Crosstalk between citrate sycle and gene expression system and inflammation and cancer

• Project/Area Number: 24657092
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Functional biochemistry
• Research Institution: Hiroshima University
• Principal Investigator: KAMATA hideaki 広島大学, 医歯薬保健学研究院, 准教授 (10233925)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: HIF1 / NF-kB / クエン酸回路 / HIF-1a / 酸素 / 翻訳 / 代謝 / クエン酸 / HIF1-α / ROS / 炎症 / 発がん

Outline of Final Research Achievements

Cross talk between metabolites of citrate cycle and transcription factors including HIF-1α and NF-κB play essential role in inflammation and cancer. HIF-1α activity is regulated by protein degradation through ubiquitin proteasome system and by NF-κB-mediated transcription. Here we found that citrate suppressed translation of HIF-1α in a cell type-specific manner, and inhibited HIF-1α-mediated gene expression.

Research Products

• [Journal Article] Nedd4-induced mono-ubiquitination of IRS-2 enhances IGF signaling and mitogenic activity. (2015)
  • Author(s): Toshiaki Fukushima, Hidehito Yoshihara, Haruka Furuta, Fumihiko Hakuno, Jing Luan, Cunming Duan, Yasushi Saeki, Keiji Tanaka, Shun-Ichiro Iemura, TohruNatsume, Kazuhiro Chida, Yusuke Nakatsu, Hideaki Kamata, Tomoichiro Asano, and Shin-Ichiro Takahashi
  • Journal Title: Nature communications Volume: 6 Issue: 1 Pages: 6780-6780
  • DOI: 10.1038/ncomms7780
  • NAID: 120006348510
  • Peer Reviewed / Open Access
• [Journal Article] Mosapride citrate improves nonalcoholic steatohepatitis with increased fecal lactic acid bacteria and plasma glucagon-like peptide-1 level in a rodent model. (2015)
  • Author(s): Hirofumi Okubo, Yusuke Nakatsu, Hideyuki Sakoda, Akifumi Kushiyama, Midori Fujishiro, Toshiaki Fukushima, Yasuka Matsunaga, Haruya Ohno, Masayasu Yoneda, Hideaki Kamata, Takanori Shinjo, Misaki Iwashita, Fusanori Nishimura, and Tomoichiro Asano
  • Journal Title: Am. J. Physiol. Gastrointest. Liver Physiol. Volume: 308 Issue: 2 Pages: 151-158
  • DOI: 10.1152/ajpgi.00198.2014
  • Peer Reviewed
• [Journal Article] Lactobacillus casei strain Shirota protects against non-alcoholic steatohepatitis development in a rodent model (2013)
  • Author(s): Okubo H, Sakoda H, Kushiyama A, Fujishiro M, Nakatsu Y, Fukushima T, Matsunaga Y, Kamata H, Asahara T, Yoshida Y, Chonan O, Iwashita M, Nishimura F, Asano T
  • Journal Title: American Journal Physiolgy-Gastrointestinal and Liver Physiogy Volume: 305 Issue: 12 Pages: 911-918
  • DOI: 10.1152/ajpgi.00225.2013
  • Peer Reviewed
• [Journal Article] Valsartan restores inflammatory response by macrophages in adipose and hepatic tissues of LPS-infused mice. (2013)
  • Author(s): Misaki Iwashita, Yusuke Nakatsu, Hideyuki Sakoda, Midori Fujishiro, Akifumi Kushiyama, Toshiaki Fukushima, Sonoko Kumamoto, Takanori Shinjo, Hideaki Kamata, Fusanori Nishimura and Tomoichiro Asano
  • Journal Title: Adipocyte Volume: 2 Pages: 28-32
  • Peer Reviewed
• [Journal Article] Resistin-Like Molecule β Is Abundantly Expressed in Foam Cells and Is Involved in Atherosclerosis Development. (2013)
  • Author(s): Kushiyama A, Sakoda H, Oue N, Okubo M, Nakatsu Y, Ono H, Fukushima T, Kamata H, Nishimura F, Kikuchi T, Fujishiro M, Nishiyama K, Aburatani H, Kushiyama S, Iizuka M, Taki N, Encinas J, Sentani K, Ogonuki N, Ogura A, Kawazu S, Yasui W, Higashi Y, Kurihara H, Katagiri H, Asano T.
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 33 Issue: 8 Pages: 1986-1993
  • DOI: 10.1161/atvbaha.113.301546
  • Peer Reviewed / Open Access
• [Journal Article] Par14 associates with IRS-1, thereby enhancing insulin-induced IRS-1 phosphorylation and metabolic actions. (2013)
  • Author(s): Zhang J, Nakatsu Y, Sinjo T, Guo Y, Sakoda H, Yamamotoya T, Otani Y, Okubo H, Kushiyama A, Fujishiro M, Fukushima T, Tsuchiya Y, Kamata H, Nishimura F, Katagiri H, Takahashi SI, Kurihara H, Uchida T, Asano T.
  • Journal Title: Ｊournal of Biological Chemistry Volume: 288 Issue: 28 Pages: 20692-20701
  • DOI: 10.1074/jbc.m113.485730
  • Peer Reviewed
• [Journal Article] Integrator complex plays anessential role inadipose differentiation (2013)
  • Author(s): Otani Y, Nakatsu Y, Sakoda H, Fukushima T, Fujishiro M, Kushiyama A, Okubo H, Tsuchiya Y, Ohno H, Takahashi S, Nishimura F, Kamata H, Katagiri H, Asano T.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 434 Issue: 2 Pages: 197-202
  • DOI: 10.1016/j.bbrc.2013.03.029
  • Peer Reviewed
• [Journal Article] Integrator complex plays anessential role inadipose differentiation (2013)
  • Author(s): Y. Otani, Y. Nakatsu, H. Sakoda, T. Fukushima, M. Fujishiro, A. Kushiyama, H. Okubo, Y. Tsuchiya, H. Ohno, S. Takahashi, F. Nishimura, H. Kamata, H. Katagiri, T. Asano
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 434 Pages: 197-202
  • Peer Reviewed
• [Journal Article] Promotion of DNA repair by nuclear IKKβ phosphorylation of ATM in response to genotoxic stimuli. (2012)
  • Author(s): Kei Sakamoto, et al.
  • Journal Title: Oncogene Volume: 32 Issue: 14 Pages: 1854-1862
  • DOI: 10.1038/onc.2012.192
  • Peer Reviewed
• [Journal Article] Role of Pin1 in the pathogenesis of non-alcoholic steatohepatitis in a rodent mode (2012)
  • Author(s): Y. Nakatsu, Y. Otani, H. Sakoda, J. H. Kamata, A. T. Asano, et.al.
  • Journal Title: J. Biol. Chem. Volume: 287 Pages: 44526-44535
  • Peer Reviewed
• [Journal Article] Angiotensin receptor 1 blocker valsartan normalizes gene expression profiles of 3T3-L1 adipocytes altered by co-culture with LPS-treated RAW264.7 macrophages (2012)
  • Author(s): S. Kumamoto, A. Kushiyama, Y. Nakatsu, H. Sakoda, M. Fujishiro, M. Iwashita, H. Ohno, J. Zhang, Y. Guo, H. Aburatani, H. Kamata, F. Nishimura, and T. Asano
  • Journal Title: Obes. Res. Clin. Pract. Volume: 6 Pages: 288-297
  • Peer Reviewed
• [Journal Article] Valsartan, independently of AT1 receptor or PPARγ, suppresses LPS-induced macrophage activation and improves insulin resistance in cocultured adipocytes. (2012)
  • Author(s): M. Iwashita, H. Sakoda, A. Kushiyama, M. Fujishiro, H. Kamata, T. Asano, et.al.
  • Journal Title: Am. J. Physiol. Endocrinol. Metab. Volume: 302 Pages: 286-296
  • Peer Reviewed
• [Presentation] 活性酸素応答ホスファターゼに連関した細胞シグナル制御機構 (2014)
  • Author(s): 鎌田英明
  • Organizer: 臨床フリーラジカル会議
  • Place of Presentation: 京都
  • Year and Date: 2014-12-06
• [Presentation] 膵β細胞機能におけるプロリン異性化酵素Pin1の役割 (2014)
  • Author(s): 中津祐介、森馨一、松永泰花、福嶋俊明、鎌田英明、山口賢、石原寿光、浅野知一郎
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-26
• [Presentation] ユビキチンリガーゼNedd4がIRS-2を介したIGFシグナルを増強する新しい分子機構 (2014)
  • Author(s): 福嶋俊明、吉原英人、吉田遥佳、伯野史彦、佐伯泰、中津祐介、鎌田英明、高橋伸一郎、浅野知一郎
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-26
• [Presentation] RelAによる遺伝子発現非依存的なIKKβ活性制御機構 (2014)
  • Author(s): 土谷佳弘、浅野知一郎、鎌田英明
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-26
• [Presentation] キサンチンオキシダーゼ阻害剤FebuxostatによるNASH改善作用の検討 (2014)
  • Author(s): 松永泰花、中津祐介、瀬野康之、片迫彩、金岡龍平、福嶋俊明、鎌田英明、浅野知一郎
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-26
• [Presentation] RelAによる遺伝子発現非依存的なIKKβ活性制御機構 (2014)
  • Author(s): 土谷佳弘、浅野知一郎、鎌田英明
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-18
• [Presentation] 転写活性非依存性のRelA によるIKKbの活性制御機構
  • Author(s): 土谷佳弘, 金本麻裕, 浅野知一郎, 鎌田英明
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸
• [Presentation] Nedd4-IRS2複合体の形成機構とこの複合体が前立腺がん細胞の過増殖に果たす役割
  • Author(s): 福嶋俊明，吉原英人，古田遥佳，伯野史彦，千田和広，佐伯泰，田中啓二，伊藤昭博，田稔，中津祐介，鎌田英明，高橋伸一郎，浅野知一郎
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸
• [Presentation] TNFに応答したRIP1/RIP3複合体形成における活性酸素種(ROS)の関与と細胞の生と死の制御
  • Author(s): 金本麻裕, 土谷佳弘, 浅野知一郎, 鎌田英明
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸
• [Presentation] プロリン異性化酵素Pin1による新規AMPK 機能制御機構の解明
  • Author(s): 中津祐介，岩下未咲，松永泰花，福嶋俊明，迫田秀之，櫛山 暁史，鎌田英明，内田隆史，高橋伸一郎，浅野知一郎
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸
• [Presentation] 松永泰花，中津祐介，福嶋俊明，大久保博史，迫田秀之，土谷 佳弘，鎌田英明，徳永 文稔，岩井 一宏，浅野知一郎
  • Author(s): 非アルコール性脂肪肝炎発症におけるLUBAC の形成の解析
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸
• [Presentation] ストレス応答による核内IKKβを介したNF-κB活性化と細胞死
  • Author(s): 土谷佳弘, 金本麻裕, 浅野知一郎, 鎌田 英明
  • Organizer: 第86回日本生化学会合同大会
  • Place of Presentation: 横浜
• [Presentation] 腫瘍壊死因子(TNF)に応答したネクロプトーシス誘導キナーゼRIP-3の細胞外分泌による細胞死の制御
  • Author(s): 金本麻裕, 土谷佳弘, 浅野知一郎, 鎌田英明
  • Organizer: 第86回日本生化学会合同大会
  • Place of Presentation: 横浜
• [Presentation] TNFに連関したシグナル系のレドックス制御と細胞死
  • Author(s): 鎌田英明
  • Organizer: 第85回日本生化学会合同大会シンポジウム
  • Place of Presentation: 福岡
  • Invited
• [Presentation] IKKβの脱リン酸化反応における転写因子RelAの関与
  • Author(s): 土谷佳弘, 金本麻裕, 菅野雅元, 浅野知一郎, 鎌田英明
  • Organizer: 第85回日本生化学会合同大会ワークショップ
  • Place of Presentation: 福岡
• [Presentation] 腫瘍壊死因子(TNFα)に応答した細胞死とRIP1とRIP3の発現変化
  • Author(s): 金本麻裕, 土谷佳弘, 浅野知一郎, 鎌田英明
  • Organizer: 第85回日本生化学会合同大会
  • Place of Presentation: 福岡
• [Presentation] Stress-induced NF-kB activation mediated by the nuclear IKK and cell death
  • Author(s): 土谷佳弘, 金本麻裕, 菅野雅元, 浅野知一郎, 鎌田英明
  • Organizer: 第35回日本分子生物学会
  • Place of Presentation: 福岡