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MOLECULAR MECHANISM OF CELL DEATH AND ITS PHYSIOLOGICAL ROLE

Research Project

Project/Area Number 12219213
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionOsaka University

Principal Investigator

NAGATA Shigekazu  Osaka University, Graduate School of Frontier Biosciences, Professor, 生命機能研究科, 教授 (70114428)

Co-Investigator(Kenkyū-buntansha) FUKUNAGA Rikiro  Osaka University, Graduate School of Frontier Biosciences, Associate Professor, 生命機能研究科, 助教授 (40189965)
TANAKA Masato  Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (00294059)
FUKUYAMA Hidehiro  Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70303956)
KAWANE Koki  Osaka University, Graduate School of Frontier Biosciences, Assistant Professor, 生命機能研究科, 助手 (60362589)
Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥289,900,000 (Direct Cost: ¥289,900,000)
Fiscal Year 2004: ¥63,500,000 (Direct Cost: ¥63,500,000)
Fiscal Year 2003: ¥63,500,000 (Direct Cost: ¥63,500,000)
Fiscal Year 2002: ¥57,500,000 (Direct Cost: ¥57,500,000)
Fiscal Year 2001: ¥55,000,000 (Direct Cost: ¥55,000,000)
Fiscal Year 2000: ¥50,400,000 (Direct Cost: ¥50,400,000)
Keywordsapoptosis / macrophages / DNA degradation / enucleation of erythroid cells / autoimmune disease / DNase II / Caspase-activated DNase / innate immunity / 樹状細胞 / 抗核抗体 / MFG-E8 / ノックアウトマウス / 貧食 / 胸線 / DNase / インターフェロン / リン脂質 / 貪食 / 胸腺 / 赤血球 / CAD / DNaseII / ネクローシス / カスパーゼ / DNA断片化 / ミトコンドリア / Fasリガンド
Research Abstract

In this project, we have examined the molecular mechanism of apoptotic DNA degradation, and its physiological role. That is, we characterized the enzymatic properties of CAD (caspase-activated DNase) that was previously identified in our laboratory as a DNase activated during apoptosis. We then demonstrated by establishing the CAD-deficient mice that CAD is solely responsible for the cell-autonomous DNA degradation in apoptotic cells. Analysis of the apoptotic cells in the CAD-deficient mice showed that the DNA of apoptotic cells could be degraded in vivo by DNase II present in the macrophages after the dead cells were engulfed by phagocytes. The DNase II-deficient mice were then established, and the analysis of the mice showed that the DNase digests not only DNA of apoptotic cells, but also the DNA expelled from erythroid precursor cells. The DNase II-null mice were embryonic lethal, which was due to the interferon-β that was produced in macrophages carrying a large amount of undigested DNA by the activation of innate immunity. Using the knowledge that the DNA of apoptotic cells can be cleaved by macrophages after the dead cells are engulfed, we established a reliable assay method for engulfment of apoptotic cells. Using this system, we identified a factor called Milk Fat Globule-EGF8 (MFG-E8). MFG-E8 recognized apoptotic cells by binding to phosphatidylserine exposed to the apoptotic cells. MFG-E8 also bound to macrophages via integrin, indicating that it serves as a bridge between apoptotic cells and phagocytes. MFG-E8 was found to be expressed in a set of macrophages including tingible-body macrophages in the germinal centers of the spleen, and in immature dendritic cells. The MFG-E8-deficient mice accumulated unengulfed apoptotic cells in the germinal centers of the spleen, and developed autoimmune diseases such as nephritis, indicating that if apoptotic cells are not swiftly cleared from our bodies, they will induce the autoimmunity.

Report

(6 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (37 results)

All 2005 2004 2003 2002 2001 Other

All Journal Article (14 results) Publications (23 results)

  • [Journal Article] Lethal anemia caused by interferon-b produced in mouse embryos carrying undigested DNA.2005

    • Author(s)
      Yoshida, H.et al.
    • Journal Title

      Nature Immunol. 6

      Pages: 49-56

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice.2004

    • Author(s)
      Hanayama, R. et al.
    • Journal Title

      Science 304

      Pages: 1147-1150

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice2004

    • Author(s)
      Hanayama, R.et al.
    • Journal Title

      Science 304

      Pages: 1147-1150

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Expression of Developmental Endothelial Locus-1 in a subset of macrophages for engulfment of apoptotic cells2004

    • Author(s)
      Hanayama, R.et al.
    • Journal Title

      J.Immunol. 172

      Pages: 3876-3882

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Expression of Mho E8 in bone marrow-derived immature dendritic cells for engulfment of apoptotic cells.2004

    • Author(s)
      Miyasaka, K.et al.
    • Journal Title

      Eur.J.Immunol. 34

      Pages: 1414-1422

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Mnk2 and Mnk1 are essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E (eIF4E) but not for cell growth or development.2004

    • Author(s)
      Ueda, T.et al.
    • Journal Title

      Mol.Cell Biol. 24

      Pages: 6539-6549

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation.2003

    • Author(s)
      Kawane, K. et al.
    • Journal Title

      Nat Immunol 4

      Pages: 138-144

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Nuclear cataract caused by a lack of DNA degradation in the mouse eye lens.2003

    • Author(s)
      Nishimoto, S. et al.
    • Journal Title

      Nature 424

      Pages: 1071-1074

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation2003

    • Author(s)
      Kawane, K. et al.
    • Journal Title

      Nat Immunol 4

      Pages: 138-144

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Identification of a factor that links apoptotic cells to phagocytes2002

    • Author(s)
      Hanayama, R. et al.
    • Journal Title

      Nature 417

      Pages: 182-187

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Identification of a factor that links apoptotic cells to phagocytes.2002

    • Author(s)
      Hanayama, R. et al.
    • Journal Title

      Nature 417

      Pages: 182-187

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Requirement of DNase II for definitive erythropoiesis in themo use fetal liver.2001

    • Author(s)
      Kawane, K. et al.
    • Journal Title

      Science 292

      Pages: 1546-1549

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver.2001

    • Author(s)
      Kawane, K. et al.
    • Journal Title

      Science 292

      Pages: 1546-1549

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] DNA degradation in development and programmed cell death.

    • Author(s)
      Nagata, S.
    • Journal Title

      Annual Review in Immunology (in press)

    • Related Report
      2004 Annual Research Report
  • [Publications] Kawane, K. et al.: "Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation."Nat.Immunol.. 4. 138-144 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nagata S.: "Degradation of chromosomal DNA during apoptosis."Cell Death and Differ.. 10. 108-116 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ogawa, H. et al.: "Regulation of myeloid zinc finger protein 2A (MZF-2A) transactivation activity through phosphorylation by MAP kinases"Biol.Chem.. 278. 2921-2927 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ogawa, H. et al.: "A SWI2/SNF2-type ATPase/helicase protein, mDomino, interacts with myeloid zinc finger protein 2A (MZF-2A) to regulate its transcriptional activity"Genes to Cells. 8. 325-339 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nishimoto, S. et al.: "Nuclear cataract caused by a lack of DNA degradation in the mouse eye lens."Nature. 424. 1071-1074 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tada, K. et al.: "Tethering of apoptotic cells to phagocytes through binding of CD47 to SHPS-1^1."J.Immunol.. 171. 5718-5726 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hanayama, R.et al.: "Identification of a factor that links apoptotic cells to phagocytes"Nature. 417. 182-187 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Mukae, N.et al.: "Activation of the innate immunity in Drosophila by endogenous chromosomal DNA that escaped apoptotic degradation"Genes & Develop. 16. 2662-2671 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sakahira, H., Nagata, S.: "Co-translational folding of caspase-activated DNase with Hsp7O, Hsp4O, and inhibitor of caspase-activated DNase"J.Biol.Chem.. 277. 3364-3370 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagata S., et al.: "Degradation of chromosomal DNA during apoptosis"Cell Death & Differ.. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Kawane, K.et al.: "Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation"Nature Immunol.. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Ogawa, H.et al.: "Regulation of myeloid zinc finger protein 2A (MZF-2A) transactivation activity through phosphorylation by MAP kinases"J.Biol.Chem.. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Itai, T. et al.: "Processing of tumor necrosis factor by the membrane-bound TNFα-converting enzyme, but not its truncated soluble form"European Journal of Biology. 268. 2074-2082 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fukumoto, T.et al.: "The fused protein kinase regulates Hedgehog-stimulated transcription activation of Drosophila schneider 2 cells"Journal of Biological Chemistry. 276. 38441-38448 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kawane, K. et al.: "Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver"Science. 292. 1546-1549 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] D´Alessio, A. et al.: "Testicular FasL is expressed by sperm cells"Proceedings of National. Academy of Science of USA. 98. 3316-3321 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fukuyama, H. et al.: "Requirement of Fas expression in B cells for tolerance induction"European Journal of Immunology. 32. 223-230 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sakahira, H. et al.: "Co-translational folding of caspase-activated DNase with Hsp70, Hsp40 and inhibitor of CAD"Journal Biology of Chemistry. (In press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Matsumara,H. et al.: "Necrotic death pathway in Fas receptor signaling."Journal of Cell Biology. 151. 1247-1255 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] McIlroy,D. et al.: "An auxiliary mode of apoptotic DNA fragmentation provided by phagocytes."Genes & Development. 14. 549-558 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Mukae,N. et al.: "Identification and developmental expression of inhibitor of caspase-activated CNase (ICAD) in Drosophila melanogaster."Journal of Biological Chemistry. 275. 21402-21408 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Otomo,T. et al.: "Structure of the heterodimeric complex between CAD domains of CAD and ICAD."Nature Structure Biology. 7. 658-662 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tamada,K. et al.: "Modulation of T cell-mediated immunity in tumor and graft versus host disease models through LIGHT costimulatory pathway."Nature Medicine. 6. 283-289 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2018-03-28  

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