ストレス応答性転写因子による代謝・病態制御

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24249015
• Research Institution: Tohoku University
• Principal Investigator: 山本 雅之 東北大学, 医学(系)研究科(研究院), 教授 (50166823)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 酸化ストレス / 転写制御 / 炎症

Outline of Annual Research Achievements

環境中の毒性物質や活性酸素種は、癌などの各種疾患の発症に寄与していると考えられている。生体は、これらストレスに対する防衛機構を備えて、遺伝子の発現レベルで厳密に制御されている。本研究では、ストレス応答転写制御を中心とした細胞内ネットワークを新たな概念として提唱し、その全容解明を試みている。
本年度は最終年度にあたり、研究期間中に樹立したマウスの解析において集大成となる成果を得た。とくに、ストレス応答転写因子Nrf2がマクロファージ系細胞では一部の遺伝子発現を強力に抑制することに気づき、その分子メカニズムの一端を明らかにした。この成果は、酸化ストレス応答のマスター制御因子としてよく知られているNrf2の新たな性質を示しただけでなく、がんや動脈硬化など、炎症が関与する多くの疾患の分子病態を明らかにしたものである。また、造血幹細胞や骨髄球におけるNrf2の役割について、遺伝子改変マウスを用いた解析を行い、Nrf2の造血細胞における役割を明らかにした。さらに、低酸素応答のマスター制御因子HIFによる腎臓からの造血因子エリスロポエチンの産生機序を明らかにした。腎臓病はエリスロポエチン産生能を低下させるが、本研究の成果により、HIFを強制的に活性化することが貧血治療に有効であることが示された。その他、低酸素応答システムを利用した創薬スクリーニング系の確立やDNAメチル化酵素による破骨細胞分化のメカニズム解明についても成果を得た。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Activation of the NRF2 pathway and its impact on the prognosis of anaplastic glioma patients (2015)
  • Author(s): Kanamori M, Higa T, Sonoda Y, Murakami S, Dodo M, Kitamura H, Taguchi K, Shibata T, Watanabe M, Suzuki H, Shibahara I, Saito R, Yamashita Y, Kumabe T, Yamamoto M, Motohashi H, and Tominaga T.
  • Journal Title: Neuro Oncol Volume: 17 Pages: 555-565
  • DOI: 10.1093/neuonc/nou282
  • Peer Reviewed
• [Journal Article] Identification of a functional antioxidant response element within the eighth intron of the human ABCC3 gene (2015)
  • Author(s): Canet MJ, Merrell MD, Harder BG, Maher JM, Wu T, Lickteig AJ, Jackson JP, Zhang DD, Yamamoto M, and Cherrington NJ.
  • Journal Title: Drug Metab Dispos. Volume: 43 Pages: 93-99
  • DOI: 10.1124/dmd.114.060103
  • Peer Reviewed
• [Journal Article] Progenitor stage-specific activity of a cis-acting double GATA motif for Gata1 gene expression (2015)
  • Author(s): Moriguchi T, Suzuki M, Yu L, Takai J, Ohneda K, and Yamamoto M. “
  • Journal Title: Mol Cell Biol Volume: 35 Pages: 805-815
  • DOI: 10.1128/MCB.01011-14)
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] MAFG Is a Transcriptional Repressor of Bile Acid Synthesis and Metabolism (2015)
  • Author(s): de Aguiar Vallim TQ, Tarling EJ, Ahn H, Hagey LR, Romanoski CE, Lee RG, Graham MJ, Motohashi H, Yamamoto M, and Edwards PA.
  • Journal Title: Cell Metab Volume: 21 Pages: 298-310
  • DOI: 10.1016/j.cmet.2015.01.007
• [Journal Article] DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway (2015)
  • Author(s): Nishikawa K, Iwamoto Y, Kobayashi Y, Katsuoka F, Kawaguchi S, Tsujita T, Nakamura T, Kato S, Yamamoto M, Takayanagi H, and Ishii M.
  • Journal Title: Nat Med Volume: 21 Pages: 281-287
  • DOI: 10.1038/nm.3774
  • Peer Reviewed
• [Journal Article] Hypoxia-sensitive reporter system for high-throughput screening (2015)
  • Author(s): Tsujita T, Kawaguchi S, Dan T, Baird L, Miyata T, and Yamamoto M.
  • Journal Title: Tohoku J Exp Med Volume: 235 Pages: 151-159
  • DOI: 10.1620/tjem.235.151
• [Journal Article] In vivo regulation of erythropoiesis by chemically inducible dimerization of the erythropoietin receptor intracellular domain (2015)
  • Author(s): Suzuki N, Mukai HY, and Yamamoto M.
  • Journal Title: PLoS One Volume: 10 Pages: e0119442
  • DOI: 10.1371/journal.pone.0119442
  • Peer Reviewed / Open Access
• [Journal Article] Nrf2 enhances cholangiocyte expansion in Pten-deficient livers. (2014)
  • Author(s): Taguchi K, Hirano I, Itoh T, Tanaka M, Miyajima A, Suzuki A, Motohashi H, and Yamamoto M. “
  • Journal Title: Mol Cell Biol Volume: 34 Pages: 900-913
  • DOI: 10.1128/MCB.01384-13
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Kinetic, Thermodynamic and Structural Characterizations of Association between Nrf2-DLGex Degron and Keap1. (2014)
  • Author(s): Fukutomi T, Takagi K, Mizushima T, Ohuchi N, and Yamamoto M.
  • Journal Title: Mol Cell Biol Volume: 34 Pages: 832-846
  • DOI: 10.1128/MCB.01191-13
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Possible involvementof nuclear factor erythroid 2-related factor 2 in the gene expression of Cyp2b10and Cyp2a5 (2014)
  • Author(s): Ashino T, Ohkubo-Morita H, Yamamoto M, Yoshida T, and Numazawa S.
  • Journal Title: Redox Biology Volume: 10 Pages: 284-288
  • DOI: 10.1016/j.redox.2013.12.025
  • Peer Reviewed
• [Journal Article] Keap1-Nrf2 system regulates cell fate determination of hematopoietic stem cells. (2014)
  • Author(s): Murakami S, Shimizu R, Romeo P-H, Yamamoto M*, and Motohashi H
  • Journal Title: Genes Cells Volume: 19 Pages: 239-253
  • DOI: 10.1111/gtc.12126
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] NRF2 immunolocalization in human breast cancer patients as a prognostic factor. (2014)
  • Author(s): Onodera Y, Motohashi H, Takagi K, Miki Y, Shibahara Y, Watanabe M, Ishida T, Hirakawa H, Sasano H, Yamamoto M, and Suzuki T.
  • Journal Title: Endocr Relat Cancer Volume: 21 Pages: 241-252
  • DOI: 10.1530/ERC-13-0234
  • Peer Reviewed
• [Journal Article] Notch-Nrf2 axis: Regulation of Nrf2 gene expression and cytoprotection by Notch signaling. (2014)
  • Author(s): Wakabayashi N, Skoko JJ, Chartoumpekis DV, Kimura S, Slocum SL, Noda K, Palliyaguru DL, Fujimuro M, Boley PA, Tanaka Y, Shigemura N, Biswal S, Yamamoto M, and Kensler TW.
  • Journal Title: Mol Cell Biol 34, Volume: 34 Pages: 653-663
  • DOI: 10.1128/MCB.01408-13
  • Peer Reviewed
• [Journal Article] Hematopoietic stem and progenitor cell activation during chronic dermatitis provoked by constitutively active aryl-hydrocarbon receptor driven by Keratin 14 promoter (2014)
  • Author(s): Murakami S, Yamamoto M, and Motohashi H.
  • Journal Title: Toxicol Sci Volume: 138 Pages: 47-58
  • DOI: 10.1093/toxsci/kft273
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Nrf2 protects pancreatic β-cells from oxidative and nitrosative stress in diabetic model mice (2014)
  • Author(s): Yagishita Y, Fukutomi T, Sugawara A, Kawamura H, Takahashi T, Pi J, Uruno A, and Yamamoto M.
  • Journal Title: Diabetes Volume: 63 Pages: 605-618
  • DOI: 10.2337/db13-0909
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Does Nrf2 gene transfer facilitate recovery after contusion spinal cord injury?” (2014)
  • Author(s): Pomeshchik Y, Kidin I, Savchenko E, Rolova T, Yamamoto M, Levonen AL, Ylä-Herttuala S, Kanninen K, Malm T, and Koistinaho J.
  • Journal Title: Antioxid Redox Signal Volume: 20 Pages: 1313-1323
  • DOI: 10.1089/ars.2013.5453
  • Peer Reviewed
• [Journal Article] Critical role of Nrf2 in oxidative stress-induced retinal ganglion cell death (2014)
  • Author(s): Himori N, Yamamoto K, Maruyama K, Ryu M, Taguchi K, Yamamoto M, and Nakazawa T. “
  • Journal Title: J Neurochem Volume: 127 Pages: 669-680
  • DOI: 10.1111/jnc.12325
  • Peer Reviewed
• [Journal Article] Nrf2 promotes compensatory liver hypertrophy after portal vein branch ligation in mice (2014)
  • Author(s): Shirasaki K, Taguchi K, Unno M, Motohashi H, and Yamamoto M.
  • Journal Title: Hepatology Volume: 59 Pages: 2371-2382
  • DOI: 10.1002/hep.27020
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Keap1 inhibition attenuates glomerulosclerosis (2014)
  • Author(s): Miyazaki Y, Shimizu A, Pastan I, Taguchi K, Naganuma E, Suzuki T, Hosoya T, Yokoo T, Saito A, Miyata T, Yamamoto M, and Matsusaka T.
  • Journal Title: Nephrol Dial Transplant Volume: 29 Pages: 783-791
  • DOI: 10.1093/ndt/gfu002
  • Peer Reviewed
• [Journal Article] The circadian clock regulates the NRF2/ARE-mediated antioxidant defence pathway in the mouse lung. (2014)
  • Author(s): Pekovic-Vaughan V, Gibbs J, Yoshitane H, Yang N, Pathiranage D, Guo B, Sagami A, Taguchi K, Bechtold D, Loudon A, Yamamoto M, Chan J, van der Horst GTJ, Fukada Y, and Meng Q-J.
  • Journal Title: Genes Dev Volume: 28 Pages: 548-560
  • DOI: 10.1101/gad.237081.113
  • Peer Reviewed
• [Journal Article] A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression (2014)
  • Author(s): Yamazaki H, Suzuki M, Otsuki A, Shimizu R, Bresnick EH, Engel JD, and Yamamoto M.
  • Journal Title: Cancer Cell Volume: 25 Pages: 415-427
  • DOI: 10.1016/j.ccr.2014.02.008
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Nrf2 enhances myocardial clearance of toxic ubiquitinated proteins. (2014)
  • Author(s): Wang W, Li S, Wang H, Li B, Shao L, Lai Y, Horvath G, Wang Q, Yamamoto M, Janicki JS, Wang XL, Tang D, and Cui T.
  • Journal Title: J Mol Cell Cardiol 72, Volume: 72 Pages: 305-315
  • DOI: 10.1016/j.yjmcc
  • Peer Reviewed
• [Journal Article] Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis (2014)
  • Author(s): Cazanave SC, Wang X, Zhou H, Rahmani M, Grant S, Durrant DE, Klaassen CD, Yamamoto M, and Sanyal AJ.
  • Journal Title: Cell Death Differ Volume: 21 Pages: 1303-1312
  • DOI: 10.1038/cdd
  • Peer Reviewed
• [Journal Article] Isocitrate dehydrogenase mutation is frequently observed in giant cell tumor of bone (2014)
  • Author(s): Kato-Kaneko M, Liu X, Oki H, Ogasawara S, Nakamura T, Saidoh N, Tsujimoto Y, Matsuyama Y, Uruno A, Sugawara M, Tsuchiya T, Yamakawa M, Yamamoto M, Takagi M, Kato Y.
  • Journal Title: Cancer Sci Volume: 105 Pages: 744-748
  • DOI: 10.1111/cas.12413
  • Peer Reviewed
• [Journal Article] Myeloid lineage-specific deletion of antioxidant system enhances tumor metastasis (2014)
  • Author(s): Hiramoto K, Satoh H, Suzuki T, Moriguchi T, Pi J, Shimosegawa T, and Yamamoto M.
  • Journal Title: Cancer Prev Res (Phila) Volume: 7 Pages: 835-844
  • DOI: 10.1158/1940-6207
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Transcription factor NF-E2-related factor 1 impairs glucose metabolism in mice (2014)
  • Author(s): Hirotsu Y, Higashi C, Fukutomi T, Katsuoka F, Tsujita T, Yagishita Y, Matsuyama Y, Motohashi H, Uruno A, and Yamamoto M.
  • Journal Title: Genes Cells Volume: 19 Pages: 650-665
  • DOI: 10.1111/gtc.12165
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Proteasome dysfunction activates autophagy and the Keap1-Nrf2 pathway (2014)
  • Author(s): Kageyama S, Sou YS, Uemura T, Kametaka S, Saito T, Ishimura R, Kouno T, Bedford L, Mayer RJ, Lee MS, Yamamoto M, Waguri S, Tanaka K, and Komatsu M.
  • Journal Title: J Biol Chem Volume: 289 Pages: 24944-24955
  • DOI: 10.1074/jbc.M114.580357
  • Peer Reviewed
• [Journal Article] Transcription factor Nrf1 negatively regulates the cystine/glutamate transporter and lipid-metabolizing enzymes (2014)
  • Author(s): Tsujita T, Peirce V, Baird L, Matsuyama Y, Takaku M, Walsh SV, Griffin JL, Uruno A, Yamamoto M, and Hayes JD.
  • Journal Title: Mol Cell Biol Volume: 34 Pages: 3800-3816
  • DOI: 10.1128/MCB.00110-14
  • Peer Reviewed
• [Journal Article] Validation of multiple single nucleotide variation calls by additional exome analysis with a semiconductor sequencer to supplement data of whole-genome sequencing of a human population (2014)
  • Author(s): Motoike IN, Matsumoto M, Danjoh I, Katsuoka F, Kojima K, Nariai N, Sato Y, Yamaguchi-Kabata Y, Ito S, Kudo H, Nishijima I, Nishikawa S, Pan X, Saito R, Saito S, Saito T, Shirota M, Tsuda K, Yokozawa J, Igarashi K, Minegishi N, Tanabe O, Fuse N, Nagasaki M, Kinoshita K, Yasuda J, and Yamamoto M.
  • Journal Title: BMC Genomics Volume: 10 Pages: 637
  • DOI: 10.1186/1471-2164-15-673
  • Peer Reviewed
• [Journal Article] PGC-1 Coactivator Activity is Required for Murine Erythropoiesis (2014)
  • Author(s): Cui S, Tanabe O, Lim K-C, Xu HE, Zhou XE, Lin JD, Shi L, Shimizu R, Schmidt L, Campbell A, Yamamoto M, and Engel JD,
  • Journal Title: Mol Cell Biol Volume: 34 Pages: 1956-1965
  • DOI: 10.1128/MCB.00247-14
  • Peer Reviewed
• [Journal Article] GATA2 regulates differentiation of bone marrow-derived mesenchymal stem cells (2014)
  • Author(s): Kamata M, Okitsu Y, Fujiwara T, Kanehira M, Nakajima S, Takahashi T, Inoue A, Fukuhara N, Onishi Y, Ishizawa K, Shimizu R, Yamamoto M, and Harigae H.
  • Journal Title: Haematologica Volume: 11 Pages: 1686-1696
  • DOI: 10.3324/haematol
  • Peer Reviewed
• [Journal Article] Nuclear factor erythroid 2-related factor 2 regulates toll-like receptor 4 innate responses in mouse liver ischemia-reperfusion injury through Akt-forkhead box protein O1 signaling network. (2014)
  • Author(s): Huang J, Yue S, Ke B, Zhu J, Shen XD, Zhai Y, Yamamoto M, Busuttil RW, and Kupiec-Weglinski JW.
  • Journal Title: Transplantation Volume: 98 Pages: 721-728
  • DOI: 10.1097/TP.0000000000000316
  • Peer Reviewed
• [Journal Article] An efficient quantitation method of next-generation sequencing libraries by using MiSeq sequencer. (2014)
  • Author(s): Katsuoka F, Yokozawa J, Tsuda K, Ito S, Pan X, Nagasaki M, Yasuda J, and Yamamoto M.
  • Journal Title: Anal Biochem Volume: 466 Pages: 27-29
  • DOI: 10.1016/j.ab.2014.08.015
• [Journal Article] Nrf2 induces fibroblast growth factor 21 in diabetic mice (2014)
  • Author(s): Furusawa Y, Uruno A, Yagishita Y, Higashi C, and Yamamoto M.
  • Journal Title: Genes Cells Volume: 19 Pages: 864-878
  • DOI: 10.1111/gtc.12186
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] エリスロポエチン産生細胞とエリスロポエチン遺伝子の発現制御機構 (2014)
  • Author(s): 山本雅之
  • Organizer: 日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪）
  • Year and Date: 2014-11-02 – 2014-11-02
  • Invited
• [Presentation] 酸素と医学 (2014)
  • Author(s): 山本雅之
  • Organizer: レドックスシンポジウム
  • Place of Presentation: 名古屋大学（名古屋）
  • Year and Date: 2014-10-11 – 2014-10-11
  • Invited
• [Presentation] Keap1-Nrf2制御系と発がん (2014)
  • Author(s): 山本雅之
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-09-27 – 2014-09-27
  • Invited
• [Presentation] 9.山本雅之、エリスロポエチン産生細胞と腎疾患、 (2014)
  • Author(s): 山本雅之
  • Organizer: 第45回新潟腎カンファランス
  • Place of Presentation: 新潟大学（新潟）
  • Year and Date: 2014-09-25 – 2014-09-25
  • Invited
• [Presentation] Erythropoietin production in neural and neural crest cells during primitive erythropoiesis (2014)
  • Author(s): Masayuki Yamamoto.
  • Organizer: 19th Hemoglobin Switching Conference
  • Place of Presentation: Oxford, UK
  • Year and Date: 2014-09-05 – 2014-09-05
  • Invited
• [Presentation] Keap1-Nrf2システムと肝臓・糖尿病 (2014)
  • Author(s): 山本雅之
  • Organizer: 第1回肝臓と糖尿病・代謝研究会
  • Place of Presentation: 東京大学（東京）
  • Year and Date: 2014-07-04 – 2014-07-04
  • Invited
• [Presentation] 腎臓EPO産生細胞を巡る最近の話題 (2014)
  • Author(s): 山本雅之
  • Organizer: 第59回日本透析医学会学術集会・総会
  • Place of Presentation: ポートピアホテル（神戸）
  • Year and Date: 2014-06-13 – 2014-06-13
  • Invited
• [Presentation] Renal erythropoietin producing cells for anemia and fibrosis (2014)
  • Author(s): Masayuki Yamamoto
  • Organizer: ISN( International Society of Nephrology ) Nexus Symposium
  • Place of Presentation: Bergamo, Italy
  • Year and Date: 2014-04-05 – 2014-04-06
  • Invited