Mechanistic insight into CCR4-NOT deadenylase-mediated heart function control and its potential application for therapeutics

• Project/Area Number: 26293050
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Akita University
• Principal Investigator: Kuba Keiji 秋田大学, 医学(系)研究科(研究院), 教授 (10451915)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000); Fiscal Year 2016: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2014: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: CCR4-NOT / heart failure / deadenylase / CNOT3 / 心不全 / デアデニレース / オートファジー / ネクローシス / RNA代謝 / 脱アデニル化 / 循環器 / RNA創薬 / 遺伝子改変マウス / ＣＣＲ４－ＮＯＴ / poly(A) / 心臓

Outline of Final Research Achievements

In this study, we analyzed the mechanisms how CCR4-NOT deadenylase regulates mRNA decay and nucleotide metabolism in controlling heart functions. mRNA decay by CCR4-NOT complex was revealed to alter adenine nucleotide levels in the heart. In addition, bulk mRNA poly(A) shortening and alteration of nucleotide levels were sensed by an autophagy molecule, which is crucial for cardiomyocyte survival. Furthermore, CCR4-NOT-mediated adenine nucleotide regulation was also shown to affect energy-sensing signaling pathway. Both pathways are likely important for CCR4-NOT-mediated heart function control. Finally, we conducted chemical compound screening for CCR4-NOT deadenylase inhibitors.

Research Products

• [Int'l Joint Research] Max Planck Institute(ドイツ)
• [Int'l Joint Research] Institute of Medical Biology, A*STAR(シンガポール)
• [Int'l Joint Research] IMBA(オーストリア)
• [Journal Article] ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage (2017)
  • Author(s): Sato T, Sato C, Kadowaki A, Watanabe H, Ho L, Ishida J, Yamaguchi T, Kimura A, Fukamizu A, Penninger JM, Reversade B, Ito H, Imai Y, Kuba K
  • Journal Title: Cardiovasc Res Volume: 113(7) Issue: 7 Pages: 760-769
  • DOI: 10.1093/cvr/cvx061
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Vps34 regulates myofibril proteostasis to prevent hypertrophic cardiomyopathy. (2017)
  • Author(s): Kimura H, Eguchi S, Sasaki J, Kuba K, Nakanishi H, Takasuga S, Yamazaki M, Goto A, Watanabe H, Itoh H, Imai Y, Suzuki A, Mizushima N, Sasaki T
  • Journal Title: JCI Insight Volume: 2 Issue: 1 Pages: 89462-89478
  • DOI: 10.1172/jci.insight.89462
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Evaluation of Lecithinized Superoxide Dismutase for the Prevention of Acute Respiratory Distress Syndrome in Animal Models. (2017)
  • Author(s): Tanaka KI, Tamura F, Sugizaki T, Kawahara M, Kuba K, Imai Y, Mizushima T
  • Journal Title: Am J Respir Cell Mol Biol Volume: 56 Pages: 179-190
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Interaction of CCR4-NOT with EBF1 regulates gene-specific transcription and mRNA stability in B lymphopoiesis. (2016)
  • Author(s): Yang CY, Ramamoorthy S, Boller S, Rosenbaum M, Rodriguez Gil A, Mittler G, Imai Y, Kuba K, Grosschedl R
  • Journal Title: Genes & Development Volume: 30 Pages: 2310-2324
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Structure-activity relationship of cyclic pentapeptide malformins as fibrinolysis enhancers. (2016)
  • Author(s): Koizumi Y, Nagai K, Hasumi K, Kuba K, Sugiyama T
  • Journal Title: Bioorg Med Chem Lett Volume: 26 Issue: 21 Pages: 5267-5271
  • DOI: 10.1016/j.bmcl.2016.09.045
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cationic nanoparticles directly bind angiotensin-converting enzyme 2 and induce acute lung injury in mice. (2015)
  • Author(s): Sun Y, Kuba K, et al.
  • Journal Title: Part Fibre Toxicol. Volume: 12 Pages: 4-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cationic nanoparticles directly bind angiotensin-converting enzyme 2 and induce acute lung injury in mice. (2015)
  • Author(s): Sun Y, Kuba K, Jiang C, et al.（23著者、13番目）
  • Journal Title: Part Fibre Toxicol Volume: 12 Issue: 1
  • DOI: 10.1186/s12989-015-0080-x
  • Peer Reviewed
• [Journal Article] The arachidonic acid metabolome as conserved regulator of cholesterol metabolism. (2014)
  • Author(s): Demetz E, Schroll A, Auer K, Heim C, Patsch JR, Eller P, Theurl M, Lener D, Stanzl U, Seifert M, Haschka D, Asshoff M, Dichtl S, Nairz M, Huber E, Stadlinger M, Li X, Pallweber P, Scharnagl H, Stojakovic T, Marz W, Kleber ME, Garlaschelli K, Uboldi P, Catapano AL, Kuba K, Imai Y, Arita M, Tancevski I.
  • Journal Title: Cell Metab. Volume: 20 Issue: 5 Pages: 787-798
  • DOI: 10.1016/j.cmet.2014.09.004
  • Peer Reviewed / Open Access
• [Presentation] 心不全病態におけるRNA分解制御の新しい生理的意義 (2017)
  • Author(s): 久場敬司
  • Organizer: 第90回日本薬理学会 シンポジウム３
  • Place of Presentation: 長崎
  • Invited
• [Presentation] Dissecting the functional role of A Novel APJ ligand, ELABELA, in heart failure (2016)
  • Author(s): 佐藤輝紀、久場敬司
  • Organizer: 日本薬理学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-09
• [Presentation] RNA分解による心臓エネルギー代謝の恒常性維持 (2016)
  • Author(s): 久場敬司
  • Organizer: 第4回 CCR4-NOT研究会
  • Place of Presentation: 秋田
  • Year and Date: 2016-02-12
• [Presentation] 心臓のmRNA poly(A)分解とエネルギー感知シグナルの相互作用機構の解明 (2016)
  • Author(s): 山口智和、鈴木享、佐藤輝紀、夏井美幸、門脇歩美、佐藤チトセ、小泉幸央、高橋明格、山本雅、今井由美子、久場敬司
  • Organizer: 第26回 日本循環薬理学会
  • Place of Presentation: 松本
• [Presentation] 心不全病態における新規APJリガンドELABELAの機能的意義の解明 (2016)
  • Author(s): 佐藤輝紀, 山口智和, 渡邊博之, 門脇歩美, 佐藤チトセ, 伊藤宏, 今井由美子, 久場敬司
  • Organizer: 第26回 日本循環薬理学会
  • Place of Presentation: 松本
• [Presentation] CCR4-NOT complex controls adenine nucleotide metabolism and energy sensing in cardiac homeostasis (2016)
  • Author(s): 久場敬司
  • Organizer: The 89th JBS meeting symposium 3S17
  • Place of Presentation: 東北大学
• [Presentation] RNA代謝制御による心機能の恒常性維持 (2016)
  • Author(s): 久場敬司
  • Organizer: 第10回 京阪神心不全研究会
  • Place of Presentation: 大阪
  • Invited
• [Presentation] RNA分解制御による心臓エネルギー恒常性維持の分子機構 (2015)
  • Author(s): 久場敬司
  • Organizer: BMB2015
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-04
• [Presentation] 心臓における新規Apelin受容体リガンドApelaの機能的意義の解析 (2015)
  • Author(s): 久場敬司
  • Organizer: 生理学研究所 研究会 2015 「心臓・血管系の包括的な機能統合研究」
  • Place of Presentation: 岡崎
  • Year and Date: 2015-10-29
• [Presentation] CNOT3を介した心臓のアデニン核酸制御機構の解析 (2015)
  • Author(s): 山口智和、久場敬司
  • Organizer: 第66回 日本薬理学会北部会
  • Place of Presentation: 富山
  • Year and Date: 2015-09-18
• [Presentation] Signaling network to maintain cardiac homeostasis in failing hearts (2015)
  • Author(s): 久場敬司
  • Organizer: The 4th Hsien Wu and Ray Wu Symposia “Proteins, Genes and Diseases”
  • Place of Presentation: 北京
  • Year and Date: 2015-08-10
  • Int'l Joint Research / Invited
• [Presentation] CCR4-NOT複合体によるアデニン核酸制御機構の解析 (2015)
  • Author(s): 山口智和、久場敬司
  • Organizer: RNA学会
  • Place of Presentation: 札幌
  • Year and Date: 2015-07-13
• [Presentation] mRNA分解制御を介した心臓の恒常性維持 (2015)
  • Author(s): 久場敬司
  • Organizer: 第一回 J-ISCP学術集会
  • Place of Presentation: 京都
  • Year and Date: 2015-06-20
  • Invited
• [Presentation] 心臓のmRNA分解とエネルギー代謝の恒常性維持 (2015)
  • Author(s): 久場敬司
  • Organizer: 第2回 仙台先進循環器研究会
  • Place of Presentation: 仙台
  • Year and Date: 2015-06-20
  • Invited
• [Presentation] アンジオテンシン変換酵素２（ACE2）の多彩な生理機能と制御機構の解明 (2015)
  • Author(s): 久場敬司
  • Organizer: 第160回日本循環器学会東北地方会
  • Place of Presentation: 盛岡
  • Year and Date: 2015-04-10
  • Invited
• [Presentation] Angiotensin converting enzyme 2 (ACE2) links Apelin and angiotensin systems in controlling heart function. (2015)
  • Author(s): 久場敬司
  • Organizer: 日本解剖学会・日本生理学会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-23
  • Invited
• [Presentation] Dissecting the role of CCR4-NOT-associated ubiquitin converting enzyme in controlling heart functions. (2015)
  • Author(s): 山口智和、門脇歩美、小泉幸央、夏井美幸、佐藤チトセ、今井由美子、久場敬司
  • Organizer: 第88回 日本薬理学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] A crucial role of CNOT3 in stem cell proliferation and early embryonic development (2015)
  • Author(s): 小泉幸央、山口智和、門脇歩美、夏井美幸、佐藤チトセ、今井由美子、久場敬司
  • Organizer: 第88回 日本薬理学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] 酵母からヒトまで保存されたCCR4-NOT複合体による心機能制御メカニズム (2014)
  • Author(s): 久場敬司
  • Organizer: 第24回 日本循環薬理学会
  • Place of Presentation: 山形
  • Year and Date: 2014-12-05
  • Invited
• [Presentation] CCR4-NOT deadenylase complex links mRNA metabolism to energy sensing in cardiac homeostasis (2014)
  • Author(s): 久場敬司
  • Organizer: 第 31 回 国際心臓研究学会（ISHR）日本部会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-11-29
  • Invited
• [Presentation] Dissecting the mechanisms for regulation of cardiac energy metabolism by CCR4-NOT complex (2014)
  • Author(s): 久場敬司
  • Organizer: 第 16 回 日本RNA学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-07-23