Analysis of novel oxidative stress response mechanism via ribosome

• Project/Area Number: 25293064
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Hirosaki University
• Principal Investigator: Itoh Ken 弘前大学, 医学研究科, 教授 (10323289)
• Co-Investigator(Kenkyū-buntansha): 松宮 朋穂 弘前大学, 医学研究科, 助教 (30344592)
• Co-Investigator(Renkei-kenkyūsha): MIMURA Junsei 弘前大学, 大学院医学研究科, 講師 (60344884) ; MARUYAMA Atsushi 東北医科薬科大学, 薬学部, 講師 (10431438) ; HIMENO Hyouta 弘前大学, 農学生命科学部, 教授 (80208785)
• Project Period (FY): 2013-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2016: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: リボソーム / アミノ酸飢餓 / GCN1L1 / Nrf2 / ATF4 / ストレス応答 / GCN1 / 酸化ストレス / ミトコンドリア / HO-1

Outline of Final Research Achievements

In order to clarify the roles of GCN1L1, we generated GCN1L1 mice lacking RWDBD (GCN1L1 delta RWDBD) that is required for GCN1L1 binding to RWD possessing proteins such as GCN2 and DFRP2. The embryos of GCN1L1 delta RWDBD mice shows growth retardation starting from at least 12.5 dpc and died soon after birth. The embryonic fibroblasts obtained from GCN1L1 delta RWDBD mice shows slower prolifferation compared to those of wild-type mice associting with G2/M cell cycle arrest and decreased levels of DRG2 that heterodimerizes with DFRP2. These results suggest that GCN1L1 controls cell proliferation via the regulation of DRG2/DFRP2.

Research Products

• [Journal Article] Increase in proapoptotic activity of inhibitory PAS domain protein via phosphorylation by MK2 (2017)
  • Author(s): Kasai Shuya、Richardson Mary J. E.、Torii Satoru、Yasumoto Ken-ichi、Shima Hiroki、Igarashi Kazuhiko、Itoh Ken、Sogawa Kazuhiro、Murayama Kazutaka
  • Journal Title: The FEBS Journal Volume: 284 Issue: 23 Pages: 4115-4127
  • DOI: 10.1111/febs.14300
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel roles of glycosaminoglycans in the degradation of type I collagen by cathepsin K (2017)
  • Author(s): Tatara Yota, Suto Shintaro, Itoh Ken
  • Journal Title: Glycobiology Volume: 284 Issue: 12 Pages: 1089-1098
  • DOI: 10.1093/glycob/cwx083
  • Peer Reviewed
• [Journal Article] Effects of deficiency of Kelch-like ECH-associated protein 1 on skeletal organization: a mechanism for diminished nuclear factor of activated T cells cytoplasmic-1 during osteoclastogenesis (2017)
  • Author(s): Sakai E., Morita M., Ohuchi M., Kido MA., Fukuma Y., Nishishita K., Okamoto K., Itoh K., Yamamoto M, and Tsukuba T
  • Journal Title: FASEB Journal Volume: 31 Issue: 9 Pages: 4011-4022
  • DOI: 10.1096/fj.201700177r
  • Peer Reviewed / Open Access
• [Journal Article] The BET bromodomain inhibitor exerts the most potent synergistic anticancer effects in combination with quinone-containing compounds and anti-microtubule drugs (2016)
  • Author(s): 2.Liu PY, Sokolowski N, Guo ST, Siddiqi F, Atmadibrata B, Telfer TJ, Sun Y, Zhang L, Yu D, Mccarroll J, Liu B, Yang RH, Guo XY, Tee AE, Itoh K, Wang J, Kavallaris M, Haber M, Norris MD, Cheung BB, Byrne JA, Ziegler DS, Marshall GM, Dinger ME, Codd R, Zhang XD, Liu T
  • Journal Title: Oncotarget Volume: 7 Issue: 48 Pages: 79217-79232
  • DOI: 10.18632/oncotarget.12640
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-Canonical Role of IKKα in the Regulation of STAT1 Phosphorylation in Antiviral Signaling. (2016)
  • Author(s): Xing F, Matsumiya T, Shiba Y, Hayakari R, Yoshida H, Imaizumi T.
  • Journal Title: PLoS One Volume: 11
  • Peer Reviewed / Open Access
• [Journal Article] Role of the Keap1/Nrf2 pathway in neurodegenerative diseases. (2015)
  • Author(s): Yamazaki H, Tanji K, Wakabayashi K, Matsuura S, Itoh K.
  • Journal Title: Pathol Int Volume: 65 Issue: 5 Pages: 210-9
  • DOI: 10.1111/pin.12261
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Role of Nrf2 in the pathogenesis of atherosclerosis. (2015)
  • Author(s): Mimura J, Itoh K
  • Journal Title: Free Radic Biol Med. Volume: 88 Pages: 221-232
  • DOI: 10.1016/j.freeradbiomed.2015.06.019
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Nrf2- and ATF4-dependent up-regulation of xCT modulates the sensitivity of T24 bladder carcinoma cells to proteasome inhibition. (2014)
  • Author(s): Peng Ye, P., Mimura J., Okada, T., Sato, H., Liu, T., Maruyama, A., Ohyama, C., and Itoh, K.
  • Journal Title: Mol. Cell. Biol. Volume: 34 Issue: 18 Pages: 3421-3434
  • DOI: 10.1128/mcb.00221-14
  • Peer Reviewed / Open Access
• [Journal Article] Non-coding RNA derived from the region adjacent to the human HO-1 E2 enhancer selectively regulates HO-1 gene induction by modulating Pol II binding. (2014)
  • Author(s): Maruyama A, Mimura J, Itoh K.
  • Journal Title: Nucleic Acids Res Volume: 42 Issue: 22 Pages: 13599-13614
  • DOI: 10.1093/nar/gku1169
  • Peer Reviewed / Open Access
• [Journal Article] Phosphorylation of serine 349 of p62 in Alzheimer’s disease brain. (2014)
  • Author(s): Tanji K, Miki Y, Ozaki T, Maruyama A, Yoshida H, Mimura J, Matsumiya T, Mori F, Imaizumi T, Itoh K, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Acta Neuropathologica Communications Volume: 未定
  • Peer Reviewed
• [Journal Article] Nrf2 activation is associated with Z-DNA formation in the human HO-1 promoter (2013)
  • Author(s): Maruyama A, Mimura J, Harada N, Itoh K
  • Journal Title: Nucleic Acids Res Volume: (in press) Issue: 10 Pages: 12-12
  • DOI: 10.1093/nar/gkt243
  • Peer Reviewed
• [Presentation] Nrf2とATF4の相互作用を基盤にした加齢性変性疾患予防法の開発 (2017)
  • Author(s): 伊東健
  • Organizer: 第１４回レドックス・ライフイノベーションシンポジウム
  • Invited
• [Presentation] マウス発生におけるリボソーム結合性因子GCN1L1の役割 (2017)
  • Author(s): 山嵜博未、叶鵬、葛西秋宅、 三村純正、 猪瀬-丸山敦史、伊東健
  • Organizer: 2017年度生命科学系学会合同年次大会
  • Int'l Joint Research
• [Presentation] Nrf2経路とATF4経路の協調作用 (2017)
  • Author(s): 三村純正、伊東 健
  • Organizer: 2017年度生命科学系学会合同年次大会
  • Int'l Joint Research
• [Presentation] ミトコンドリア統合的ストレス応答におけるGCN1L1-GCN2の関与 (2017)
  • Author(s): 葛西秋宅、伊東健
  • Organizer: 2017年度生命科学系学会合同年次大会
  • Int'l Joint Research
• [Presentation] Elucidation of Nrf2-centered transcriptional network toward the disease prevention and therapy (2016)
  • Author(s): Ken Itoh
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター（宮城県、仙台市）
  • Year and Date: 2016-09-25
  • Int'l Joint Research
• [Presentation] 酸化ストレス鍵転写因子Nrf2の生理的役割・進化論的意義と疾患予防 (2016)
  • Author(s): 伊東健
  • Organizer: 第69回日本酸化ストレス学会学術集会
  • Place of Presentation: 仙台国際センター（宮城県、仙台市）
  • Year and Date: 2016-08-30
  • Invited
• [Presentation] Nrf2とeIF2α-ATF4ストレス応答経路のクロストークによるレドックス応答機構 (2016)
  • Author(s): 伊東健
  • Organizer: 第５８回歯科基礎医学会学術大会
  • Place of Presentation: 札幌コンべンションセンター（北海道、札幌市）
  • Year and Date: 2016-08-24
• [Presentation] Nrf2を中心とした転写因子ネットワークによる疾患制御 (2016)
  • Author(s): 伊東健
  • Organizer: 第３７回日本循環制御医学会総会
  • Place of Presentation: ステーションコンファレンス東京（東京都）
  • Year and Date: 2016-07-08
• [Presentation] Elucidation of Nrf2-centered transcriptional network toward the development of novel neuroprotective strategy (2016)
  • Author(s): Ken Itoh
  • Organizer: 第９回国際NO学会
  • Place of Presentation: 仙台国際センター（宮城県、仙台市）
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] Nrf2を中心とした転写因子ネットワークの活性化を利用した食品機能性成分による脳神経変性疾患予防戦略 (2016)
  • Author(s): 伊東健
  • Organizer: 第7回岐阜薬科大学機能性健康食品（蜂産品）研究講演会
  • Place of Presentation: じゅうろくプラザ（岐阜県、岐阜市）
  • Invited
• [Presentation] Nrf2-FPN1経路を介した抗炎症の分子機構の解析 (2015)
  • Author(s): 伊東健
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: ポートアイランド（兵庫県・神戸市）
  • Year and Date: 2015-12-01
• [Presentation] Carnosic acid activates ATF4 signaling pathway (2015)
  • Author(s): 三村純正，丸山敦史，小坂邦男，伊東健
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: ポートアイランド（兵庫県・神戸市）
  • Year and Date: 2015-12-01
• [Presentation] Associated gene regulation by long non-coding RNA transcribed from heme oxygenase-1 E2 enhancer region (2015)
  • Author(s): Maruyama A, Itoh K.
  • Organizer: BMB2015
  • Place of Presentation: Port Island (Hyogo, Kobe)
  • Year and Date: 2015-12-01
• [Presentation] SCREENING OF MITOPHAGY INDUCERS IN HELA CELLS. (2015)
  • Author(s): Yamazaki H, Itoh K
  • Organizer: The 6th World Congress on Targeting Mitochondria
  • Place of Presentation: Deutschland, Berlin
  • Year and Date: 2015-10-28
  • Int'l Joint Research
• [Presentation] Carnosic acid transcriptionally induces genes related to glutathione synthesis by the concomitant activation of ATF4 and Nrf2. (2015)
  • Author(s): Mimura J, Kosaka K, Itoh K.
  • Organizer: ISANH Antioxidant World Congress
  • Place of Presentation: France, Paris
  • Year and Date: 2015-06-22
  • Int'l Joint Research
• [Presentation] Development of a novel neuroprotective strategy by the cooperative transcriptional network centered on Nrf2. (2014)
  • Author(s): Itoh K.
  • Organizer: SFRBM Annual meeting 2014
  • Place of Presentation: Seattle
  • Year and Date: 2014-11-19 – 2014-11-23
• [Presentation] Nrf2- and ATF4-dependent up-regulation of xCT modulates the sensitivity of T24 bladder carcinoma cells to proteasome inhibition (2014)
  • Author(s): Ye P, Mimura J, Okada T, Sato H, Liu T, Maruyama A, Ohyama C, Itoh K.
  • Organizer: The 87th Annual Meeting of the Japanese Biochemical Society
  • Place of Presentation: Kyoto
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] Functional role of enhancer RNA derived from human HO-1 enhancer regions for HO-1 gene induction (2014)
  • Author(s): Maruyama A, Mimura J, Itoh K.
  • Organizer: 8th International Conference on Heme Oxygenases
  • Place of Presentation: Sydney
  • Year and Date: 2014-10-08 – 2014-10-11
• [Presentation] Nrf2 regulates NGF mRNA expression in human glioma cells and normal human astrocytes. (2014)
  • Author(s): Mimura J, Yoshida H, Kosaka K, Itoh K.
  • Organizer: The 2014 Alzhimer’s Disease Congress
  • Place of Presentation: London
  • Year and Date: 2014-06-23 – 2014-06-25
• [Presentation] Functional role of eRNAs derived from human HO-1 enhancer regions for HO-1 gene induction. (2014)
  • Author(s): Maruyma A, Mimura J, Itoh K.
  • Organizer: IIAS Research Conference 2014 Choromatin Decoding
  • Place of Presentation: Kyoto
  • Year and Date: 2014-05-12 – 2014-05-15
• [Presentation] Emerging molecular mechanisms of Nrf2-mediated gene induction (2014)
  • Author(s): Itoh K
  • Organizer: The Environmental Response IV
  • Place of Presentation: Sendai
  • Invited
• [Presentation] The mechanism of human xCT gene induction by proteasome inhibitors. (2014)
  • Author(s): Ye P, Mimura J, Itoh K
  • Organizer: 17th Bennial Meeting of Society for Free Radical Research International
  • Place of Presentation: Kyoto
• [Presentation] Activation of ATF4 signaling pathway by carnosic acid. (2014)
  • Author(s): Mimura J, Maruyama A, Kosaka K, Itoh K.
  • Organizer: 17th Bennial Meeting of Society for Free Radical Research International
  • Place of Presentation: Kyoto
• [Presentation] The role of ribosomal interacting protein GCN1L1 in oxidative stress-mediated Nrf2 activation. (2014)
  • Author(s): Liu T, Kimura S, Yamazaki H, Maruyama A, Nishikawa K, Harada N, Mimura J, Yamamoto M, Itoh K.
  • Organizer: 17th Bennial Meeting of Society for Free Radical Research International
  • Place of Presentation: Kyoto
• [Presentation] 酸化ストレスで活性化する転写経路のクロストーク (2013)
  • Author(s): 伊東健
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌市
  • Invited
• [Presentation] Nrf2転写調節経路とeIF2αリン酸化経路とのクロストーク (2013)
  • Author(s): 伊東健
  • Organizer: 日本放射線影響学会
  • Place of Presentation: 青森市
  • Invited
• [Presentation] Nrf2を介した抗酸化・抗炎症機構による病態制御 (2013)
  • Author(s): 伊東健
  • Organizer: 第30回臨床フリーラジカル会議
  • Place of Presentation: 京都
  • Invited
• [Book] 2.ATFとNrf2によるミトコンドリアホメオスタシスレドックス制御 (2018)
  • Author(s): 葛西秋宅、對馬迪子、伊東健
  • Total Pages: 5
  • Publisher: 羊土社
• [Book] Fukushima Nuclear Accident: Global Implications, Long-Term Health Effects, and Ecological Consequences. (2015)
  • Author(s): Itoh K, Maruyama A.
  • Total Pages: 18
  • Publisher: Nova
• [Remarks] 弘前大学大学院医学研究科附属高度先進医学研究センター分子生体防御学講座
  • URL: http://www.med.hirosaki-u.ac.jp/~admed/department/index.html