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Isolation and characterization of genes involved in radiogenic mouse thymic lymphomas

Research Project

Project/Area Number 15201011
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Risk sciences of radiation/Chemicals
Research InstitutionNiigata University

Principal Investigator

KOMINAMI Ryo  Niigata University, Institute of Medicine and Dentistry, Professor, 医歯学系, 教授 (40133615)

Co-Investigator(Kenkyū-buntansha) MISHIMA Yukio  Niigata University, Institute of Medicine and Dentistry, Associate Professor, 医歯学系, 助教授 (30166003)
KATSURAGI Yoshinori  Niigata University, Institute of Medicine and Dentistry, Assistant, 医歯学系, 助手 (60401759)
OBATA Miki  Niigata University, Institute of Medicine and Dentistry, Instructor, 医学部, 教務職員 (00420307)
井上 順  新潟大学, 大学院・医歯学総合研究科, 助手 (70323962)
Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥42,510,000 (Direct Cost: ¥32,700,000、Indirect Cost: ¥9,810,000)
Fiscal Year 2005: ¥11,830,000 (Direct Cost: ¥9,100,000、Indirect Cost: ¥2,730,000)
Fiscal Year 2004: ¥14,820,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥3,420,000)
Fiscal Year 2003: ¥15,860,000 (Direct Cost: ¥12,200,000、Indirect Cost: ¥3,660,000)
Keywordslymphomas / radiation / susceptibility / Atrophic thymus / Bcl11b / ROS / リンパ腫抑制遺伝子 / 発がん感受性遺伝子 / アポーシス / MTF-1 / Chk1 / 2 / アポトーシス
Research Abstract

Mouse thymic lymphomas are one of the classic models of ionizing radiation-induced malignancies, resulting form a series of somatic mutations. Our results obtained in this project were as follows.
1. Whole-body γ-irradiation causes thymic atrophy and most of them eventually develop lymphomas. Thus, atrophic thymus may found precancerous cells. Examination of atrophic thymuses at various times after irradiation revealed that DNA changes occur at Bcl11b and Myc earlier than at Ikaros, Pten, and Notch1, suggesting the order of gene mutations during lymphomagenesis. These successive mutations probably give the cells a growth advantage, so that it forms an expanded clone eventually leading to lymphomas.
2. We also examined early effects of γ-ray on ROS levels in vivo because ROS may be a main cause for cancer development. ROS levels were compared between congenic mice of two different Mtf-1 genotypes that show distinct susceptibility to thymic lymphomas. Susceptible mice tended to retain larg … More e thymocytes with higher ROS levels more than resistant mice when examined at 7 days after irradiation. The high retention of such large thymocytes may be the foundation of prelymphoma cells.
3. Recurrent chromosomal rearrangements at BCL11B are found in human hematopoietic malignancies mostly of T-cell origin. We showed that Bcl11b+/-p53+/-mice exhibit greater susceptibility to lymphomas than Bcl11b+/+p53+/-mice but most lymphomas retained and expressed the wild-type Bcl11b allele. This suggests that Bcl11b is haploinsufficient for suppression of thymic lymphoma development in mice of the p53+/-background.
4. Thymocytes of Bcl11b-/-newborn mice exhibit apoptosis at a certain developmental stage when thymocytes reenter into the cell cycle. We showed that Bcl11b-knockdown T-cell lines, when exposed to growth stimuli, exhibit apoptosis at the S phase, consistent with in the in vivo result. The apoptosis was accompanied with decreases in a cell-cycle inhibitor, p27, and an anti-apoptotic protein, Bcl-xL, due to transcriptional repression. This repression was a likely consequence of the impairment of Sirt1, a NAD-dependent deacetylase associating with Bcl11b. These results implicate Bcl11b in the remedy for DNA replication stress and maintenance of genomic integrity. Less

Report

(4 results)
  • 2006 Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (34 results)

All 2007 2006 2005 2004 Other

All Journal Article (29 results) Publications (5 results)

  • [Journal Article] Haploinsufficiency of Bcl11b for suppression of lymphomagenesis and thymocyte development.2007

    • Author(s)
      K.Kamimura
    • Journal Title

      Biochemical and Biophysical Research Communications 355

      Pages: 538-542

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Lack of Bel11b tumor suppressor results in vulnerability to DNA replication stress andd amages.2007

    • Author(s)
      K.Kamimura
    • Journal Title

      Oncogene (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Multi-step lymphomagenesis deduced from DNA changes in thymic lymphomas and atrophic thymuses at various times after γ-irradiation.2007

    • Author(s)
      H.Ohi
    • Journal Title

      Oncogene (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Mtf-1 lymphoma-susceptibility locus affects retention of large thymocytes with high ROS levels in mice after γ-irradiation.2007

    • Author(s)
      M.Maruyama
    • Journal Title

      Biochemical and Biophysical Research Communications 354

      Pages: 209-215

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Lack of Bcl11b tumor suppressor results in vulnerability to DNA replication stress and amages.2007

    • Author(s)
      K.Kamimura
    • Journal Title

      Oncogene (inpress)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Multi-step lymphomagenesis deduced from DNA changes in thymic lymphomas and atrophic thymuses at various times after y-irradiation.2007

    • Author(s)
      H.Ohi
    • Journal Title

      Oncogene (inpress)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Mtf-1 lymphoma-susceptibility locus affects retention of large thymocytes with high ROS levels in mice after y-irradiation.2007

    • Author(s)
      M.Maruyama
    • Journal Title

      Biochemical and Biophysical Research Communications 354

      Pages: 209-215

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Expression of TCRαβ partly rescues developmental arrest and apoptosis of αβT cells in Bcl11b-/- mice1.2006

    • Author(s)
      J.Inoue
    • Journal Title

      The Journal of Immunology 176

      Pages: 5871-5879

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Trp53 Affects the Developmental Anomaly of Clefts of the Palate in Irradiated Mouse Embryos but not Clefts of the Lip with or without the Palate.2006

    • Author(s)
      S.Narai
    • Journal Title

      Radiation Research 166

      Pages: 877-882

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Radiation carcinogenesis in mouse thymic lymphomas2006

    • Author(s)
      R.Kominami
    • Journal Title

      Cancer Science 97

      Pages: 575-581

    • NAID

      10018175404

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Expression of TCRαβ partly rescues developmental arrest and apoptosis of αβT cells in Bcl11b-/-mice.2006

    • Author(s)
      J.Inoue
    • Journal Title

      The Journal of Immunologym 176

      Pages: 5871-5879

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Expression of TCRab partly rescues developmental arrest and apoptosis of ab T cells in Bcl11b^<-/->mice^12006

    • Author(s)
      Jun Inoue
    • Journal Title

      The Journal of Immunology (発表予定)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Radiation carcinogenesis in mouse thymic lymphomas2006

    • Author(s)
      Ryo Kominami
    • Journal Title

      Cancer Science (発表予定)

    • NAID

      10018175404

    • Related Report
      2005 Annual Research Report
  • [Journal Article] p53 prevents maturation of T cell development to the immature CD4-CD8+ stage in Bcl11b-/- mice.2005

    • Author(s)
      K.Okazuka
    • Journal Title

      Biochem. Biophys. Res. Commun 328

      Pages: 545-549

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Comparison of properties of spontaneous and radiation-induced mouse thymic lymphomas : role of Trp53 and radiation.2005

    • Author(s)
      T.Kubota
    • Journal Title

      Radiation Research 163

      Pages: 159-164

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo.2005

    • Author(s)
      P.Arlotta
    • Journal Title

      Neuron 45

      Pages: 207-221

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Predisposition to mouse thymic lymphomas in response to ionizing radiation depends on variant alleles encoding metal-responsive transcription factor-1 (Mtf-1).2005

    • Author(s)
      Y.Tamura
    • Journal Title

      Oncogene 24

      Pages: 399-406

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] p53 prevents maturation of T cell development to the immature CD4-CD8+ stage in Bcl11b-/-mice.2005

    • Author(s)
      K.Okazuka
    • Journal Title

      Biochem.Biophys.Res.Commun 328

      Pages: 545-549

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Mutant analysis reveals whirlin as a dynamic organizer in the growing hair cell stereocilium.2005

    • Author(s)
      Y.Kikkawa
    • Journal Title

      Human Molecular Genetics 14(3)

      Pages: 391-400

    • Related Report
      2005 Annual Research Report 2004 Annual Research Report
  • [Journal Article] Comparison of properties of spontaneous and radiation-induced mouse thymic lymphomas: role of Trp53 and radiation.2005

    • Author(s)
      T.Kubota
    • Journal Title

      Radiation research 163(2)

      Pages: 159-164

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo.2005

    • Author(s)
      P.Arlotta
    • Journal Title

      Neuron 45(2)

      Pages: 207-221

    • Related Report
      2005 Annual Research Report 2004 Annual Research Report
  • [Journal Article] Comparison of properties of spontaneous and radiation-induced mouse thymic lymphomas : role of Trp53 and radiation.2005

    • Author(s)
      T.Kubota
    • Journal Title

      Radiation research 163(2)

      Pages: 159-164

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Predisposition to mouse thymic lymphomas in response to ionizing radiation depends on variant alleles encoding metal-responsive transcription factor-1 (Mtf-1).2005

    • Author(s)
      Y.Tamura
    • Journal Title

      Oncogene 24(3)

      Pages: 399-406

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Involvement of V(D)J recombinase in generation of intragenic deletions of Rit1/Bcl11b tumor suppressor gene in {gamma}-ray-induced thymic lymphomas and in normal thymus of the mouse.2004

    • Author(s)
      J.Sakata
    • Journal Title

      Carcinogenesis 25

      Pages: 1069-1075

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Two distinct methods analyzing chromatin structure using centrifugation and antibodies to modified histone H3 : both provide similar chromatin states of the Rit1/Bcl11b gene.2004

    • Author(s)
      T.Togashi
    • Journal Title

      Biochem. Biophys. Res. Commun. 313

      Pages: 489-495

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Involvement of V(D)J recombinase in generation of intragenic deletions of Ritl/Bcl11b tumor suppressor gene in {gamma}-ray-induced thymic lymphomas and in normal thymus of the mouse.2004

    • Author(s)
      J.Sakata
    • Journal Title

      Carcinogenesis 25

      Pages: 1069-1075

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Two distinct methods analyzing chromatin structure using centrifugation and antibodies to modified histone H3 : both provide similar chromatin states of the Ritl/Bcl11b gene.2004

    • Author(s)
      T.Togashi
    • Journal Title

      Biochem.Biophys.Res.Commun. 313

      Pages: 489-495

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Ahl3,a third locus on mouse chromosome 17 affecting age-related hearing loss.2004

    • Author(s)
      M.Nemoto
    • Journal Title

      Biochemical and Biophysical Research Communications 324(4)

      Pages: 1283-1288

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Involvement of V(D)J recombinase in generation of intragenic deletions of Rit1/Bcl11b tumor suppressor gene in γ-ray-induced thymic lymphomas and in normal thymus of the mouse.2004

    • Author(s)
      J.Sakata
    • Journal Title

      Carcinogenesis 25(6)

      Pages: 1069-1075

    • Related Report
      2004 Annual Research Report
  • [Publications] Jun Sakata: "Involvement of V(D)J recombinase in generation of intragenic deletions of Rit1/Bcl11b tumor suppressor gene in γ-ray-induced thymic lymphomas and in normal thymus of the mouse"Carcinogenesis. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tadayuki Togashi: "Two distinct methods analyzing chromatin structure using centrifugation and antibodies to modified histone H3 : both provide similar chromatin states of the Rit1/Bcl11b gene"Biochemical and Biophysical Research Communications. 313. 489-495 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yasumitsu Kodama: "The D5Mit7 locus on mouse chromosome 5 provides resistance to γ-ray induced but not N-methyl-N-nitrosourea induced thymic lymphomas"Carcinogenesis. 25. 143-148 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hiroki Sato: "The D4Mit12 locus on mouse chromosome 4 provides susceptibility to both γ-ray-induced and N-methyl-N-nitrosourea-induced thymic lymphomas"Cancer Science. 94. 668-671 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yuichi Wakabayashi: "Bcl11b is required for differentiation and survival of αβ T lymphocyte"Nature Immunology. 4. 533-539 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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