Involvement of NF-kB regulation by nuclear IKKb in inflammation and cancer

• Project/Area Number: 23370062
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• 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)
• Co-Investigator(Renkei-kenkyūsha): SOTOMARU Yusuke 広島大学, 自然科学研究支援開発センター, 教授 (90309352)
• Project Period (FY): 2011-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥20,280,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥4,680,000); Fiscal Year 2013: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2012: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2011: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
• Keywords: NF-κB / IKK / 細胞質 / 核 / 炎症 / 発がん / IKKb / NF-kB / 肝臓 / ネクローシス / 酸化ストレス / 線維化 / 肝硬変 / ROS / アポトーシス / 腫瘍壊死因子 / 発癌 / タンパク質分解

Outline of Final Research Achievements

Proinflammatory stimuli, including tumor necrosis factor α (TNFα), activate IκB kinase (IKK) complex and induces NF-κ activation. We previously found that nuclear IKKβ acts as an adaptor protein for IκBα degradation and NF-κB activation. To elucidate the role of IKKβ in vivo, we developed mice expressing nuclear-localized IKKβ and lacking cytoplasmic IKKβ in hepatocytes. These mice showed massive hepatic necrosis and developed liver cirrhosis. Whereas, liver failure of these mice was ameliorated by crossing with mice expressing cytoplasmic-localized IKKβ. These results suggest that nuclear IKKβ promote cell death and cytoplasmic IKKβ protect cells from death in vivo. The opposite effect of IKKβ in the nucleus and cytoplasm is closely linked to hepatitis and hepatocellular carcinoma.

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): Iwashita M, Nakatsu Y, Sakoda H, Fujishiro M, Kushiyama A, Fukushima T, Kumamoto S, Shinjo T, Kamata H, Nishimura F, Asano T.
  • 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] 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 model (2012)
  • Author(s): Nakatsu Y, Otani Y, Sakoda H, Zhang J, Guo Y, Okubo H, Kushiyama A, Fujishiro M, Kikuchi T, Fukushima T, Ohno H, Tsuchiya Y, Kamata H, Nagamachi A, Inaba T, Nishimura F, Katagiri H, Takahashi SI, Kurihara H, Uchida T, Asano T
  • Journal Title: J Biol Chem Volume: 287 Issue: 53 Pages: 44526-44535
  • DOI: 10.1074/jbc.m112.397133
  • 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): Kumamoto S, Kushiyama A, Nakatsu Y, Sakoda H, Fujishiro M, Iwashita M, Ohno H, Zhang J, Guo Y, Aburatani H, Kamata H, Nishimura F, Asano T.
  • Journal Title: Obesity Research and Clinical Practice Volume: 6 Issue: 4 Pages: 288-297
  • DOI: 10.1016/j.orcp.2012.05.005
  • Peer Reviewed
• [Journal Article] LST8 level controls basal p70 S6 kinase and Akt phosphorylations, and mTORC1 and mTORC2 negatively regulate each other by competing for association with LST8. (2012)
  • Author(s): Kikuchi T, Zhang J, Sakoda H, Koketsu Y, Fujishiro M, Kushiyama A, Nakatsu Y, Kamata H, Inoki K, Takahashi S, Kurihara H, Hideki K, Oka Y, Asano T
  • Journal Title: Obesity Research and Clinical Practice Volume: 6 Issue: 3 Pages: 175-262
  • DOI: 10.1016/j.orcp.2011.10.002
  • 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): Iwashita M, Sakoda H, Kushiyama A, Fujishiro M, Ohno H, Nakatsu Y, Fukushima T, Kumamoto S, Tsuchiya Y, Kikuchi T, Kurihara H, Akazawa H, Komuro I, Kamata H, Nishimura F, Asano T.
  • Journal Title: American Journal of Physiology - Endocrinology and Metabolism Volume: 302 Issue: 3 Pages: 286-296
  • DOI: 10.1152/ajpendo.00324.2011
  • 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): Misaki Iwashita, et.al.
  • Journal Title: American Journal of Physiology-Endocrinology and Metabolism Volume: 302 Pages: 286-296
  • Peer Reviewed
• [Journal Article] Xanthine oxidoreductase is involved in macrophage foam cell formation and atherosclerosis development (2011)
  • Author(s): Akifumi Kushiyama, et.al.
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 32 Pages: 291-298
  • Peer Reviewed
• [Journal Article] On off system for P13-kinase Akt signaling through S-nitrosylation of phosphatase with sequence homology to tensin (PTEN) (2011)
  • Author(s): Naoki Numajiria, et.al.
  • Journal Title: Poceedings of the National Academy of Sciences of the United States of America Volume: 108 Pages: 10349-10354
  • Peer Reviewed
• [Journal Article] Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 associates with IRS-1 and enhances insulin actions and adipogenesis (2011)
  • Author(s): Yusuke Nakatsu, et.al.
  • Journal Title: Journal of Biological Chemistry Volume: 286 Pages: 20812-20822
  • Peer Reviewed
• [Journal Article] 4F2hc stabilizes GLUT1 protein and increases glucose transport activity (2011)
  • Author(s): Haruya Ohno, et.al.
  • Journal Title: American Journal of Physiology ; Cell Physiology Volume: 300 Pages: 1047-1054
  • 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: 第31回 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: 2014-11-27
• [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] Nuclear IKKβ acts as an adaptor protein for IκBα ubiquitination and degradation in UV- and oxidative stress-induced NF-κB activation (2012)
  • Author(s): Yoshihiro Tsuchiya, et.al.
  • Organizer: Keystone Symposium, "NF-kappaB Signaling and Biology : From Bench to Bedside"
  • Place of Presentation: Whistler, BritishColumbia, Canada
  • Year and Date: 2012-03-25
• [Presentation] IKKβの多重的活性制御機構-転写因子p65によるネガティブフィードバックとレドックス制御の関与 (2011)
  • Author(s): 土谷佳弘, ら
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-16
• [Presentation] Nuclear IKKβ phosphrylates ATM in response to genotoxic stimuli, which promotes DNA repair (2011)
  • Author(s): Kei Sakamoto, et.al.
  • Organizer: 第34回日本分子生物学会年会ワークショップ
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-15
• [Presentation] アルコール性脂肪性肝炎発症における肝および血球系細胞のプロリン異性化酵素Pin1の役割 (2011)
  • Author(s): 中津祐介
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-14
• [Presentation] プロリン異性化酵素Par14とPin1のインスリンシグナルと糖・脂質代謝における役割 (2011)
  • Author(s): 浅野知一郎
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-14
• [Presentation] 転写因子NF-κBの活性化機構と細胞の生と死の制御 (2011)
  • Author(s): 鎌田英明
  • Organizer: 第48回広島大学・生命科学フォーラム
  • Place of Presentation: 東広島(招待講演)
  • Year and Date: 2011-11-11
• [Presentation] 非アルコール性脂肪性肝炎発症におけるプロリン異性化酵素Pin1の役割 (2011)
  • Author(s): 中津祐介
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-22
• [Presentation] Ubiquitin-like domain (ULD)内におけるL353A変異体を用いたIKKbetaタンパク質分解機構の解析 (2011)
  • Author(s): 金本麻裕
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-22
• [Presentation] IKKβ act as an adaptor protein for IκBα ubiquitination and degradation in UV-induced NF-κB activation ; possible involvement in the TNF signaling (2011)
  • Author(s): Yoshihiro Tsuchiya, et.al.
  • Organizer: 13th International TNF Conference
  • Place of Presentation: Awajishima, Japan
  • Year and Date: 2011-05-17
• [Presentation] 肥満、脂肪肝およびNASH発症におけるプロリンイソメラーゼPin1の関与 (2011)
  • Author(s): 中津祐介
  • Organizer: 第52回日本生化学会中国・四国支部例会
  • Place of Presentation: 広島
  • Year and Date: 2011-05-14
• [Presentation] Nedd4によるインスリン受容体基質(IRS)のユビキチン化はインスリン・1GF-1シグナルを増強する (2011)
  • Author(s): 福島俊明
  • Organizer: 第52回日本生化学会中国・四国支部例会
  • Place of Presentation: 広島
  • Year and Date: 2011-05-09
• [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): 2. 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] 非アルコール性脂肪肝炎発症におけるLUBAC の形成の解析
  • Author(s): 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
  • 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: 日本生化学会合同大会
  • 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: 日本生化学会合同大会
  • 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): 12. 金本麻裕, 土谷佳弘, 浅野知一郎, 鎌田英明
  • Organizer: 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