Analysis of mouse teeth hyperplasia and gut tissue enlargement by mutation of transcription factor Bcl11b

• Project/Area Number: 22592062
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Niigata University
• Principal Investigator: MISHIMA Yukio 新潟大学, 医歯学系, 准教授 (30142029)
• Co-Investigator(Kenkyū-buntansha): OBATA Miki 新潟大学, 医学部, 教務職員 (00420307)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 過剰歯形成 / 腸管組織の肥厚 / 転写因子Bcl11b/BCL11B / p^53 / Mdm2/HDM2 / シグナル伝達 / がん抑制遺伝子 / Bcl11b / p53 / Ｍｄｍ2/HDM2 / 発現制御 / がん抑制因子 / Mdm2 / Lucレポーターアッセイ / Bck11b / p27遺伝子 / p57遺伝子 / βカテニン / 転写制御 / 腸管組織肥厚

Research Abstract

Bcl11b/BCL11B is a C_2H_2 zinc finger transcription factor that acts as a haploinsufficient tumor suppressor. Mutations and deletion in the human orthologue BCL11B have been identified in human T-cell acute lymphoblastic leukemia (T-ALL) and a mouse model of thymic lymphomas. We have examined whether or not BCL11B directly affects the p^53 signaling pathway including HDM2, an ubiquitin ligase for p^53 degradation. This is because that the p^53 pathway regulates cell proliferation and the response to DNA damages to maintain genome integrity. We have obtained the results that BCL11B binds to human HDM2-P2 promoter by ChIP (chromatin immuno-precipitation) assay and inhibits HDM2 expression in a p^53-dependent manner. These date suggest that BCL11B affects the activity of the p53-HDM2 feedback loop. This may be a mechanism for the leukemic transformation in T-ALL and for the impairment of incisor development and the enlargement of intestine crypts in Bcl11b S826G/KO mouse.

Research Products

• [Journal Article] Impairment in differentiation and cell cycle of thymocytes by loss of a Bcl11b tumor suppressor allele that contributes to leukemogenesis (2012)
  • Author(s): R. Go, K. Takizawa, S. Hirose, Y. Katsuragi,Y. Aoyagi, S, Y. Mishima and R. Kominami
  • Journal Title: Leukemia Research Volume: 36 Issue: 8 Pages: 1035-1040
  • DOI: 10.1016/j.leukres.2012.04.028
  • Peer Reviewed
• [Journal Article] BCL11B tumor suppressor inhibits HDM2 expression in a p^53-dependent manner (2012)
  • Author(s): M. Obata, R. Kominami and Y. Mishima
  • Journal Title: Cellular Signalling Volume: 24 Issue: 5 Pages: 1047-1052
  • DOI: 10.1016/j.cellsig.2011.12.026
  • Peer Reviewed
• [Journal Article] Bcl11b heterozygosity leads to age-related hearing loss and degeneration of outer hair cells of the mouse cochlea (2011)
  • Author(s): H. Okumura, Y. Miyasaka, Y. Morita, T. Nomura, Y. Mishima, S. Takahashi and R. Kominami
  • Journal Title: Experimental Animals Volume: 60 Pages: 355-361
  • NAID: 10029550638
  • Peer Reviewed
• [Journal Article] Bcl11b heterozygousity promotes clonal expansion and differentiation arrest of thymocytes in γ-irradiated mice (2010)
  • Author(s): R. Go, S. Hirose, S. Morita, T. Yamamoto, Y. Katsuragi, Y. Mishima and R. Kominami
  • Journal Title: Cancer Science Volume: 101 Issue: 6 Pages: 1347-1353
  • DOI: 10.1111/j.1349-7006.2010.01546.x
  • Peer Reviewed
• [Journal Article] Clonally expanding thymocytes having lineage capability in γ-ray induced mouse atrophic thymus (2010)
  • Author(s): T. Yamamoto, S. Morita, E. Go, M. Obata, Y. Katsuragi, Y. Fujita, Y. Maeda, M. Yokoyama, Y. Aoyagi, H. Ichikawa, Y. Mishima and R. Kominami
  • Journal Title: International Journal of Radiation Oncology. Biology. Physics Volume: 77 Issue: 1 Pages: 235-243
  • DOI: 10.1016/j.ijrobp.2009.11.005
  • Peer Reviewed
• [Journal Article] Cell of origin in radiation-induced premalignant thymocytes with differentiation capability in mice conditionally losing one Bcl11b allele
  • Author(s): R. Go, S. Hirose, Y. Katsuragi, M. Obata, M. Abe, Y. Mishima, K. Sakimura and R.Kominami
  • Journal Title: Cancer Science Volume: (in press)
  • Peer Reviewed
• [Presentation] ヒトT細胞急性リンパ芽球性白血病で見いだされたBCL11B突然変異はp53依存性にHDM2プロモーター活性の抑制効果を阻害する (2012)
  • Author(s): 小幡美貴、木南凌、三嶋行雄
  • Organizer: 第35回日本分子生物学会年
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-13
• [Presentation] 転写因子Bcl11bはマウス上顎切歯におけるエナメル芽細胞前駆細胞の恒常性に寄与する (2012)
  • Author(s): 葛城美徳、安楽純子、中富満城、依田浩子、三嶋行雄、櫻庭喜行、権藤洋一、高木律男、大島勇人、木南凌
  • Organizer: 第35回日本分子生物学会年
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-12
• [Presentation] 放射線照射後の腸上皮におけるBcl11bの働き (2012)
  • Author(s): 葛城美徳、坂牧僚、小幡美貴、三嶋行雄、大塚健介、木南凌
  • Organizer: 第55回日本放射線影響学会
  • Place of Presentation: 仙台
  • Year and Date: 2012-09-07
• [Presentation] BCL11B inhibits HDM2 expression in a p^53-denpendent manner (2011)
  • Author(s): 小幡美貴、木南凌、三嶋行雄
  • Organizer: 第34回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-16
• [Presentation] Bcl11b transcription factor controls the formation and maintenance of ameloblast-lineage cells in mouse adult maxillary incisor (2011)
  • Author(s): 葛城美徳、安楽純子、中富満城、井出浩子、 三嶋行雄 、桜場喜行、権藤洋一、高木律夫、大島勇人、木南凌
  • Organizer: 第34回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-15
• [Presentation] Bcl11bの片アリル欠損はγ線照射後のマウス小腸上皮幹細胞の増殖を促進する (2011)
  • Author(s): 葛城美徳、坂牧僚、小幡美貴、三嶋行雄、木南凌
  • Organizer: 第54回日本放射線影響学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2011-11-17
• [Presentation] 転写因子Bcl11bはp^53経路を介して細胞増殖を抑制する (2011)
  • Author(s): 小幡美貴、坂牧僚、木南凌、三嶋行雄
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-23
• [Presentation] 転写因子Bcl11bはp53経路を介して細胞増殖を抑制する (2011)
  • Author(s): 小幡、坂牧、木南、三嶋
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都国際会議場(京都府)
  • Year and Date: 2011-09-23
• [Presentation] BCL11B inhibits HDM2 expression in a p53-dependent manner (2011)
  • Author(s): 小幡、木南、三嶋
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2011-09-23
• [Presentation] Loss of a Bcl11b allele promotes proliferation of stem cells in the mouse small intestine after γ-irradiation (2011)
  • Author(s): 葛城美徳、小幡美貴、三嶋行雄、木南凌
  • Organizer: 第14回国際放射線研究会議
  • Place of Presentation: ワルシャワ、ポーランド
  • Year and Date: 2011-08-28
• [Presentation] p27/p57遺伝子内のBcl11b依存性転写活性化及び抑制化制御配列 (2010)
  • Author(s): 小幡美貴、西川敦、木南凌、三嶋行雄
  • Organizer: 第83回日本生化学会大会/第33回日本分子生物学会年会合同学会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-09
• [Presentation] P27/p57遺伝子内のBcl11b依存性転写活性化及び抑制化制御配列 (2010)
  • Author(s): 小幡美貴
  • Organizer: 第33回日本分子生物学会年会,第83回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド(神戸)
  • Year and Date: 2010-12-09
• [Presentation] Bcl11bは腸上皮細胞の恒常性を制御する大腸がん抑制遺伝子である (2010)
  • Author(s): 葛城美徳、坂牧僚、小幡美貴、郷梨江香、三嶋行雄、権藤洋一、落合雅子、中釜斉、木南凌
  • Organizer: 第83回日本生化学会大会/第33回日本分子生物学会年会合同学会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-08
• [Presentation] Bcl11b is an intestinal tumor suppressor that controls intestinal cell homeostasis (2010)
  • Author(s): 坂牧僚、葛城美徳、小幡美貴、落合雅子、中釜斉、権藤洋一、三嶋行雄、木南凌
  • Organizer: 第69回 日本癌学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-22
• [Presentation] Bcl111b heterozygosity promotes clonal expansion and differentiation arrest of thymocytes in gamma-irradiated mice (2010)
  • Author(s): 郷梨江香、広瀬智史、葛城美徳、三嶋行雄、木南凌
  • Organizer: 第69回日本癌学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-22
• [Presentation] 放射線照射後の腸上皮におけるBcl11bの働き
  • Author(s): 葛城 美徳
  • Organizer: 第五十五回日本放射線影響学会
  • Place of Presentation: 仙台市
• [Presentation] 転写因子Bcl11bはマウス上顎切歯におけるエナメル芽細胞前駆細胞の恒常性に寄与する
  • Author(s): 葛城 美徳
  • Organizer: 第三十五回日本分子生物学会年会
  • Place of Presentation: 福岡市
• [Presentation] ヒトT細胞急性リンパ芽球性白血病で見いだされたBCL11B突然変異はp53依存性にHDM2プロモーター活性の抑制効果を阻害する
  • Author(s): 小幡 美貴
  • Organizer: 第三十五回日本分子生物学会年会
  • Place of Presentation: 福岡市
• [Remarks] 研究室ホームページ
  • URL: http://www.med.niigata-u.ac.jp/bcl/welcome.html