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FUNCTIONAR ROFE OF C-FOS IN DIFFERENTIATION AND PROLIFERATION OF MATURE B CELLS

Research Project

Project/Area Number 09836001
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 免疫の制御機構
Research InstitutionCHIBA UNIVERSITY

Principal Investigator

TOKUHISA Takeshi  Graduate School of Medicine, Developmental Genetics Professor, 大学院・医学研究科, 教授 (20134364)

Co-Investigator(Kenkyū-buntansha) OKADA Seiji  Chiba University, Graduate School of Medicine, Developmental Genetics, Assistant, 大学院・医学研究科, 助手 (50282455)
HATANO Masahiko  Chiba University, Graduate School of Medicine, Developmental Genetics, Associate, 大学院・医学研究科, 助教授 (20208523)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1997: ¥2,000,000 (Direct Cost: ¥2,000,000)
Keywordsc-Fos / Mature B cells / Transgenic mice / Apoptosis / Hematopoietic stem cells / Dormant satae / Inducible promoter / 胚中心 / B細胞 / クラススイッチ
Research Abstract

c-Fos Induces Apoptosis in Germinal Center B Cells
We examined a role of c-Fos in differentiation of mature B cells into IgG producing cells using transgenic mice carrying the c-fos gene under the control of the IFN-a/b-inducible Mx promoter (Mx-c-fos) or the constitutive H-2^b promoter (H2-c-fos). Splenic B cells from Mx-c-fos mice were cultured with LPS and rlL-4, and IgG1^+ B cells were developed in the culture after d 3. When IEN-a/b was added in the culture from d 2, development of IgG1^+ B cells was perturbed and the number of apoptotic cells increased within 24 h, suggesting that c-Fos induces apoptosis in Ig class-switching B cells. To confirm the effect of c-Fos on the B cell differentiation in vivo, H2-c-fos mice were immunized with DNP-OVA.The mice produced primary IgM but not IgG anti-DNP Ab in sera and failed to generate germinal centers in spleen. The perturbation of germinal center formation in H2-c-fos mice was rescued by mating them with transgenic mice carrying the bcl … More -2 gene with the Ig promoter. However, primary IgG1 anti-DNP Ab production was still suppressed in doubly transgenic mice, suggesting that Bcl-2 can delay time of c-Fos-induced apoptosis in Ig class-switching B cells but cannot rescue the death. Since c-Fos is induced in mature B cells reacted with Ags and clonal deletion of self-reactive B cells in germinal centers is insensitive to Bcl-2, these results suggest that c-Fos plays a causal role in clonal deletion of germinal center B cells.
Prolonged Expression of c-fos Suppresses Cell Cycle Entry of Dormant Hematopoietic Stem Cells
The proto-oncogene c-fos was transiently up-regulated in primitive hematopoietic stem (Lin^-Sca-1^+) cells stimulated with stem cell factor, interleukin-3, and interleukin-6. To investigate a role of the c-fos in hematopoietic stem cells, we used bone marrow (BM) cells from transgenic mice carrying the c-fos gene under the control of the interferon-a/b inducible Mx-promoter (Mx-c-fos), and fetal liver cells from c-fos-deficient mice. Prolonged expression of the c-fos in Lin^- Sca-1^+ BM cells inhibited factor dependent colony formation and hematopoiesis on a stromal cell layer by keeping them at G0/G1 phase of the cell cycle. These Lin^- Sca-1^+ BM cells on a stromal layer entered into the cell cycle whenever exogenous c-fos was down-regulated. However, ectopic c-fos did not perturb colony formation by Lin^- Sca-1^+ BM cells after they entered the cell cycle. Furthermore, endogenous c-fos is not essential to cell cycle progression of hematopoietic stem cells since the factor dependent and the stroma dependent hematopoiesis by Lin^- Sca-1^+ fetal liver cells from c-fos-deficient mice were not impaired. These results suggest that the c-fos induced in primitive hematopoietic stem cells negatively controls cell cycle progression and maintains them in a dormant state. Less

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] Okada S., et al.: "A physiological role of Bcl-xL induced in activated macrophages." J.Immunol.160. 2590-2596 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Okabe S., et al.: "BAZF, a novel Bcl6 homolog, functions as a transcriptional repressor." Mol.Cell.Biol.18. 4235-4244 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Inada K., et al.: "c-Fos induces apoptosis in germinal center B cells." J.Immunol.161. 3853-3861 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Okada S., et al.: "Overexpression of c-fos suppresses cell cycle entry of dormant hematopoietic stem cells." Blood. 93. 816-825 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kobayashi K., et al.: "Expression of a murine homologue of inhibitor of apoptosis protein (IAP) is related to cell proliferation." Proc.Natl.Acad.Sci.USA.96・4. 1457-1462 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kobayashi, K., et al.: "Overexpression of c-fos inhibits down-regulation of a cdk2 inhibitor p27Kipl in splenic B 〓lls activated by sIg cross-linking." J.Immunol.158. 2050-2056 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yoshida T., et al.: "A role of Bc16 in mature cardiac myocytes." Cardiovasc.Res.(in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Okada S., et al.: "Overexpression of c-fos suppresses cell cycle entry of dormant hematopoitic stem cells." Blood. 93. 816-825 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kobayashi K., et al.: "Expression of a murine homologue of inhibitor of apoptosis protein (LAP) is related to cell proliferation." Proc.Natl.Acad.Sci.USA.96. 1457-1462 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Okada S., et al.: "A physiological role of Bcl-XL induced in activated macrophages." J.Immunol.160. 2590-2596 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Okabe S., et al.: "BAZF,a novel Bc16 homolog, functions as a transcriptional repressor." Mol.Cell.Biol.18. 4235-4244

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Inada, K., et al.: "c-Fos induces apoptosis in germinal center B cells." J.Immunol.161. 3853-3861 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kobayashi, K., et al.: "Overexpression of c-Fos inhibits down-regulation of a cdk2 inhibitor p27Kip1 in splenic B cells activated by sIg cross-linking." J.Immunol.158. 2050-2056 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Fukuda.T., et al.: "Disruption of the Bc16 gene results in an impaired germinal center formation." J.Exp.Med.186. 439-448 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Okada S.,et al.: "A physiological role of Bcl-xL induced in activated macrophages." J.Immunol.160. 2590-2596 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Okabe S.,et al.: "BAZF,a novel Bc16 homolog,functions as a transcriptional repressor." Mol.Cell.Biol.18. 4235-4244 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Inada K.,et al.: "c-Fos induces apoptosis in germinal center B cells." J.Immunol.161. 3853-3861 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Okada S.,et al.: "Overexpression of c-fos suppresses cell cycle entry of dormant hematopoietic stem cells." Blood. 93. 816-825 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kobayashi K.,et al.: "Expression of a murine homologue of inhibitor of apoptosis protein(IAP)is related to cell proliferation." Proc.Natl.Acad.Sci.USA.96・4. 1457-1462 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tetsu O.,et al.: "mel-18 negatively regulates cell cycle progression upon B cell antigen receptor stimulation though a cascade leading to c-myc/cdc25." Immunity. 9. 439-448 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kobayashi,K.: "Overexpression of c-fos inhibits down-regulation of a colk2 inhibitor p27Kipl in splenic B cells activated by sIg cross-linking." J.Immunol.158. 2050-2056 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Masuda,K.: "Phenotypes and invariant ab T cell antigen receptor expression of peripheral Va14+NKT cells." J.Immunol.158. 2076-2082 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Fukuda,T.: "Disruption of the Bc16 gene results in an impaired germinal center formation." J.Exp.Med.186. 439-448 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hatano,M.: "A novel pathogenesis of megacolon in Ncx/Hox11L.1 deficient mice." J.Clin.Invest.100. 795-801 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Okada,S.: "A Physiological Role of Bcl-xL Induced in Activated Macrophages." J.Immunol.(In press). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Okabe,S.: "Bazf,a novel Bc16 homologue,funcitions as a transcriptional repressor." Mol.Cell.Biol.(In press). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tokuhisa,T.: "Epitope-specific regulation of antibody respopnses.In:Handbook of experimental Immunology." Vth eddition.ed by L.A.Herzenberg,D.M.Weir,L.A.Herzenberg,and C.Blackwell.Blackwell Science,Inc., 4 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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