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Functional analysis of a cancer suppressor gene, PTEN, in hematopoietic cells

Research Project

Project/Area Number 12670988
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionAkita Univ. (2001)
Osaka University (2000)

Principal Investigator

SUZUKI Akira  Akita Univ. School of Medicrne, Professor, 医学部, 教授 (10311565)

Co-Investigator(Kenkyū-buntansha) 仲野 徹  大阪大学, 微生物病研究所, 教授 (00172370)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2001: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2000: ¥2,100,000 (Direct Cost: ¥2,100,000)
KeywordsPTEN / hematopoietic / ガン抑制遺伝子 / 欠損マウス / 造血
Research Abstract

PTEN, atumor suppressor gene,is essential for embryogenesis.
We used the Cre-1oxP system to generate a T. cell-specific deletion of the Pten gene (LckCrePten^<flox/-> (Pten^<flox/->)mice). All Pten^<flox/-> mice developed CD4^+ T cell lymphomas by 17 weeks. Pten^<flox/-> mice showed increased thymic cellularity due in part to a defect in thymic negative selection. Pten^<flox/-> mice exhibited elevated levels of B cells and CD4^+ T cells in the periphery, spontaneous activation of CD4^+ T cells, autoantibody production, and hyperimmunbglobuhnemia. Pten^<flox/-> T cells hyperproliferateed, were autoreactive, secreteed increased levels of Th1/Th2 cytoianes, resisted apoptosis and showed increased phosphorylation of PKB/Akt. Peripheral tolerance to SEB was also impaired in Pten^<flox/-> mice. PTEN is thus an important regulator of T cell homeostasis and selftolerance.
We also generated a B cell-specific null mutation of Pten in mice (CD19CrePten^<flox/flox> (bPten^<flox/flox>) mice). bPten^< … More flox/flox> mice showed a marked accumulation of B la cells and increased levels of serum autoantibodies. Among B2 cells in bRen^<flox/flox> spleens, numbers of marginal zone B (MZB) cells were significantly increased while those of follicular B (FOB) cells were correspondingly decreased. Pten-deficient B cells hyperproliferated, were resistant to apoptotic stimuli, and showed enhanced migration. The survival kinase PKB/Akt was highly activated in Pten-deficient splenic B cells. In addition, bPten^<flox/flox> mice exhibited a defect of immunoglobulin class switch recombination that may have been associated with impaired induction of activation-induced cytidine deaminase (AID). Thus, Pten plays a role in developmental fate determination of B cells and is an indispensable regulator of B cell homeostasis.
To investigate the function of Pten in non-lymphoid cells, we first examine the differentiation of Pten defective ES cells into hematopoietic cells by op9 system. Pten defective ES cells showed significant impairment of differentiation into hematopoietic cells. We are now trying to establish other Pten defective ES cell lines to confirm whether the difference is really significant or not.
We also generated a hematopoietic stem cell-specific null mutation of Pten in mice (Tie2Cre Pten^<flox/flox> mice).These mice are embryonic lethal. We are now trying to analyze whether the lethality is due to hematopoietic disorder or not. Less

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Suzuki A et al.: "T cell-Apeeafic loss of Pten leads to defects in control and peripheral tolerance"Immunity. 14. 523-534 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Backman SA et al.: "Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease"Nature Genetics. 29. 396-403 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Higuchi M et al.: "Akt mediates Rac/cdc42-regulated cell motility in growth factor-stimulated cells and in invasive PTEN-Knockout cells"Current Biology. 11. 1958-1962 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Suzuki A et al.: "Development of Hematopoietic cells form embryonic stem cells"International Journal of Hematology. 73. 1-5 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sasaki T et al.: "Colorectal carcinomas in mice lacking the catalytic subunit of Pl(3)K-gamma"Nature. 406. 897-902 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Stambolic V et al.: "High incidence of breast and endometrial neoplesia resembling human Cowden syndrome in Pten^<+/-> mice"Cancer Research. 60. 3605-3611 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sasaki T et al.: "Function of P13k gamma in thymocyte clevelopment, Tall activation, and neutrophil migration"Science. 287. 1040-1046 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Suzuki A et al.: "Cell-Specific Loss of Pten Leads to Defects in Central and Peripheral Tolerance"IMMUNITY. 14. 523-534 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Backman SA et al.: "Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease"NATURE GENETICS. 29. 396-403 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Higuchi, M et al.: "Akt mediates Rac/Cdc42-Regulated Cell Motility in Growth Factor-Stimulated Cells and in Invasive PTEN-KnockoutCells"CURRENT BIOLOGY. 11. 1958-1965 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Suzuki A et al.: "Development of Hematopoietic Cells from embryonic stem cells"INTERNATIONAL JOURNAL of HEMATOLOGY. 73. 1-5 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sasaki T et al.: "Colorectal carcinomas in mice lacking the catalytic subunit of PI(3 )K-gammma"NATURE. 406. 897-902 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Stambolic V et al.: "High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice"CANCER RESEARCH. 60. 3605-11 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sasaki T et al.: "Function of PI3Kgammma in thymocyte development, T cell activation, and neutrophil migration"SCIENCE. 287. 1040-1046 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Suzuki A et al.: "T cell-specific loss of PTEN leads to defects in central and peripheral toleoeoance"Immunity. 14(5). 523-534 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Backman SA et al.: "Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos Disease"Pature Genetics. 29(4). 396-403 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Higuchi M et al.: "Akt mediates Rac/Cdc42-regulated cell motility in growth factor-stimulated cells and in invasive PTEN-knockout cells"Corrent Biology. 11(24). 1958-1962 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Suzuki A et al.: "Development of Hematopoietic cells from embryonic stem cells"International Journal of Hematology. 73. 1-5 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sasaki,T.,Irie-Sasaki,J., et al.: "Colorectal carcinomas in mice lacking the catalytic subunit of PI(3)K gamma."Nature. 406. 897-902 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Stambolic,V.,Tsao,M.S., et al.: "High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice."Cancer Res. 60. 3605-11 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sasaki,T.,Irie-Sasaki,J., et al.: "Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration."Science. 287. 1040-6 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 鈴木聡,仲野徹: "PTEN変異と自己免疫疾患"実験医学. (印刷中). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 山口麻奈絵,鈴木聡,仲野徹: "トレランス形成におけるPTENの意義"臨床免疫. (印刷中). (2001)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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