoid of FKBP38 is still activated by Rheb. The addition of Rheb results in a significant increase of binding of the substrate protein 4E-BP1 to mTORC1. PRAS40, a TOR signaling (TOS) motif-containing protein that competes with the binding of 4EBP1 to mTORC1, inhibits Rheb-induced activation of mTORC1. A preparation of mTORC1 that is devoid of raptor is not activated by Rheb. Rheb does not induce autophosphorylation of mTOR. These results suggest that Rheb induces alteration in the binding of 4E-BP1 with mTORC1 to regulate mTORC1 activation.
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2009年05月, JOURNAL OF BIOLOGICAL CHEMISTRY, 284 (19), 12783 - 12791, 英語研究論文（学術雑誌）
The target of rapamycin (Tor) protein plays central roles in cell growth. Rapamycin inhibits cell growth and promotes cell cycle arrest at G1 (G0). However, little is known about whether Tor is involved in other stages of the cell division cycle. Here we report that the rapamycin-sensitive Tor complex 1 (TORC1) is involved in G2/M transition in S. cerevisiae. Strains carrying a temperature-sensitive allele of KOG1 (kog1-105) encoding an essential component of TORC1, as well as yeast cell treated with rapamycin show mitotic delay with prolonged G2. Overexpression of Cdc5, the yeast polo-like kinase, rescues the growth defect of kog1-105, and in turn, Cdc5 activity is attenuated in kog1-105 cells. The TORC1-Type2A phosphatase pathway mediates nucleocytoplasmic transport of Cdc5, which is prerequisite for its proper localization and function. The C-terminal polo-box domain of Cdc5 has an inhibitory role in nuclear translocation. Taken together, our results indicate a novel function of Tor in the regulation of cell cycle and proliferation.
PUBLIC LIBRARY SCIENCE, 2008年05月, PLOS ONE, 3 (5), 英語[査読有り]
研究論文（学術雑誌）
Sufficiency and depletion of nutrients regulate the cellular activities through the protein phosphorylation reaction; however, many protein substrates remain to be clarified. GBF1 (Golgi-specific brefeldin A resistance factor 1), a guanine nucleotide exchange factor for the ADP-ribosylation factor family associated with the Golgi apparatus, was isolated as a phosphoprotein from the glucose-depleted cells by using the phospho-Akt-substrate antibody, which recognizes the substrate proteins of several protein kinases. The phosphorylation of GBF1 was induced by 2-deoxyglucose (2-DG), which blocks glucose utilization and increases the intracellular AMP concentration, and by AICAR, an AMP-activated protein kinase (AMPK) activator. This phosphorylation was observed in the cells expressing the constitutively active AMPK. The 2-DG-induced phosphorylation of GBF1 was suppressed by Compound C, an AMPK inhibitor, and by the overexpression of the kinase-negative AMPK. Analysis using the deletion and point mutants identified Thr(1337) as the 2-DG-induced phosphorylation site in GBF1, which is phosphorylated by AMPK in vitro. ATP depletion is known to provoke the Golgi apparatus disassembly. Immunofluorescent microscopic analysis with the Golgi markers indicated that GBF1 associates with the fragmented Golgi apparatus in the cells treated with 2-DG and AICAR. The expression of the kinase-negative AMPK and the GBF1 mutant replacing Thr(1337) by Ala prevented the 2-DG-induced Golgi disassembly. These results indicate that GBF1 is a novel AMPK substrate and that the AMPK-mediated phosphorylation of GBF1 at Thr1337 has a critical role, presumably by attenuating the function of GBF1, in the disassembly of the Golgi apparatus induced under stress conditions that lower the intracellular ATP concentration.
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2008年02月, JOURNAL OF BIOLOGICAL CHEMISTRY, 283 (7), 4430 - 4438, 英語研究論文（学術雑誌）
TBC7, a TBC (Tre-2/Bub2/Cdcl6) I domain protein, was identified as a novel binding protein to the TSC1-TSC2 tumor suppressor complex by peptide mass fingerprinting analysis of the proteins immunoprecipitated with FLAG-epitope tagged TSC1 and TSC2 from the transfected mammalian cells. The in vivo and in vitro association of TBC7 and the TSC1-TSC2 complex was confirmed by the co-immunoprecipitation and pull-down analysis, respectively, and TBC7 was revealed to bind to the C-terminal half region of TSC1, which is distinct from the binding site with TSC2. The immunofluorescence microscopy and subcellular fractionation showed that TBC7 co-localizes with the tumor suppressor complex in the endomembrane. Overexpression of TBC7 enhanced ubiquitination of TSC1 and increased phosphorylation of S6 protein by S6 kinase, that is located in the mTOR-signaling pathway. These results indicate TBC7 could take a part in the negative regulation of the tumor suppressor complex through facilitating the downregulation of TSC1. (C) 2007 Elsevier Inc. All rights reserved.
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2007年09月, Biochemical and Biophysical Research Communications, 361 (1), 218 - 223, 英語, 国際誌[査読有り]
研究論文（学術雑誌）
The proline-rich Akt substrate of 40 kilodaltons (PRAS40) was identified as a raptor-binding protein that is phosphorylated directly by mammalian target of rapamycin ( mTOR) complex 1 (mTORC1) but not mTORC2 in vitro, predominantly at PRAS40 (Ser(183)). The binding of S6K1 and 4E-BP1 to raptor requires a TOR signaling (TOS) motif, which contains an essential Phe followed by four alternating acidic and small hydrophobic amino acids. PRAS40 binding to raptor was severely inhibited by mutation of PRAS40 (Phe(129) to Ala). Immediately carboxyl-terminal to Phe(129) are two small hydrophobic amino acid followed by two acidic residues. PRAS40 binding to raptor was also abolished by mutation of the majormTORC1phosphorylation site, Ser(183), to Asp. PRAS40 (Ser(183)) was phosphorylated in intact cells; this phosphorylation was inhibited by rapamycin, by 2- deoxyglucose, and by overexpression of the tuberous sclerosis complex heterodimer. PRAS40 ( Ser183) phosphorylation was also inhibited reversibly by withdrawal of all or of only the branched chain amino acids; this inhibition was reversed by overexpression of the Rheb GTPase. Over-expressed PRAS40 suppressed the phosphorylation of S6K1 and 4E-BP1 at their rapamycin-sensitive phosphorylation sites, and reciprocally, overexpression of S6K1 or 4E-BP1 suppressed phosphorylation of PRAS40 (Ser(183)) and its binding to raptor. RNA interference-induced depletion of PRAS40 enhanced the amino acid-stimulated phosphorylation of both S6K1 and 4E-BP1. These results establish PRAS40 as a physiological mTORC1 substrate that contains a variant TOS motif. Moreover, they indicate that the ability of raptor to bind endogenous substrates is limiting for the activity of mTORC1 in vivo and is therefore a potential locus of regulation.
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2007年07月, JOURNAL OF BIOLOGICAL CHEMISTRY, 282 (28), 20329 - 20339, 英語研究論文（学術雑誌）
Schizosaccharomyces pombe isp6(+) gene encodes a vacuolar serine protease, which is specifically induced during nitrogen starvation. An isp6-disruption mutant, isp6 Delta, grew normally under normal conditions but was defective in large-scale protein degradation during nitrogen starvation, a hallmark of autophagy. Vacuoles are the organelles for such drastic protein degradation but those of isp6 Delta were apparently aberrant. isp6 Delta was infertile under nitrogen source-free conditions with poor expression of ste11(+), a gene critical for sexual development. A protein kinase A-disruption mutant, pka1 Delta, is prone to sexual development because expression of ste11(+) is derepressed. However, isp6 Delta pka1 Delta still showed defects in ste11(+) expression and sexual development under nitrogen source-free conditions. isp6 Delta and isp6 Delta pka1 Delta were able to initiate sexual development to produce spores when only a small amount of a nitrogen source was present. Pat1 protein kinase negatively controls meiosis, and a temperature-sensitive mutant of pat1, pat1-114, initiates meiosis irrespective of ploidy at the restrictive temperature. However, isp6 Delta pat1-114 did not start meiosis under nitrogen source-free conditions even at the restrictive temperature. These observations suggest that isp6(+) contributes to sexual development by providing a nitrogen source through autophagy.
SPRINGER, 2006年06月, CURRENT GENETICS, 49 (6), 403 - 413, 英語[査読有り]
研究論文（学術雑誌）
Heat shock protein 90 (Hsp90) was co-immunoprecipitated with raptor, the binding partner of the mammalian target of rapamycin (mTOR) from HEK293 cells. Hsp90 was detected in the anti-raptor antibody immunoprecipitates prepared from the cell extract by immunoblot analysis using the anti-Hsp90 antibody, and the association of these two proteins was confirmed by immunoprecipitation from the cells co-expressing Hsp90 and raptor as epitope-tagged molecules. Geldanamycin, a potent inhibitor of Hsp90, disrupted the in vivo binding of Hsp90 to raptor without affecting the association of raptor and mTOR, and suppressed the phosphorylation by mTOR of the downstream translational regulators p70 S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). The protein kinase activity of S6K as well as the phosphorylation of the substrate, 40S ribosomal protein S6, were lowered in the geldanamycin-treated cells. These results indicate that Hsp90 is involved in the regulation of protein translation by facilitating the phosphorylation reaction of 4E-BP1 and S6K catalyzed by the mTOR/raptor complex through the association with raptor, and that the mTOR signaling pathway is a novel target of geldanamycin.
JAPANESE BIOCHEMICAL SOC, 2006年01月, JOURNAL OF BIOCHEMISTRY, 139 (1), 129 - 135, 英語研究論文（学術雑誌）
The fission yeast gene isp6(+) is needed in nitrogen-starvation response but its transcriptional regulation has been unclear. isp6(+) was repressed under nutrient conditions, in which cAMP-dependent protein kinase A, the stress-activated protein kinase cascade, and the CCAAT-binding complex were concerned. The CCAAT-binding complex also was involved in the induction of isp6(+) during nitrogen starvation.
TAYLOR & FRANCIS LTD, 2002年10月, Bioscience.Biotechnology,＆Biochemistry, 66 (10), 2224 - 2227, 英語[査読有り]
研究論文（学術雑誌）
- Genes for a Nudease and a Protease Are Involved in the Drastic Decrease in Cellular RNA Amount in Fission Yeast Cells during Nitrogen Starvation 「First Author」
Cellular RNA in Schizosaccharomyces pombe cells drastically decreases in amount during nitrogen starvation. Previously, we found and purified a soluble RNA-degrading enzyme whose activity drastically increased in the cells of S. pombe undergoing nitrogen starvation. The enzyme was a nuclease encoded by pnu1(+). In this study, the increase in the RNA-degrading activity and the decrease in cellular RNA level are examined in a null-mutant of pnu1(+) (pnu1Delta). During nitrogen starvation, wild-type cells show an apparent increase in RNA-degrading activity, whereas the pnu1Delta cells do not. The wild-type cells show a drastic decrease in cellular RNA amount, whereas the pnu1Delta cells show only a slight decrease. These results suggest that Pnu1 nuclease is implicated in the decrease in cellular RNA amount during nitrogen starvation, probably via the RNA-degrading activity. The increase in the RNA-degrading activity is independent of both the Wis1 stress-activated MAP kinase cascade and Tor1 signaling pathway, but it is strongly dependent on isp6(+), a gene for a possible protease, whose expression is induced during nitrogen starvation. A disruption mutant for isp6(+) (isp6Delta) is deficient in both the increase in the RNA-degrading activity and the drastic decrease in the cellular RNA amount during nitrogen starvation, which suggests that isp6(+) is involved in the RNA degradation via regulating the RNA-degrading activity of Pnu1.
OXFORD UNIV PRESS, 2002年03月, Journal of Biochemistry, 131 (3), 391 - 398, 英語[査読有り]
研究論文（学術雑誌）
A target of rapamycin (TOR) protein is a protein kinase that exerts cellular signal transduction to regulate cell growth in response to extracellular nutrient conditions. In the Schizosaccharomyces pombe genome database, there are two genes encoding TOR-related proteins, but their functions have not been analyzed. Here we report that one of the genes, referred to as tor1(+), is required for sexual development induced by nitrogen starvation. Ste11 is a key transcription factor for the initiation of sexual development. The expression of ste11(+) is normally regulated in tor1(-) cells; and overexpression of ste11(+) hardly rescues the defect in fertility in tor1(-). Upon nitrogen starvation, tor1(+) cells promote two rounds of the cell cycle to become arrested at the G1 phase before initiation of sexual development. The tor1(-) cells do not promote such a cell cycle, suggesting that Tor1 is necessary for the response to nitrogen starvation, The tor1(-) cells show no growth or very slow growth under various stress conditions, including external high pH, high concentrations of salts or sorbitol, and high temperature. These results suggest that Tor1 is necessary for any response to a wide range of stresses. The vegetative growth of tor1(-) cells is inhibited by rapamycin, although tor1(+) cells are resistant to the drug. The tor1(-) cells are hypersensitive to fluphenazine and cyclosporin A, which specifically inhibit calmodulin and calcineurin respectively.
SPRINGER, 2001年05月, CURRENT GENETICS, 39 (3), 166 - 174, 英語[査読有り]
研究論文（学術雑誌）
MISC
Target of rapamycin (TOR) kinase controls cell metabolism and growth in response to environmental cues such as nutrients, growth factors, and stress. TOR kinase is widely conserved across eukaryotes. As in other organisms, the fission yeast Schizosaccharomyces pombe has two types of TOR complex, namely TOR complex 1 (TORC1) and TORC2. It is interesting that the two TOR complexes in S. pombe have opposite roles in sexual differentiation, which is induced by nutrient starvation. TORC1, which contains Tor2 as a catalytic subunit, promotes vegetative growth and represses sexual differentiation in nutrient-rich conditions, while TORC2 is required for the initiation of sexual differentiation. Multiple targets of TORC1 have been identified. Some of these, such as S6 kinase and an autophagy regulator Atg13, are known targets in other organisms. In addition, there is a novel group of TORC1 targets involved in the regulation of sexual differentiation. Here, we review recent findings on phosphorylation targets of TORC1 in S. pombe. Furthermore, we briefly report a novel S. pombe target of TORC1.
MDPI AG, 2017年09月01日, Biomolecules, 7 (3), e50, 英語[査読有り][招待有り]
書評論文,書評,文献紹介等
- JAPANESE PHARMACOLOGICAL SOC, 2014年, JOURNAL OF PHARMACOLOGICAL SCIENCES, 124, 100P - 100P, 英語mTOR is involved in both kinase activity-dependent and -independent pathways of DGK beta-regulated neurite and branch induction
研究発表ペーパー・要旨（国際会議）
- WILEY-BLACKWELL, 2012年09月, FEBS JOURNAL, 279, 383 - 384, 英語Involvement of mTOR in diacylglycerol kinase beta (DGK beta)-induced neurite blanching and spine formation
研究発表ペーパー・要旨（国際会議）
- 羊土社, 2011年, 実験医学, 29, 865 - 870, 日本語アミノ酸センシングシステムとしてのmTOR複合体１の機序
[招待有り]
記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
The TSC/Rheb/TORC1/S6K/S6 signaling pathway plays critical roles in regulating protein synthesis and growth in eukaryotes. Our recent work using fission yeast Schizosaccharomyces pombe revealed that this signaling pathway is conserved from humans to fission yeast. In addition to target of rapamycin (TOR) homologs and tuberous sclerosis complex (TSC) homologs, fission yeast but not budding yeast, has a functional homolog of Rheb, a small G-protein acting as an activator of TOR complex 1 (TORC1). Several lines of genetic evidence suggest that the Tsc1-Tsc2 complex and Rheb act as upstream players of TORC1 in fission yeast. We have recently demonstrated that TORC1, but not TORC2, regulates phosphorylation of ribosomal protein S6 in response to nutrient availability. Candidate S6 kinase (S6K) protein has been identified. In addition, we find that rapamycin prevents a subset of TORC1 activity to regulate S6 phosphorylation in fission yeast. © 2010 Elsevier Inc.
ELSEVIER, 2010年, Enzymes, 28 (C), 167 - 187, 英語[招待有り]
その他
- Rheb-mTORシグナルと細胞がん化への関与
mTORは,アミノ酸やインスリンなどの栄養・増殖因子に反応し,細胞の増殖や大きさ,オートファジー,アクチン細胞骨格の形成の制御などを行なう多機能蛋白質である.多くのがん細胞ではmTORシグナルの破綻が見受けられ,mTORシグナルの異常活性化はがん細胞の増殖などを促進していると考えられる.近年,mTORが2つの複合体を形成することがわかり,そのシグナル伝達機構や活性化機構が徐々に明らかになってきた.(著者抄録)
共立出版, 2010年01月, 蛋白質 核酸 酵素, 55 (1), 11 - 17, 日本語[招待有り]
記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 医学書院, 2008年, 生体と科学, 59 (6), 497 - 503, 日本語
[招待有り]
記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 北隆館, 2004年, BIO Clinica, 19, 18 - 22, 日本語細胞環境中のアミノ酸バランスを感知するmTORシグナル伝達機構
[招待有り]
記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
書籍等出版物
- 共著, Conservation of the Tsc/Rheb/TORC1/S6K/S6 signaling in fission yeast, 2010年The Enzymes
- 共著, 共立出版, 2010年01月, 日本語Rheb-mTORシグナルと細胞がん化への関与/蛋白質 核酸 酵素
学術書
- 共著, 北陸館, 2004年, 日本語BIO Clinica Vol. 19 / 細胞環境中のアミノ酸バランスを感知するmTORシグナル伝達機構
学術書
講演・口頭発表等
- 第44回日本分子生物学会年会, 2021年12月01日, 日本語分裂酵母の減数分裂におけるオートファジー制御
ポスター発表
- 第11回TOR研究会, 2021年07月15日, 日本語分裂酵⺟の減数分裂におけるTORC1活性とオートファジー
口頭発表（一般）
- 第４２回日本分子生物学会年会, 2019年12月, 日本語分裂酵母サイクリン依存性キナーゼPef1はTORC１を介して減数分裂の開始・進行を制御する
ポスター発表
- 酵母遺伝学フォーラム第52回研究報告, 2019年09月06日, 日本語分裂酵母Pef1/TORC1シグナル伝達機構の解析
口頭発表（一般）
- 第９回TOR研究会, 2019年06月, 日本語, 久留米シティプラザ 久留米市, 国内会議分裂酵母Pef1/CDK5によるTORC1制御機構
口頭発表（一般）
- 第41回日本分子生物学会年会, 2018年11月, 日本語, 横浜市，パシフィコ横浜, 国内会議有性生殖過程における分裂酵母Pef1(CDK5)/TORC1シグナル伝達機構の解析
ポスター発表
- 第41回日本分子生物学会年会, 2018年11月, 日本語, 国内会議LY6Dは老化細胞の細胞膜脂質ラフト上でSrcやRasと会合することによりマクロピノサイトーシスを誘導する
ポスター発表
- 酵母遺伝学フォーラム第51回研究報告会, 2018年09月, 日本語, 福岡市，九州大学医学部百年講堂, 国内会議分裂酵母Pef1/CDK5はTORC1を介して有性生殖過程の開始・進行を制御する
ポスター発表
- 第８回TOR研究会, 2018年06月, 日本語, 蛋白研セミナー“TORを介した細胞成長統御の総合的理解”, 大阪市，大阪大学中之島センター, 国内会議分裂酵母Pef1/CDK5はTORC1制御に関与する？
口頭発表（一般）
- ConBio2017（生命科学系学会合同年次大会）, 2017年12月, 日本語, 神戸ポートアイランド, 国内会議減数分裂における分裂酵母TORC1の制御
[招待有り]
口頭発表（招待・特別）
- ConBio2017, 2017年12月, 日本語, 神戸, 国内会議LY6Dにより誘導されるマクロピノサイトーシスは老化細胞の生存促進に働く
口頭発表（一般）
- 第四回バイオシグナル研究会「栄養シグナリングTOR と細胞機能制御〜基礎研究から創薬へ〜」, 2017年09月, 日本語, 神戸大学瀧川記念学術交流会館, 国内会議モデル生物を用いたTORC1 の減数分裂における制御と機能
[招待有り]
口頭発表（招待・特別）
- 日本分子生物学会, 2016年11月, 日本語, 横浜, 国内会議p53によるアミノ酸代謝経路の調節が細胞老化を誘導する
シンポジウム・ワークショップパネル（公募）
- 第６回TOR研究会, 2016年09月, 日本語, 東京大学 分子細胞生物学研究所, 国内会議フェロモン応答シグナルによる分裂酵母TORC1制御の可能性
口頭発表（一般）
- Biochemistry and Molecular Biology 2015, 2015年12月, 日本語, 特定非営利活動法人 日本分子生物学会, 神戸ポートアイランド, 国内会議減数分裂における分裂酵母TORC1の制御と機能
[招待有り]
口頭発表（招待・特別）
- THE EIGHTH INTERNATIONAL FISSION YEAST MEETING, 2015年06月, 英語, Kobe, 国際会議Regulation of TORC1 signaling in meiosis under nitrogen starvation
ポスター発表
- 第37回日本分子生物学会, 2014年11月, 日本語, 横浜, 国内会議新規細胞老化誘導因子としてのDアミノ酸酸化酵素DAOの機能解析
ポスター発表
- 第37回日本分子生物学会年会, 2014年11月, 日本語, パシフィコ横浜, 国内会議プロリン脱水素酵素（PRODH）は細胞老化誘導に関わる新規因子である
ポスター発表
- 第47回酵母遺伝学フォーラム報告会, 2014年09月, 日本語, 東京大学農学部弥生キャンパス東京大学弥生講堂, 国内会議分裂酵母 TORC1 の窒素源飢餓時の再活性化と生理機能
ポスター発表
- 第186回酵母細胞研究会例会 平成24年度地神芳文記念研究助成金研究成果報告会, 2014年07月, 日本語, 国内会議多機能性 TORC1 キナーゼの液胞依存性栄養シグナルによる活性制御システムの解明
[招待有り]
口頭発表（招待・特別）
- 第36回日本分子生物学会年会, 2013年12月, 日本語, 日本分子生物学会, 国内会議栄養枯渇時の分裂酵母TORC1の活性と機能
口頭発表（一般）
- 第46回酵母遺伝学フォーラム年会, 2013年09月, 日本語, 酵母遺伝学フォーラム, 国内会議分裂酵母TORC1の窒素源飢餓時の再活性化と生理機能の検討
口頭発表（一般）
- 第35回日本分子生物学会年会, 2012年12月, 日本語, 日本分子生物学会, 国内会議分裂酵母アレスチン様タンパク質Arn1とそのユビキチン化を介したアミノ酸の細胞内取り込みの制御
ポスター発表
- 第45回酵母遺伝学フォーラム年会, 2012年09月, 日本語, 酵母遺伝学フォーラム, 国内会議アミノ酸トランスポーターCat1のアレスチン様タンパク質による機能制御
ポスター発表
- 第35回日本神経科学大会, 2012年09月, 日本語, 日本神経科学会, 名古屋国際会議場, 国内会議Molecular mechanism of DGKβ- mediated neurite blanching and spine formation
ポスター発表
- The 22nd IUBMB & the 37th FEBS, 2012年09月, 英語, IUBMB & FEBS, Sevilla, Spain, 国際会議Involvement of mTOR in Diacylglycerol kinase β (DGKβ)-induced neurite branching and spine formation.
ポスター発表
- 第54回日本脂質生化学会大会, 2012年06月, 日本語, 日本脂質生化学会, 九州大学, 国内会議ジアシルグリセロールキナーゼ_による特徴的な神経突起伸にはmTORが関与する
口頭発表（一般）
- 第34回日本分子生物学会年会, 2011年12月, 英語, 日本分子生物学会, 国内会議Mammalian TIP41-like protein, mTIP41, as a positive regulator of the amino acid-stimulated mTORC1 signaling.
口頭発表（一般）
- 第44回酵母遺伝学フォーラム年会, 2011年09月, 日本語, 酵母遺伝学フォーラム, 国内会議アレスチン様タンパク質Art1によるアミノ酸透過酵素Cat1の機能解析
ポスター発表
- BMB2010（日本生化学会・日本分子生物学会合同大会）, 2010年12月, 日本語, 日本分子生物学会, 国内会議分裂酵母TORC1によるS6キナーゼPsk1の制御
口頭発表（一般）
- 第43回酵母遺伝学フォーラム年会, 2010年09月, 日本語, 酵母遺伝学フォーラム, 国内会議分裂酵母TORC1による栄養依存的なリボソームタンパクS6のリン酸化制御
口頭発表（一般）
- The 5th international fission yeast meeting, 2009年, 英語, 国際会議THE TORC1-S6K-S6 SIGNALING IN FISSION YEAST.
ポスター発表
所属学協会
共同研究・競争的資金等の研究課題
- 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), 神戸大学, 2019年06月28日 - 2021年03月31日ウシ精子の鞭毛機能の評価基準の見直しを目的とした3次元ローテーション運動の解析
- 学術研究助成基金助成金／基盤研究(C), 2016年04月 - 2019年03月
競争的資金
- 学術研究助成基金助成金／基盤研究(C), 2014年04月 - 2017年03月, 研究代表者
競争的資金
- 科学研究費補助金／若手研究(B), 2011年04月 - 2013年03月, 研究代表者
競争的資金
- 科学研究費補助金／基盤研究(B), 2010年
競争的資金
- 分裂酵母のストレス適応機構の研究.
競争的資金
- ストレス適応の分子メカニズムの研究
競争的資金
- TORを介する栄養シグナリングの解明と細胞制御機構の解析
競争的資金
- Research on the molecular mechanism of the stress-response.
競争的資金
- Study of the stress-response mechanism in fission yeast.
競争的資金