Involvement of cellular stress-medicated NF-kB activation in inflammation and cancer

• Project/Area Number: 21570141
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Hiroshima University
• Principal Investigator: KAMATA Hideaki Hiroshima University, 大学院・医歯薬学総合研究科, 准教授 (10233925)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2009: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 細胞情報伝達機構 / NF-kB / ストレス応答 / UV / ユビキチン / プロテアソーム細胞死 / 酸化ストレス / 核移行 / NF-κB / IKKβ / 炎症 / ユビキチン化 / TNF

Research Abstract

Tumor necrosis factor α (TNFα) activates NF-κB using the IκB kinase (IKK) complex that phosphorylates inhibitory proteins (IκBs) at N-terminal sites resulting in their ubiquitination and degradation in the cytoplasm. Ultraviolet (UV) irradiation also activates NF-κB by IκBα degradation, but its mechanism was unknown. In this study, we have revealed that, although UV does not lead to IKK activity and N-terminal phosphorylation of IκBα, IKK acts as an adaptor protein and activates NF-κB. UV irradiation induces the nuclear translocation of IκBα and association with IKKβ, which constitutively interacts with β-TrCP through heterogeneous ribonucleoprotein-U (hnRNP-U) leading to IκBα ubiquitination and degradation. NF-κB activated by the nuclear IKKβ adaptor protein suppresses anti-apoptotic gene expression and promotes UV-induced cell death. Importantly, IκBα translocates into the nucleus and associates with IKKβ and then is degraded when cells are subjected not only to UV stress but also to other types of oxidative stress.

Research Products

• [Journal Article] On-off system for PI3-kinase-Akt signaling through S-nitrosylation of phosphatase with sequence homology to tensin (PTEN). (2011)
  • Author(s): Numajiria, N., Takasawa, K, Nishiy, T., Tanaka, H., Ohno, K., Hayakawa, W., Asada, M., Matsuda, H., Azumi, K.,Kamata, H.Tomohiro Nakamura, Hideaki Hara, Masabumi Minami, Stuart A.Lipton, Takashi Uehara.
  • Journal Title: Poc.Nat.Acad.Sci.USA. in press
  • 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): Nakatsu, Y., Sakoda, H., Kushiyama, A., Zhang, J., Ono, H., Fujishiro, M., Kikuchi, T., Fukushima, T., Yoneda, M., Ohno, H., Horike, N., Kanna, M., Tsuchiya, Y., Kamata, H., Nishimura, F., Isobe, T., Ogihara, T., Katagiri, H., Oka, Y., Takahashi, S., Kurihara, H., Uchida, T., Asano, T.
  • Journal Title: J.Biol.Chem 286 Pages: 20812-20822
  • Peer Reviewed
• [Journal Article] 4F2hc stabilizes GLUT1 protein and increases glucose transport activity. (2011)
  • Author(s): Ohno, H., Nakatsu, Y., Sakoda, H., Kushiyama, A., Ono, H., Fujishiro, M., Yuichiro Otani, Hirofumi Okubo, Yoneda, M., Fukushima, T., Tsuchiya, Y., Kamata, H., Nishimura, F., Kurihara, H., Katagiri, H., Oka, Y., Asano, T.
  • Journal Title: Am.J.Physiol.Cell Physiol. 300 Pages: 1047-1054
  • Peer Reviewed
• [Journal Article] IKKβis an adaptor protein for β-TrCP mediated IκBα ubiquitination in UV-induced NF-κB activation. (2010)
  • Author(s): Tsuchiya, Y., Asano, T., Nakayama, K., Kato, Jr., K., Karin, M., Kamata, H.
  • Journal Title: Mol.Cell 39 Pages: 570-582
  • Peer Reviewed
• [Journal Article] IκBβ is a positive and negative regulator of NF-κB activity during inflammation. (2010)
  • Author(s): Kamata, H., Tsuchiya, Y., Asano, T.
  • Journal Title: Cell Res. 20 Pages: 1178-1180
  • Peer Reviewed
• [Journal Article] Pin1 associates with and induces translocation of CRTC2 to the cytosol, thereby suppressing CRE transcriptional activity. (2010)
  • Author(s): Nakatsu, Y., Sakoda, H., Kushiyama, A., Ono, H., Fujishiro, M., Horike, N., Yoneda, M., Ohno, H., Tsuchiya, Y., Kamata, H., Hidetoshi Tahara, Toshiaki Isobe, Nishimura, F., Katagiri, H., Oka, Y., Fukushima, T., Takahashi, S., Kurihara, H., Uchida, T., Asano, T.
  • Journal Title: J.Biol.Chem. 285 Pages: 33018-33027
  • Peer Reviewed
• [Journal Article] Decreased SIRT1 expression and LKB1 phosphorylation occurs with long-term high-fat diet feeding, in addition to AMPK phosphorylation impairment in the early phase. (2010)
  • Author(s): Yoneda M., Guo Y., Ono H., Nakatsu Y., Zhang J., Cui X., Iwashita M., Kumamoto S., Tsuchiya Y., Sakoda H., Fujishiro M., Kushiyama A., Koketsu Y., Kikuchi T., Kamata H., Nishimura F., Asano T.
  • Journal Title: Obes.Res.Clin.Pract. 4 Pages: 201-207
  • Peer Reviewed
• [Journal Article] Macrophage foam cell formation is augmented in serum from patients with diabetic angiopathy. (2010)
  • Author(s): Cui X., Kushiyama A., Yoneda M., Nakatsu Y., Guo Y., Zhang J., Ono H., Kanna M., Sakoda H., Ono H., Kikuchi T., Fujishiro M., Shiomi M., Kamata H., Kurihara H., Kikuchi M., Kawazu S., Nishimura F., Asano T.
  • Journal Title: DiabetesRes.Clin.Pract. 87 Pages: 57-63
  • Peer Reviewed
• [Journal Article] Nuclear IKKβ is an adaptor protein for IκBα ubiquitination and degradation in UV-induced NF-κB activation (2010)
  • Author(s): Yoshihiro Tsuchiya, et al
  • Journal Title: Molecular Cell Volume: 39 Pages: 570-582
  • Peer Reviewed
• [Journal Article] IκBβ is a positive and negative regulator of NF-κB activity during inflammation (2010)
  • Author(s): Hideaki Kamata
  • Journal Title: Cell Research Volume: 20 Pages: 1178-1180
  • Peer Reviewed
• [Journal Article] Decreased SIRT1 expression and LKB1 phosphorylation occurs with long-term high-fat diet feeding, in addition to AMPK phosphorylation impairment in the early phase (2010)
  • Author(s): Masayasu Yoneda
  • Journal Title: Obesity Research and Clinical Practice Volume: 40
  • Peer Reviewed
• [Journal Article] Pin1 associates with and induces translocation of CRTC2 to the cytosol, thereby suppressing CRE transcriptional activity (2010)
  • Author(s): Yusuke Nakatsu
  • Journal Title: Journal of Biological Chemistry Volume: 285 Pages: 33018-33027
  • Peer Reviewed
• [Journal Article] Macrophage foam cell formation is augmented in serum from patientswith diabetic angiopathy (2010)
  • Author(s): Cui X.
  • Journal Title: Diabetes Res.Clin.Pract. 87 Pages: 57-63
  • Peer Reviewed
• [Journal Article] 活性酸素によるリン酸化シグナル制御 (2009)
  • Author(s): 鎌田英明
  • Journal Title: 実験医学増刊:活性酸素シグナルと酸化ストレス 27 Pages: 2366-2372
• [Presentation] IKKβ act as an adaptor protein for Iκ Bαubiquitination and degradation in UV-induced NF-κB activation ; possible involvement in the TNF signaling. (2011)
  • Author(s): 土谷佳弘, 鎌田英明
  • Organizer: 13th International TNF Conference
  • Place of Presentation: Awajishima,Japan
  • Year and Date: 2011-05-17
• [Presentation] エネルギー状態によるCRTC3の発現制御と脂肪分化における役割の解明 (2010)
  • Author(s): 中津祐介, 迫田秀之, 櫛山暁史, 張君, 福嶋俊明, 内田隆史, 鎌田英明, 浅野知一郎
  • Organizer: 第33回日本分子生物学会・第83回日本生化学会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-10
• [Presentation] 新規Pin1結合タンパク質Trk-fused geneはAktの活性化を促進する (2010)
  • Author(s): 大崎慶子, 中津祐介, 迫田秀之, 櫛山暁史, 大野晴也, 渡辺俊明, 内田隆史, 福嶋俊明, 鎌田英明, 浅野知一郎
  • Organizer: 第33回日本分子生物学会・第83回日本生化学会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-10
• [Presentation] NF-κBと活性酸素(ROS)シグナルに連関したタンパク質のリン酸化と分解による細胞応答 (2010)
  • Author(s): 鎌田英明, 土谷佳弘, 浅野知一郎
  • Organizer: 第33回日本分子生物学会・第83回日本生化学会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-09
• [Presentation] 細胞内ストレスに応答した核内IKKβを介した新規NF-κB活性化機構 (2010)
  • Author(s): 土谷佳弘, 浅野知一郎, 鎌田英明
  • Organizer: 第33回日本分子生物学会・第83回日本生化学会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-09
• [Presentation] NF-κBと活性酸素(ROS)シグナルに連関したタンパク質のリン酸化と分解による細胞応答 (2010)
  • Author(s): 鎌田英明
  • Organizer: 第33回日本分子生物学会・第83回日本生化学会合同大会
  • Place of Presentation: 神戸(招待講演)
  • Year and Date: 2010-12-09
• [Presentation] Nuclear IKKb acts as an adaptor protein for IκBα degradation in UV-induced NF-κB activation (2010)
  • Author(s): 鎌田英明, 土谷佳弘
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: シンポジウム,大阪
  • Year and Date: 2010-09-24
• [Presentation] Nuclear IKKb acts as an adaptor protein for IκBα degradation in UV-induced NF-κB activation (2010)
  • Author(s): 鎌田英明
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪(招待講演)
  • Year and Date: 2010-09-24
• [Presentation] Nuclear IKKb acts as an adaptor protein for IκBα degradation in UV-induced NF-κB activation and promotes cell death. (2010)
  • Author(s): 鎌田英明
  • Organizer: International Symposium on the Innovation for Health And Sustainable Life Hiroshima University
  • Place of Presentation: Japan
  • Year and Date: 2010-03-09
• [Presentation] Nuclear IKKb acts as an adaptor protein for IkBa degradation in UV-induced NF-kB activation and promotes cell death (2010)
  • Author(s): Hideaki Kamata
  • Organizer: International Symposium on the Innovation for Health And Sustainable Life
  • Place of Presentation: Hiroshima University
  • Year and Date: 2010-03-09
• [Presentation] LPSによる脂肪組織インスリン抵抗性へのマクロファージの関与と,ARBによるインスリン抵抗性改善作用の機序 (2009)
  • Author(s): 岩下未咲, 熊本園子, 迫田秀之, 櫛山暁史,藤城緑, 中津祐介, 大野晴也, 大谷裕一郎, 土谷佳弘, 鎌田英明, 西村英紀, 浅野知一郎
  • Organizer: 第21回分子糖尿病学シンポジウム
  • Place of Presentation: 和歌山
  • Year and Date: 2009-12-12
• [Presentation] LPSによる脂肪組織インスリン抵抗性へのマクロファージの関与と、ARBによるインスリン抵抗性改善作用の機序 (2009)
  • Author(s): 岩下未咲
  • Organizer: 第21回分子糖尿病学シンポジウム
  • Place of Presentation: 和歌山
  • Year and Date: 2009-12-12
• [Presentation] 核内IKKを介したNF-κB活性化による細胞死亢進 (2009)
  • Author(s): 土谷佳弘, 浅野知一郎, 中山啓子, 加藤友久, Michael Karin, 鎌田英明
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-09
• [Presentation] GLUT1と相互作用を有する膜タンパク質4F2hcの同定と糖取り込みに与える影響 (2009)
  • Author(s): 大野晴也, 中津祐介, 大久保博史, 大谷祐一郎, 崔興龍, 張君, 郭瑩, 迫田秀之, 藤城緑, 堀家なな緒, 櫛山暁史, 土谷佳弘, 鎌田英明, 浅野知一郎
  • Organizer: 第82回日本生化学会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-24
• [Presentation] 細胞内ストレスに応答した核内IKKβを介した新規NF-κB活性化機構 (2009)
  • Author(s): 土谷佳弘, 浅野知一郎, 中山啓子, 加藤友久, Michael Karin, 鎌田英明
  • Organizer: 第82回日本生化学会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-23
• [Presentation] プロリン異性化酵素Pin1はTORC2と結合してCRE活性を抑制することで,肝の糖新生系を制御する (2009)
  • Author(s): 中津祐介, 堀家なな緒, 櫛山暁史, 迫田秀之, 大野晴也, 神名真智, 鎌田英明, 栗原裕基, 内田隆史, 浅野知一郎
  • Organizer: 第82回日本生化学会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-23
• [Presentation] プロリン異性化酵素Pin1はTORC2と結合してCRE活性を抑制することで、肝の糖新生系を制御する (2009)
  • Author(s): 中津祐介
  • Organizer: 第82回日本生化学会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-23
• [Remarks] ホームページ等
  • URL: http://first.lifesciencedb.jp/archives/1010
• [Remarks]
  • URL: http://home.hiroshima-u.ac.jp/ikagaku/
• [Remarks] 土谷佳弘、鎌田英明「第3のNF-κB活性化機構:紫外線はIKKβのアダプター機能を介してNF-κBの活性化を誘導する」文部科学省委託研究開発事業統合データベースプロジェクト:ライフサイエンス新着論文レビュー
  • URL: http://first.lifesciencedb.jp/archives/1010(2010)