研究者データベース

今城 正道(イマジヨウ マサミチ)
創成研究機構化学反応創成研究拠点
特任准教授

基本情報

所属

  • 創成研究機構化学反応創成研究拠点

職名

  • 特任准教授

学位

  • 博士(生命科学)(京都大学)

J-Global ID

研究分野

  • ライフサイエンス / 細胞生物学

研究活動情報

論文

  • Akira Hirota, Shaikha AlMusawi, Abdolrahman S. Nateri, Paloma Ordóñez-Morán, Masamichi Imajo
    Acta Biomaterialia 2021年09月 [査読有り]
  • 池口 絵理, 原田 範雄, 金丸 良徳, 三小田 亜希子, 山根 俊介, 岩崎 可南子, 今城 正道, 村田 由貴, 鈴木 和代, 城尾 恵里奈, 稲垣 暢也
    日本内分泌学会雑誌 95 1 471 - 471 (一社)日本内分泌学会 2019年04月
  • Yu Muta, Michiyuki Matsuda, Masamichi Imajo, corresponding author
    Cancers 11 4 513  2019年04月 [査読有り][通常論文]
  • Yu Muta, Michiyuki Matsuda, Masamichi Imajo, corresponding author
    Molecular & Cellular Oncology 5 5 e1506684  Informa {UK} Limited 2018年09月 [査読有り][通常論文]
  • Eri Ikeguchi, Norio Harada, Yoshinori Kanemaru, Akiko Sankoda, Shunsuke Yamane, Kanako Iwasaki, Masamichi Imajo, Yuki Murata, Kazuyo Suzuki, Erina Joo, Nobuya Inagaki
    American Journal of Physiology - Gastrointestinal and Liver Physiology 315 2 G272 - G282 2018年08月09日 [査読有り][通常論文]
     
    © 2018 American Physiological Society. All rights reserved. Fat accumulation with aging is a serious problem; glucosedependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) is an incretin that plays an important role in fat accumulation. GIP receptor knockout mice show reduced fat mass and improved insulin sensitivity associated with aging. Therefore, GIP is involved in fat accumulation and insulin resistance with aging. However, agerelated changes of GIP secretion remain unclear. The present study aimed to elucidate age-related changes of GIP secretion and enteroendocrine K cells using GIP reporter [GIP-green fluorescent protein (GFP) knock-in heterozygous (GIPgfp/+)] mice. Aged 1-yr-old GIPgfp/+ mice exhibited a phenotype of fat accumulation, insulin resistance, and GIP hypersecretion compared with young (3–4 mo old) GIPgfp/+ mice. In aged mice, K-cell number in the small intestine and the mRNA expression levels of GIP and transcriptional factor pancreatic and duodenal homeobox-1 (Pdx1) in K cells were increased. K-cell number, GIP mRNA expression and content in small intestine, and GIP secretion were decreased after posteriori suppression of Pdx1 using intestine-specific gene transfer. Thus, Pdx1 positively regulates GIP mRNA and K-cell number in small intestine. Increased Pdx1 expression might be involved in GIP hypersecretion with aging. NEW & NOTEWORTHY Age-related changes of glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) secretion and K cells were investigated. We found that K-cell number and GIP and pancreatic and duodenal homeobox-1 (Pdx1) expression in K cells were increased in aged mice, which showed greater GIP secretion compared with young mice. In addition, we have succeeded in posteriori suppression of Pdx1 in small intestine using the method of intestine-specific gene transfer, and showed that K-cell number, GIP expression, and GIP secretion were decreased in the Pdx1-knockdown intestine.
  • Composite regulation of ERK activity dynamics underlying tumour-specific traits in the intestine
    Yu Muta, Yoshihisa Fujita, Kenta Sumiyama, Atsuro Sakurai, Makoto M. Taketo, Tsutomu Chiba, Hiroshi Seno, Kazuhiro Aoki, Michiyuki Matsuda, Masamichi Imajo, corresponding author
    Nature Communications 9 1 2174 - 2174 2018年06月 [査読有り][通常論文]
  • 転写因子Pdx1は小腸内のGIP遺伝子を正に制御して加齢に伴うGIP分泌亢進に関与する
    池口 絵理, 原田 範雄, 金丸 良徳, 三小田 亜希子, 山根 俊介, 岩崎 可南子, 今城 正道, 村田 由貴, 鈴木 和代, 城尾 恵里奈, 稲垣 暢也
    糖尿病 61 Suppl.1 S - 134 (一社)日本糖尿病学会 2018年04月
  • Yumi Konagaya, Kenta Terai, Yusuke Hirao, Kanako Takakura, Masamichi Imajo, Yuji Kamioka, Norio Sasaoka, Akira Kakizuka, Kenta Sumiyama, Tomoichiro Asano, Michiyuki Matsuda
    CELL REPORTS 21 9 2628 - 2638 2017年11月 [査読有り][通常論文]
     
    AMP-activated protein kinase (AMPK), a master regulator of cellular metabolism, is a potential target for type 2 diabetes. Although extensive in vitro studies have revealed the complex regulation of AMPK, much remains unknown about the regulation in vivo. We therefore developed transgenic mice expressing a highly sensitive fluorescence resonance energy transfer (FRET)-based biosensor for AMPK, called AMPKAR-EV. AMPKAR-EV allowed us to readily examine the role of LKB1, a canonical stimulator of AMPK, in drug-induced activation and inactivation of AMPK in vitro. In transgenic mice expressing AMPKAR-EV, the AMP analog AICAR activated AMPK in muscle. In contrast, the antidiabetic drug metformin activated AMPK in liver, highlighting the organ-specific action of AMPK stimulators. Moreover, we found that AMPK was activated primarily in fast-twitch muscle fibers after tetanic contraction and exercise. These observations suggest that the AMPKAR-EV mouse will pave a way to understanding the heterogeneous responses of AMPK among cell types in vivo.
  • Antagonistic Interactions between Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and Retinoic Acid Receptor Signaling in Colorectal Cancer Cells
    Masamichi Imajo, Kunio Kondoh, Takuya Yamamoto, Kei Nakayama, May Nakajima-Koyama, Eisuke Nishida, corresponding author
    Molecular and Cellular Biology 37 15 e00012-17  2017年07月 [査読有り][通常論文]
  • Takuya Hiratsuka, Takeshi Sano, Hisashi Kato, Naoki Komatsu, Masamichi Imajo, Yuji Kamioka, Kenta Sumiyama, Fumiaki Banno, Toshiyuki Miyata, Michiyuki Matsuda
    Journal of Thrombosis and Haemostasis 15 7 1487 - 1499 2017年07月 [査読有り][通常論文]
     
    Background: The dynamic features of thrombus formation have been visualized by conventional video widefield microscopy or confocal microscopy in live mice. However, owing to technical limitations, the precise spatiotemporal regulation of intracellular signaling molecule activities, which have been extensively studied in vitro, remains elusive in vivo. Objectives: To visualize, by the use of two-photon excitation microscopy of transgenic mice expressing Forster resonance energy transfer (FRET) biosensors for extracellular signal-regulated kinase (ERK) and protein kinase A (PKA), ERK and PKA activities during thrombus formation in laser-injured subcutaneous arterioles. Results: When a core of densely packed platelets had developed, ERK activity was increased from the basal region close to the injured arterioles. PKA was activated at the downstream side of an unstable shell overlaying the core of platelets. Intravenous administration of a MEK inhibitor, PD0325901, suppressed platelet tethering and dislodged platelet aggregates, indicating that ERK activity is indispensable for both initiation and maintenance of the thrombus. A cAMP analog, dbcAMP, inhibited platelet tethering but failed to dislodge the preformed platelet aggregates, suggesting that PKA can antagonize thrombus formation only in the early phase. Conclusion: In vivo imaging of transgenic mice expressing FRET biosensors will open a new opportunity to visualize the spatiotemporal changes in signaling molecule activities not only during thrombus formation but also in other hematologic disorders.
  • Shunsuke Kon, Kojiro Ishibashi, Hiroto Katoh, Sho Kitamoto, Takanobu Shirai, Shinya Tanaka, Mihoko Kajita, Susumu Ishikawa, Hajime Yamauchi, Yuta Yako, Tomoko Kamasaki, Tomohiro Matsumoto, Hirotaka Watanabe, Riku Egami, Ayana Sasaki, Atsuko Nishikawa, Ikumi Kameda, Takeshi Maruyama, Rika Narumi, Tomoko Morita, Yoshiteru Sasaki, Ryosuke Enoki, Sato Honma, Hiromi Imamura, Masanobu Oshima, Tomoyoshi Soga, Jun-ichi Miyazaki, Michael R. Duchen, Jin-Min Nam, Yasuhito Onodera, Shingo Yoshioka, Junichi Kikuta, Masaru Ishii, Masamichi Imajo, Eisuke Nishida, Yoichiro Fujioka, Yusuke Ohba, Toshiro Sato, Yasuyuki Fujita
    NATURE CELL BIOLOGY 19 5 530 - + 2017年05月 [査読有り][通常論文]
     
    Recent studies have revealed that newly emerging transformed cells are often apically extruded from epithelial tissues. During this process, normal epithelial cells can recognize and actively eliminate transformed cells, a process called epithelial defence against cancer (EDAC). Here, we show that mitochondrial membrane potential is diminished in RasV12-transformed cells when they are surrounded by normal cells. In addition, glucose uptake is elevated, leading to higher lactate production. The mitochondrial dysfunction is driven by upregulation of pyruvate dehydrogenase kinase 4 (PDK4), which positively regulates elimination of RasV12-transformed cells. Furthermore, EDAC from the surrounding normal cells, involving filamin, drives the Warburg-effect-like metabolic alteration. Moreover, using a cell-competition mouse model, we demonstrate that PDK-mediated metabolic changes promote the elimination of RasV12-transformed cells from intestinal epithelia. These data indicate that non-cell-autonomous metabolic modulation is a crucial regulator for cell competition, shedding light on the unexplored events at the initial stage of carcinogenesis.
  • Yoshihisa Okuchi, Masamichi Imajo, Rei Mizuno, Yuji Kamioka, Hiroyuki Miyoshi, Makoto Mark Taketo, Satoshi Nagayama, Yoshiharu Sakai, Michiyuki Matsuda
    PLOS ONE 11 9 2016年09月 [査読有り][通常論文]
     
    Aging-associated alterations of cellular functions have been implicated in various disorders including cancers. Due to difficulties in identifying aging cells in living tissues, most studies have focused on aging-associated changes in whole tissues or certain cell pools. Thus, it remains unclear what kinds of alterations accumulate in each cell during aging. While analyzing several mouse lines expressing fluorescent proteins (FPs), we found that expression of FPs is gradually silenced in the intestinal epithelium during aging in units of single crypt composed of clonal stem cell progeny. The cells with low FP expression retained the wildtype Apc allele and the tissues composed of them did not exhibit any histological abnormality. Notably, the silencing of FPs was also observed in intestinal adenomas and the surrounding normal mucosae of Apc-mutant mice, and mediated by DNA methylation of the upstream promoter. Our genome-wide analysis then showed that the silencing of FPs reflects specific gene expression alterations during aging, and that these alterations occur in not only mouse adenomas but also human sporadic and hereditary (familial adenomatous polyposis) adenomas. Importantly, pharmacological inhibition of DNA methylation, which suppresses adenoma development in Apc-mutant mice, reverted the aging-associated silencing of FPs and gene expression alterations. These results identify aging-associated gene expression signatures that are heterogeneously induced by DNA methylation and precede intestinal tumorigenesis triggered by Apc inactivation, and suggest that pharmacological inhibition of the signature genes could be a novel strategy for the prevention and treatment of intestinal tumors.
  • Paloma Ordonez-Moran, Caroline Dafflon, Masamichi Imajo, Eisuke Nishida, Joerg Huelsken
    CANCER CELL 28 6 815 - 829 2015年12月 [査読有り][通常論文]
     
    Hierarchical organization of tissues relies on stem cells, which either self-renew or produce committed progenitors predestined for lineage differentiation. Here we identify HOXA5 as an important repressor of intestinal stem cell fate in vivo and identify a reciprocal feedback between HOXA5 and Wnt signaling. HOXA5 is suppressed by the Wnt pathway to maintain stemness and becomes active only outside the intestinal crypt where it inhibits Wnt signaling to enforce differentiation. In colon cancer, HOXA5 is downregulated, and its re-expression induces loss of the cancer stem cell phenotype, preventing tumor progression and metastasis. Tumor regression by HOXA5 induction can be triggered by retinoids, which represent tangible means to treat colon cancer by eliminating cancer stem cells.
  • Masamichi Imajo, Miki Ebisuya, Eisuke Nishida
    NATURE CELL BIOLOGY 17 1 7 - + 2015年01月 [査読有り][通常論文]
     
    The rapidly self-renewing intestinal epithelium represents an exquisite model for stem cell biology. So far, genetic studies in mice have uncovered crucial roles for several signalling pathways in the tissue. Here we show, by using intestine-specific gene transfer (iGT), that Hippo signalling effectors, YAP and TAZ, promote both the proliferation of intestinal stem/progenitor cells and their differentiation into goblet cells. These functions of YAP/TAZ are regulated by the upstream Hippo pathway kinases MST1/2 and LATS1/2. Moreover, we identify TEADs and Klf4 as partner transcription factors of YAP/TAZ in the proliferation and differentiation processes, respectively. These results indicate that Hippo signalling plays a dual role in renewal of the intestinal epithelium through the regulation of two different processes, stem/progenitor cell proliferation and differentiation into goblet cells, using two different types of transcription factor. Moreover, iGT should provide a robust platform to elucidate molecular mechanisms of intestinal epithelium self-renewal.
  • HVJ-E-mediated gene transfer into the intestinal epithelium
    M. Imajo, M. Ebisuya, E. Nishida
    Protocol Exchange doi: 10.1038/protex.2014.049 2014年12月 [査読無し][通常論文]
  • Rei Mizuno, Yuji Kamioka, Kenji Kabashima, Masamichi Imajo, Kenta Sumiyama, Eiji Nakasho, Takeshi Ito, Yoko Hamazaki, Yoshihisa Okuchi, Yoshiharu Sakai, Etsuko Kiyokawa, Michiyuki Matsuda
    JOURNAL OF EXPERIMENTAL MEDICINE 211 6 1123 - 1136 2014年06月 [査読有り][通常論文]
     
    Many chemical mediators regulate neutrophil recruitment to inflammatory sites. Although the actions of each chemical mediator have been demonstrated with neutrophils in vitro, how such chemical mediators act cooperatively or counteractively in vivo remains largely unknown. Here, by in vivo two-photon excitation microscopy with transgenic mice expressing biosensors based on Frster resonance energy transfer, we time-lapse-imaged the activities of extracellular signal-regulated kinase (ERK) and protein kinase A (PKA) in neutrophils in inflamed intestinal tissue. ERK activity in neutrophils rapidly increased during spreading on the endothelial cells and showed positive correlation with the migration velocity on endothelial cells or in interstitial tissue. Meanwhile, in the neutrophils migrating in the interstitial tissue, high PKA activity correlated negatively with migration velocity. In contradiction to previous in vitro studies that showed ERK activation by prostaglandin E-2 (PGE(2)) engagement with prostaglandin receptor EP4, intravenous administration of EP4 agonist activated PKA, inhibited ERK, and suppressed migration of neutrophils. The opposite results were obtained using nonsteroidal antiinflammatory drugs (NSAIDs). Therefore, NSAID-induced enteritis may be caused at least partially by the inhibition of EP4 receptor signaling of neutrophils. Our results demonstrate that ERK positively regulates the neutrophil recruitment cascade by promoting adhesion and migration steps.
  • M. Imajo, K. Miyatake, A. Iimura, A. Miyamoto, E. Nishida
    The EMBO Journal 31 5 1109 - 1122 2012年03月 [査読有り][通常論文]
     
    The Hippo signalling pathway has emerged as a key regulator of organ size, tissue homeostasis, and patterning. Recent studies have shown that two effectors in this pathway, YAP/TAZ, modulate Wnt/beta-catenin signalling through their interaction with beta-catenin or Dishevelled, depending on biological contexts. Here, we identify a novel mechanism through which Hippo signalling inhibits Wnt/beta-catenin signalling. We show that YAP and TAZ, the transcriptional co-activators in the Hippo pathway, suppress Wnt signalling without suppressing the stability of beta-catenin but through preventing its nuclear translocation. Our results show that YAP/TAZ binds to beta-catenin, thereby suppressing Wnt-target gene expression, and that the Hippo pathway-stimulated phosphorylation of YAP, which induces cytoplasmic translocation of YAP, is required for the YAP-mediated inhibition of Wnt/beta-catenin signalling. We also find that downregulation of Hippo signalling correlates with upregulation of beta-catenin signalling in colorectal cancers. Remarkably, our analysis demonstrates that phosphorylated YAP suppresses nuclear translocation of beta-catenin by directly binding to it in the cytoplasm. These results provide a novel mechanism, in which Hippo signalling antagonizes Wnt signalling by regulating nuclear translocation of b-catenin. The EMBO Journal ( 2012) 31, 1109-1122. doi: 10.1038/emboj.2011.487; Published online 10 January 2012
  • Masamichi Imajo, Eisuke Nishida
    GENES TO CELLS 15 10 1089 - 1097 2010年10月 [査読有り][通常論文]
     
    Tribbles encode an evolutionarily conserved protein family that regulates cell proliferation, motility, metabolism and oncogenic transformation. Emerging evidence suggests that Tribbles function as adaptor or scaffold proteins to facilitate the degradation of their target proteins and to control the activation of various key signaling pathways. In this study, we uncover a novel function of human Tribbles homolog 1 (Trib1) as a regulator of retinoic acid receptor (RAR) signaling. We show that shRNA-mediated knockdown of Trib1 promotes transcriptional activity of RARs, leading to enhanced expression of endogenous RAR-target genes. Moreover, our results show that Trib1 directly interacts with RAR alpha and retinoid X receptor-alpha (RXR alpha) through its kinase-like domain. Consistently, Trib1 colocalizes with RAR alpha and RXR alpha in the nucleus. Biochemical analyses show that the ligand-binding domain (LBD) of RAR alpha mediates the interaction with Trib1. Ligand treatment, however, does not affect the binding of Trib1 to RAR alpha/RXR alpha. Furthermore, a putative LXXLL motif, which is a potential LBD-binding site and locates in the kinase-like domain of Trib1, is not required for the binding. These results suggest a unique feature of the binding. Taken together, these results suggest that Trib1 functions as a negative regulator of RARs and shed new light on the molecular mechanisms for nuclear receptor-mediated transcriptional repression.
  • M Imajo, Y Tsuchiya, E Nishida
    IUBMB LIFE 58 5-6 312 - 317 2006年05月 [査読有り][通常論文]
     
    Mitogen-activated protein kinase (MAPK) pathways play central roles in controlling diverse cellular functions. They are finely regulated by several mechanisms, including scaffolding of their components, and phosphorylation/dephosphorylation and compartmentalization of MAPKs. A number of molecules have been identified as regulators involved in these mechanisms. They modulate the magnitude and the specificity of MAPK signaling, and thereby regulate the wide variety of signaling outputs. Recent studies have identified novel functions of the MAPK signaling pathways. It is becoming clear that strict regulation of the MAPK pathways underlies their manifold functions in numerous biological processes.

書籍

  • 実験医学 Vol.33 No.18 (11月号) 2015
    今城 正道, 西田栄介 (担当:分担執筆範囲:腸上皮恒常性におけるHippoシグナル伝達経路の役割)
    羊土社 2015年11月
  • 「生体の科学」66巻5号
    今城 正道 (担当:分担執筆範囲:26. Wntシグナル)
    公益財団法人金原一郎記念医学医療振興財団「生体の科学」編集室 2015年

講演・口頭発表等

  • 新規オルガノイド培養法を用いた肝芽腫発生機構の解析  [通常講演]
    今城 正道, 松田 道行
    第68回細胞生物学会大会 2016年06月
  • 腸上皮の幹細胞依存的な更新におけるHippo経路の役割  [招待講演]
    今城 正道, 西田栄介
    第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会 2015年12月 口頭発表(招待・特別)
  • 組織幹細胞の制御におけるHippo経路の新たな役割  [招待講演]
    今城 正道
    第8回Symphony 2015年09月 口頭発表(招待・特別)
  • 生体内遺伝子導入法により解明された腸上皮幹細胞機能の新たな制御機構  [招待講演]
    今城 正道, 西田栄介
    第66回日本細胞生物学会大会 2014年06月 口頭発表(招待・特別) 奈良県新公会堂 日本細胞生物学会
  • 腸上皮ホメオスタシスを制御するシグナル伝達ネットワークの解析  [招待講演]
    今城正道, 西田栄介
    第84回日本生化学会大会 2011年09月 口頭発表(招待・特別) 日本生化学会

その他活動・業績

教育活動情報

主要な担当授業

  • ソフトマター医工学特論
    開講年度 : 2020年
    課程区分 : 修士課程
    開講学部 : 生命科学院
    キーワード : 基礎医学、再生医学、バイオマテリアル、がん生物学


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