Molecular Genetic basis of neural selection by cell death during development and pathological condition

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 15100007
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Graduate School of Pharmaceutical Sciences, The University of Tokyo
• Principal Investigator: MIURA Masayuki The University of Tokyo, Graduate School of Pharmaceutical Sciences, Professor, 大学院薬学系研究科, 教授 (50202338)
• Project Period (FY): 2003 – 2006
• Keywords: caspase / Drosophila / genetics / neural development / IAP family / imaging / kinase / proteasome

Research Abstract

Programmed cell death and neurodegeneration occur in the brain. To elucidate the mechanisms of neural cell death including neurodegeneration, we developed a novel screen for genes involved in the neuronal cell death associated with neurodegeneration, involving the overexpression of individual genes throughout much of the Drosophila genome (GS screening). As a result of the screen of approximately 5000 fly strains, we identified and characterized the endd2 gene, which encodes the Drosophila ortholog of Sec61α (DSec61α) located in endoplasmic reticulum, as a new component of the neural cell death and degeneration pathways. We then performed a dominant-modifier screen of reaper for identification of neural-cell death related genes using a set of deficiency strains that cover more than 70% of the Drosophila genome. In this screening, we identified DmIKKε as a candidate component in the pathway of Reaper-induced cell death. DmIKKε was also identified as a candidate gene of neural cell death promoting gene in GS screening. Biochemical studies indicated that DmIKKε that promotes degradation of Drosophila IAP (DIAP 1) through direct phosphorylation. Inactivation of DmIKKε causes DIAP 1 accumulation without affecting developmental cell death. DmIKKε is a DIAP 1-degrading kinase that regulates endogenous levels of DIAP 1, which in turn regulates neural cell fate through non-apoptotic functions of caspases in vivo.

Research Products

• [Journal Article] Involvement of ER stress in retinal cell death. (2007)
  • Author(s): Shimazawa, M., Inokuchi, Y., Ito, Y., Murata, H., Aihara, M., Miura, M., Hara, H
  • Journal Title: Mol. Vision (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] いま、なぜ、「生活の協同」なのか (2007)
  • Author(s): 大沢 真理
  • Journal Title: 生活の協同-排除を超えてともに生きる社会へ(大沢真理編)(日本評論社) Pages: 3-28
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Comparative Livelihood Security Systems from a Gender Perspective, with a Focus on Japan (2007)
  • Author(s): Mari Osawa
  • Journal Title: Gendering the Knowledge Economy, Comparative Perspectives(Walby, S., H. Gottfried, K. Gottschall and Mari Osawa (eds.))(PalgraveMacmillan) Pages: 81-108
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Are Care Workers Knowledge Workers? (2007)
  • Author(s): Nishikawa, Makiko, Kazuko Tanaka
  • Journal Title: Gendering the Knowledge Economy, Comparative Perspectives(Walby, S., H. Gottfried, K. Gottschall and Mari Osawa (eds.))(PalgraveMacmillan) Pages: 207-227
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Caspase-mediated changes in Sir2α during apoptosis. (2006)
  • Author(s): Ohsawa, S., Miura, M
  • Journal Title: FEBS Lett. 580 Pages: 5875-5879
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Dronc coordinates cell death and compensatory proliferation. (2006)
  • Author(s): Kondo, S., Senoo-Matsuda, N., Hiromi, Y., Miura, M
  • Journal Title: Mol. Cell. Biol. 26 Pages: 7258-7268
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Drosophila IKK-related kinaseregulatesnonapoptoticfunction of caspases via degradation of IAPs. (2006)
  • Author(s): Kuranaga, E., Kanuka, H., Tonoki, A., Takemoto, K., Tomioka, T., Kobayashi, M., Hayashi, S., Miura, M
  • Journal Title: Cell 126 Pages: 583-596
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] IKKε regulates F actin assembly and interacts with Drosophila IAP1 in cellular morphogenesis. (2006)
  • Author(s): Oshima, K., Takeda, M., Kuranaga, E., Ueda, R., Aigaki, T., Miura, M., Hayashi, S
  • Journal Title: Curr. Biol. 16 Pages: 1531-1537
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 「生活の協同」の意義-社会的排除の文脈の中で (2006)
  • Author(s): 大沢 真理
  • Journal Title: 現代生協論の探求<理論編>(現代生協論編集委員会・編)(コープ出版) Pages: 31-58
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 社会的排除の装置となった「男性稼ぎ主」型セーフティネット (2006)
  • Author(s): 大沢 真理
  • Journal Title: 福祉レジームの日韓比較 社会保障・ジェンダー・労働市場(武川正吾、イ・ヘギョン編)(東京大学出版会) Pages: 231-255
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 社会政策の比較ジェンダー分析とアジア (2006)
  • Author(s): 大沢 真理
  • Journal Title: アジア女性研究 Pages: 20-28
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 空洞化する社会的セーフティネット-社会保障改革の失われた15年 (2006)
  • Author(s): 大沢 真理
  • Journal Title: 「失われた10年」を超えて[2]小泉改革への時代(東京大学社会科学研究所編)(東京大学出版会) Pages: 279-309
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Caspase-mediated changes in Sir2α during apoptosis. (2006)
  • Author(s): Ohsawa, S., Miura, M.
  • Journal Title: FEBS Lett. 580 Pages: 5875-5879
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Dronc coordinates cell death and compensatory proliferation. (2006)
  • Author(s): Kondo, S., Senoo-Matsuda, N., Hiromi, Y., Miura, M.
  • Journal Title: Mol.Cell.Biol. 26 Pages: 7258-7268
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Drosophila IKK-related kinase regulates nonapoptotic function of caspases via degradation of IAPs. (2006)
  • Author(s): Kuranaga, E., Kanuka, H., Tonoki, A., Takemoto, K., Tomioka, T., Kobayashi, M., Hayashi, S., Miura, M.
  • Journal Title: Cell 126 Pages: 583-596
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] IKKε regulates F actin assembly and interacts with Drosophila IAP 1 in cellular morphogenesis. (2006)
  • Author(s): Oshima, K., Takeda, M., Kuranaga, E., Ueda, R., Aigaki, T., Miura, M., Hayashi, S.
  • Journal Title: Current Biol. 16 Pages: 1531-1537
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of 14-3-3γ in FE65-dependent gene transactivation mediated by the APP cytoplasmic fragment. (2005)
  • Author(s): Sumioka, A., Nagaishi, S., Yoshida, T., Lin, A., Miura, M., Suzuki, T.
  • Journal Title: J. Biol. Chem. 280 Pages: 42364-42374
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Gain-of-function screen identifies a role of the Sec61α translocon in Drosophila postmitotic neurotoxicity. (2005)
  • Author(s): Kanuka, H., Hiratou, T., Igaki, T., Kanda, H., Kuranaga, E., Sawamoto, K., Aigaki, T., Okano., H., Miura, M.
  • Journal Title: BBA 1726 Pages: 225-237
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Drosophila caspase transduces Shaggy/GSK-3β kinase activity in neural precuorsor development. (2005)
  • Author(s): Kanuka, H., Kuranaga, E., Takemoto, K., Hiratou, T., Okano, H., Miura, M.
  • Journal Title: EMBO J. 24 Pages: 3793-3806
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Bax-like protein Drob-1 protects neurons from expanded polyglutamine-induced toxicity in Drosophila. (2005)
  • Author(s): Senoo-Matsuda, N., Igaki, T., Miura, M.
  • Journal Title: EMBO J. 24 Pages: 2700-2713
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Targeted expression of anti-apoptotic protein p35 in oligodendrocytes reduces delayed demyelination and functional impairment after spinal cord injury. (2005)
  • Author(s): Tamura, M., Nakamura, M., Ogawa, Y., Toyama, Y., Miura, M., Okano, H.
  • Journal Title: Glia 51 Pages: 312-321
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Isolation of gene sets affected specifically by polyglutamine expression : implication of the TOR signaling pathway in neurodegeneraton. (2005)
  • Author(s): Nelson, B., Nishimura, S., Kanuka, H., Kuranaga, E., Inoue, M., Hori, G., Nakahara, H., Miura, M.
  • Journal Title: Cell Death Diff. 12 Pages: 1115-1123
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A novel function of neuronal PAS domain protein 1 (NPAS1) in erythropoietin expression in neuronal cells. (2005)
  • Author(s): Ohsawa, S., Hamada, S., Kakinuma, Y., Yagi, T., Miura, M.
  • Journal Title: J. Neurosci. Res. 79 Pages: 451-458
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 福祉 : 生活保障から逃避する日本企業 (2005)
  • Author(s): 大沢 真理
  • Journal Title: 現代日本企業正業体制 下 秩序変容のダイナミクス(工藤章・橘川武郎・グレン・D、フツク編)(有斐閣) Pages: 155-179
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Role of 14-3-3γ in FE65-dependent gene transactivation mediated by the APP cytoplasmic fragment. (2005)
  • Author(s): Sumioka, A., Nagaishi, S., Yoshida, T., Lin, A., Miura, M., Suzuki, T.
  • Journal Title: J.Biol.Chem. 280 Pages: 42364-42374
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Gain-of-function screen identifies a role of the Sec61α translocon in Drosophila postmitotic neurotoxicity. (2005)
  • Author(s): Kanuka, H., Hiratou, T., Igaki, T., Kanda, H., Kuranaga, E., Sawamoto, K., Aigaki, T., Okano, H., Miura, M.
  • Journal Title: BBA 1726 Pages: 225-237
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Drosophila caspase transduces Shaggy/GSK-313 kinase activity in neural precuorsor development. (2005)
  • Author(s): Kanuka, H., Kuranaga, E., Takemoto, K., Hiratou, T., Okano, H., Miura, M.
  • Journal Title: EMBO J. 24 Pages: 3793-3806
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A novel function of neuronal PAS domain protein 1 (NPAS1) in erythropoietin expression in neuronal cells. (2005)
  • Author(s): Ohsawa, S., Hamada, S., Kakinuma, Y., Yagi, T., Miura, M.
  • Journal Title: J.Neurosci.Res. 79 Pages: 451-458
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Neurotoxic effects of lipopolysaccharide on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1b and expression of caspase-11 in mice. (2004)
  • Author(s): Arai, H., Furuya, T., Yasuda, T., Miura, M., Mizuno, Y., Mochizuki, H.
  • Journal Title: J. Biol. Chem. 279 Pages: 51647-51653
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A mechanism of impaired mobility of oligodendrocyte progenitor cells by tenascin C through modification of Wnt signaling. (2004)
  • Author(s): Kakinuma, Y., Saitoh, F., Osawa, S., Miura, M.
  • Journal Title: FEBS Lett. 568 Pages: 60-64
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A sulfatase regulating the migratory potency of oligodendrocyte progenitor cells through tyrosine phosphorylation of b-catenin. (2004)
  • Author(s): Kakinuma, Y., Saitoh, F., Ohsawa, S., Furuichi, T., Miura, M
  • Journal Title: J. Neurosci. Res. 77 Pages: 653-661
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Caspase-11 mediates inflammatory dopaminergic cell death in the 1-Methyl-4-Phenyl-1, 2, 3, 6-Tetrahydropyridine mouse model of Parkinson's disease. (2004)
  • Author(s): Furuya, T., Hayakawa, H., Yamad M., Yoshimi, K., Hisahara, S., Miura, M., Yoshikuni Mizuno, Y., Mochizuki, H
  • Journal Title: J. Neurosci. 24 Pages: 1865-1872
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A transgenic mouse model for monitoring endoplasmic reticulum stress. (2004)
  • Author(s): Iwawaki, T., Akai, R., Kohno, K, Miura, M.
  • Journal Title: Nature Medicine 10 Pages: 98-102
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The crucial role of caspase-9 in the disease progression of a transgenic ALS mouse model. (2004)
  • Author(s): Inoue, H., Tsukita, K., Iwasato, T., Suzuki, Y., Tomioka, M., Tateno, M., Nagao, M., Kawata, A., Saido, TC, Miura, M., Itohara, S., Takahashi, R.
  • Journal Title: EMBO J. 22 Pages: 6665-6674
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Neurotoxic effects of lipopolysaccharide on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1β and expression of caspase-11 in mice. (2004)
  • Author(s): Arai, H., Furuya, T., Yasuda, T., Miura, M., Mizuno, Y., Mochizuki, H.
  • Journal Title: J.Biol.Chem. 279 Pages: 51647-51653
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A sulfatase regulating the migratory potency of oligodendrocyte progenitor cells through tyrosine phosphorylation of β-catenin. (2004)
  • Author(s): Kakinuma, Y., Saitoh, F., Ohsawa, S., Furuichi, T., Miura, M.
  • Journal Title: J.Neurosci.Res. 77 Pages: 653-661
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Caspase-11 mediates inflammatory dopaminergic cell death in the 1-Methyl-4-Phenyl-1, 2, 3, 6-Tetrahydropyridine mouse model of Parkinson's disease. (2004)
  • Author(s): Furuya, T., Hayakawa, H., Yamada, M., Yoshimi, K., Hisahara, S., Miura, M., Mizuno, Y., Mochizuki, H.
  • Journal Title: J.Neurosci. 24 Pages: 1865-1872
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A transgenic mouse model for monitoring endoplasmic reticulum stress. (2004)
  • Author(s): Iwawaki, T., Akai, R., Kohno, K., Miura, M.
  • Journal Title: Nature Medicine 10 Pages: 98-102
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cytosol-ER interplay by Sec61 a translocon in polyglutamine-mediate neurotoxicity in Drosophila. (2003)
  • Author(s): Kanuka, H., Kuranaga, E., Hiratou, T., Igaki, T., Nelson, B., Okano, H., Miura, M.
  • Journal Title: Proc. Natl. Acad. Sci. USA. 100 Pages: 11723-11728
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Phosphorylation of alpha-synuclein characteristic of synucleinopathy lesions is recapitulated in alpha-synuclein transgenic Drosophila. (2003)
  • Author(s): Takahashi, M., Kanuka, H., Fujiwara, H., Koyama, A., Hasegawa, M., Miura, M., Iwatsubo, T.
  • Journal Title: Neurosci Lett. 336 Pages: 155-158
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Spatio-temporal activation of caspase revealed by indicator that is insensitive to environmental effects. (2003)
  • Author(s): Takemoto, K., Nagai, T., Miyawaki, A., Miura, M.
  • Journal Title: J. Cell Biol. 160 Pages: 235-243
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cytosol-ER interplay by Sec6lα translocon in polyglutamine-mediated neurotoxicity in Drosophila. (2003)
  • Author(s): Kanuka, H., Kuranaga, E., Hiratou, T., Igaki, T., Nelson, B., Okano, H., Miura, M.
  • Journal Title: Proc.Natl.Acad.Sci.USA. 100 Pages: 11723-11728
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Spatio-temporal activation of caspase revealed by indicator that is insensitive to environmental effects. (2003)
  • Author(s): Takemoto, K., Nagai, T., Miyawaki, A., Miura, M.
  • Journal Title: J.Cell Biol. 160 Pages: 235-243
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of ER stress in retinal cell death.
  • Author(s): Shimazawa, M., Inokuchi, Y., Ito, Y., Murata, H., Aihara, M., Miura, M., Hara, H.
  • Journal Title: Mol. Vision. (in press)
  • Description: 「研究成果報告書概要(欧文)」より