Molecular mechanism of neuronal cell death induced by methyl mercury via endoplasmic reticulum stress

• Project/Area Number: 22310039
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Risk sciences of radiation/Chemicals
• Research Institution: Okayama University
• Principal Investigator: UEHARA Takashi 岡山大学, 大学院・医歯薬学総合研究科, 教授 (00261321)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2012: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2011: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2010: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: メチル水銀 / 一酸化窒素 / 酸化ストレス / 神経細胞 / アポトーシス / 経変性疾患 / シグナル伝達 / 神経細胞死 / 小胞体ストレス / 水銀 / 水俣病 / S-ニトロシル化 / 重金属

Research Abstract

We found that methyl mercury results in neuronal cell death and the reduction of S-nitrosylated PDI formation in a concentration-dependent manner in SH-SY5Y cells. These observations suggested methyl mercury affects same cysteine residue that is oxidized by nitric oxide. Treatment with methyl mercury stimulated the specific splicing of XBP1 mRNA and phosphorylation of IRE1α. Thus, methyl mercury might induce apoptosis via endoplasmic reticulum stress caused by dysfunction of protein maturation system.

Research Products

• [Journal Article] Participation of metabotropic glutamate receptors in pentetrazol-induced kindled seizure (2011)
  • Author(s): Watanabe, Y., Kaida, Y., Fukuhara, S., Takechi, K., Uehara, T., and Kamei, C
  • Journal Title: Epilepsia Volume: 52 Issue: 1 Pages: 140-150
  • DOI: 10.1111/j.1528-1167.2010.02764.x
• [Journal Article] On-off system for PI3-kinase-Akt signaling through S-nitrosylation of phosphatase with sequence homology to tensin (PTEN) (2011)
  • Author(s): Numajiri N., Takasawa K., Nishiya T., Tanaka H., Ohno K., Hayakawa W., Asada M., Matsuda H., Azumi K., Kamata H., Nakamura T., Hara H., Minami M., Lipton S.A., Uehara T.
  • Journal Title: Proceedings of the National Academy of Sciences, USA Volume: 108 Issue: 25 Pages: 10349-10354
  • DOI: 10.1073/pnas.1103503108
  • Peer Reviewed
• [Journal Article] Screening systems for identification of S-nitrosylated proteins (2011)
  • Author(s): Uehara, T. and Nishiya, T
  • Journal Title: Nitric Oxide Volume: 25 Issue: 2 Pages: 108-111
  • DOI: 10.1016/j.niox.2010.11.002
  • Peer Reviewed
• [Journal Article] The ECS (SPSB) E3 ubiquitin ligase is the master regulator of the lifetime of inducible nitric-oxide synthase. Biochem (2011)
  • Author(s): Matsumoto, K., Nishiya, T., Maekawa, S., Horinouchi, T., Ogasawara, K., Uehara, T., and Miwa, S
  • Journal Title: Biophys. Res. Commun Volume: 409 Issue: 1 Pages: 46-51
  • DOI: 10.1016/j.bbrc.2011.04.103
  • Peer Reviewed
• [Journal Article] SPRY domain-containing SOCS box protein-1 (SPSB1), SPSB2, and SPSB4 are master regulators of proteasome-dependent degradation of iNOS (2011)
  • Author(s): Nishiya, T., Matsumoto, K., Maekawa, S., Horinouchi, T., Fujimuro, M., Ogasawara, K., Uehara, T., and Miwa, S
  • Journal Title: J. Biol. Chem Volume: 286 Issue: 11 Pages: 9009-9019
  • DOI: 10.1074/jbc.m110.190678
  • Peer Reviewed
• [Journal Article] Participation of metabotropic glutamate receptors in pentetrazol-induced kindled seizure (2011)
  • Author(s): Watanabe Y, et al
  • Journal Title: Epilepsia Volume: 52 Pages: 140-150
  • Peer Reviewed
• [Journal Article] SSPRY domain-containing SOCS box protein-1 (SPSB1), SPSB2, and SPSB4 are master regulators of proteasome-dependent degradation of iNOS. (2011)
  • Author(s): Nishiya, T.
  • Journal Title: J.Biol.Chem. Volume: 286 Pages: 9009-9019
  • Peer Reviewed
• [Journal Article] Sustained activation of ERK signaling in astrocytes is critical for neuronal injury-induced monocyte chemoattractant protein-1 production in rat corticostriatal slice cultures. (2010)
  • Author(s): Katayama, T.
  • Journal Title: Eur.J.Neurosci. Volume: 31 Pages: 1359-1367
  • Peer Reviewed
• [Journal Article] Screening systems for identification of S-nitrosylated proteins.
  • Author(s): Uehara, T.
  • Journal Title: Nitric Oxide Volume: (印刷中)
  • Peer Reviewed
• [Presentation] ガス状分子の神経細胞死に対する作用機構 (2012)
  • Author(s): 上原 孝
  • Organizer: 第39回日本毒性学会学術年会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2012-07-19
• [Presentation] NOによる蛋白質修飾と神経細胞死制御 (2012)
  • Author(s): 上原 孝
  • Organizer: 第53回日本生化学会 中国・四国支部例会
  • Place of Presentation: 岡山大学
  • Year and Date: 2012-05-18
• [Presentation] PTENのS-ニトロシル化を介するAktシグナル制御機構 (2012)
  • Author(s): 上原孝
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 北海道大学
  • Year and Date: 2012-03-29
• [Presentation] ニトロソ化/酸化ストレスによる小胞体蛋白質の機能不全 (2012)
  • Author(s): 柴田万里, 西屋禎, 上原孝
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2012-03-16
• [Presentation] A novel modulatory 'on-off' system for PI 3-kinase-Akt signaling through S-nitrosylation of PTEN (2011)
  • Author(s): Takashi Uehara
  • Organizer: 41^<st> Annual Meeting Neuroscience 2011
  • Place of Presentation: Walter E.Washington Convention Center, USA
  • Year and Date: 2011-11-13
• [Presentation] 一酸化窒素による細胞死連関シグナル制御機構 (2011)
  • Author(s): 上原孝
  • Organizer: 第6回小胞体ストレス研究会
  • Place of Presentation: 岡山大学
  • Year and Date: 2011-10-28
• [Presentation] A novel modulatory 'on-off' system for PI 3-kinase-Akt signaling through S-nitrosylation (2011)
  • Author(s): 上原 孝
  • Organizer: 第11回日本NO学会学術集会
  • Place of Presentation: 昭和薬科大学
  • Year and Date: 2011-05-14
• [Presentation] A novel modulatory 'on-off' system for PI 3-kinase-Akt signaling through S-nitrosylation (2011)
  • Author(s): 上原孝
  • Organizer: 第11回日本NO学会学術集会
  • Place of Presentation: 昭和薬科大学(招待講演)
  • Year and Date: 2011-05-14
• [Presentation] Compression of MgSiO3 and (Mg, Fe) SiO3 perovskites based on the pressure generation technique using sintered diamond anvils in a Kawai-type (2010)
  • Author(s): Daisuke Yamazaki, Eiji Ito, Xinzhuan Guo, Takashi, Yoshino.
  • Organizer: American Geophysical Union Fall Meeting 2010
  • Place of Presentation: モスコーニコンベンションセンター(米国)
  • Year and Date: 2010-12-15
• [Presentation] 抗体アレイを使用した新規S-ニトロシル化蛋白質の探索 (2010)
  • Author(s): 上原 孝
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会 合同大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2010-12-09
• [Presentation] Detection of oxidized protein-disulfide isomerase with a specific antibody (2010)
  • Author(s): Takashi Uehara
  • Organizer: 40th Annual Meeting Neuroscience 2010
  • Place of Presentation: San Diego Convention Centre
  • Year and Date: 2010-11-15
• [Presentation] NOによる小胞体ストレス惹起機構 (2010)
  • Author(s): 上原孝
  • Organizer: 第5回小胞体ストレス研究会
  • Place of Presentation: 東京大学薬学部
  • Year and Date: 2010-10-29
• [Presentation] 焼結ダイヤモンドアンビルを用いた川井型装置での圧力発生とペロフスカイトの圧縮率 (2010)
  • Author(s): 山崎大輔、伊藤英司、芳野極、下宿彰、肥後祐司、舟越賢一
  • Organizer: 第51回高圧討論会
  • Place of Presentation: 仙台市戦災復興記念館(宮城県)
  • Year and Date: 2010-10-21
• [Presentation] ニトロソ化ストレスを切り口とした神経変性疾患の早期診断/治療薬開発へのアプローチ (2010)
  • Author(s): 上原 孝
  • Organizer: 生体機能と創薬シンポジウム 2010京都
  • Place of Presentation: グランヴィア京都
  • Year and Date: 2010-09-09
• [Presentation] ニトロソ化ストレスを切り口とした神経変性疾患の早期診断/治療薬開発へのアプローチ (2010)
  • Author(s): 上原孝
  • Organizer: 生体機能と創薬シンポジウム 2010京都
  • Place of Presentation: グランビア京都
  • Year and Date: 2010-09-09
• [Presentation] The SPRY domain-containing SOCS box protein family regulates the lifetime of iNOS by linking iNOS with elongin BC-Cul5-Rbx2 E3 ubiquitin ligase complex. (2010)
  • Author(s): Nishiya, T.
  • Organizer: The 14th International Congress of Immunology (ICI2010)
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2010-08-23
• [Presentation] The life time of iNOS is regulated by the SPRY domain-containing SOCS box protein family linking iNOS to the elongin BC-Cul5-Rbx2 E3 ubiquitin ligase complex (2010)
  • Author(s): Tadashi Nishiya, Satoshi Maekawa, Masahiro Fujimuro, Kouetsu Ogasawara, Takashi Uehara, and Soichi Miwa
  • Organizer: The 6thInternational Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric oxide
  • Place of Presentation: The 6thInternational Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric oxide
  • Year and Date: 2010-06-17
• [Presentation] The life time of iNOS is regulated by the SPRY domain-containing SOCS box protein family linking iNOS to the elongin BC-Cul5-Rbx2 E3 ubiquitin ligase complex (2010)
  • Author(s): Nishiya, T.
  • Organizer: The 6th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric oxide
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2010-06-17
• [Presentation] Detection of oxidized ER protein by nitrosative/oxidative stress with a specific antibody (2010)
  • Author(s): Takashi Uehara
  • Organizer: The 6th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric oxide
  • Place of Presentation: 京都
  • Year and Date: 2010-06-16
• [Presentation] Detection of oxidized ER protein by nitrosative/oxidative stress with a specific antibody (2010)
  • Author(s): Uehara, T.
  • Organizer: The 6th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric oxide
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2010-06-16
• [Presentation] Rheology of the subducted slab in the lower mantle inferred from the connectivity of ferro-periclase in the post-spinel aggregates (2010)
  • Author(s): 山崎大輔
  • Organizer: 日本地球惑星科学連合2010年大会
  • Place of Presentation: 幕張メッセ(千葉)
  • Year and Date: 2010-05-27
• [Presentation] Mechanism of transformation from perovskite to post-perovskite (2010)
  • Author(s): D.Yamazaki, M.Murakami, M.Miyahara
  • Organizer: 日本地球惑星科学連合2010大会
  • Place of Presentation: 幕張メッセ(千葉)
  • Year and Date: 2010-05-25
• [Presentation] NOによる蛋白質修飾と神経細胞死制御
  • Author(s): 上原 孝
  • Organizer: 第５３回日本生化学会 中国・四国支部例会
  • Place of Presentation: 岡山大学
  • Invited
• [Presentation] ガス状分子の神経細胞死に対する作用機構
  • Author(s): 上原 孝
  • Organizer: 第３９回日本毒性学会学術年会
  • Place of Presentation: 仙台国際センター
  • Invited
• [Presentation] 一酸化窒素によるAkt シグナリング調節機構
  • Author(s): 上原 孝
  • Organizer: 第12回分子予防環境医学研究会
  • Place of Presentation: つくばサイエンス・インフォメーションセンター
  • Invited
• [Presentation] SPSB ファミリー蛋白質を介したCDC14A phosphatase のユビキチン－プロテアソーム依存的分解機構
  • Author(s): 西屋 禎
  • Organizer: 第８６回日本薬理学会年会
  • Place of Presentation: 福岡国際会議場
• [Presentation] メチル水銀によって惹起される神経細胞死における小胞体ストレスの関与
  • Author(s): 牧野堅人
  • Organizer: 日本薬学会第１３３回年会
  • Place of Presentation: パシフィコ横浜
• [Book] 一酸化窒素(NO)結合性(S-ニトロシル化)タンパク質の網羅的同定, 生化学85(1) (2013)
  • Author(s): 上原 孝
  • Total Pages: 6
• [Book] 小胞体内ニトロシル化による神経変性疾患の発症,脳21 (2013)
  • Author(s): 上原 孝
  • Total Pages: 6
  • Publisher: 金芳堂
• [Book] 金芳堂 (2013)
  • Author(s): 上原 孝
  • Total Pages: 6
  • Publisher: 脳２１
• [Book] 日本生化学会 (2013)
  • Author(s): 上原 孝
  • Total Pages: 6
  • Publisher: 生化学
• [Book] タンパク質ニトロシル化による細胞生死調節,実験医学30(17) (2012)
  • Author(s): 上原 孝
  • Total Pages: 7
  • Publisher: 羊土社
• [Book] 発癌/神経細胞の生死に関わる細胞内ROSシグナル制御,細胞工学31(2) (2012)
  • Author(s): 鎌田英明,上原 孝
  • Total Pages: 6
  • Publisher: 秀潤社
• [Book] 細胞工学 (2012)
  • Author(s): 鎌田英明
  • Total Pages: 6
  • Publisher: 秀潤社
• [Book] 実験医学 (2012)
  • Author(s): 上原 孝
  • Total Pages: 6
  • Publisher: 羊土社
• [Book] 細胞工学 (2012)
  • Author(s): 鎌田英明, 上原孝
  • Publisher: 秀潤社
• [Book] NOはPI3-キナーゼ-Aktシグナルのスイッチ分子として機能している,実験医学29(18) (2011)
  • Author(s): 上原 孝
  • Total Pages: 4
  • Publisher: 羊土社
• [Book] 実験医学 (2011)
  • Author(s): 上原孝
  • Publisher: 羊土社
• [Book] NO・ニトロソ化シグナルと細胞死,実験医学27(15) (2009)
  • Author(s): 上原 孝
  • Total Pages: 5
  • Publisher: 羊土社
• [Remarks]
  • URL: http://www.pharm.okayama-u.ac.jp/lab/yakuri/Uehara_Lab/Welcome.html
• [Remarks] 岡山大学大学院医歯薬学総合研究科薬効解析学分野
  • URL: http://pharm.okayama-u.ac.jp/lab/yakuri/Uehara_Lab/Welcome.html
• [Remarks]
  • URL: http://web.mac.com/takashi_uehara