Uncovering the molecular mechanism of c-Myc/Max transcriptional factor complex-mediated preservation of embryonic stem cell state

• Project/Area Number: 22590275
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Saitama Medical University
• Principal Investigator: OKUDA Akihiko 埼玉医科大学, 医学部, 教授 (60201993)
• Co-Investigator(Kenkyū-buntansha): KATO Hidemasa 埼玉医科大学, 医学部, 講師 (50292123)
• 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: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 発生医学 / ES細胞 / 未分化性 / 自己増殖性 / 多分化能 / 転写因子 / Myc / Max / Oct3/4 / c-Myc / 自己増殖 / Myc module活性 / Core module活性 / 細胞移植

Research Abstract

Embryonic stem (ES) cells are defined by their two remarkable properties, i.e., pluripotent and indefinite self-renewal properties. Although some papers had suggested the involvement of Myc family proteins including c-Myc protein for sustaining these prominent properties which ES cells have, this issue has never been addressed from the gene targeting analyses. Therefore, we conducted homozygous knockout of Max gene encoding an indispensable partner protein for all three Myc proteins (c-Myc, N-Myc and L-Myc) to exert their transcriptional activities as well as oncogensis promoting activities.

Research Products

• [Journal Article] Max was identified as a repressor of germ-cell related gene expression in mouse embryonic stem cells. (2013)
  • Author(s): Maeda I, Okamura D, Tokitake Y, Ikeda M, Kawaguchi H, Mise N, Abe K, Noce T, Okuda A, Matsui Y.
  • Journal Title: Nat. Commun. Volume: 4巻 Pages: 1754-1754
  • Peer Reviewed
• [Journal Article] Transcription factors interfering with dedifferentiation induce cell type-specific transcriptional profiles. (2013)
  • Author(s): Hikichi T, Matoba R, Ikeda T, Watanabe A, Yamamoto T, Yoshitake S, Tamura-Nakano M, Kimura T, Kamon M, Shimura M, Kawakami K, Okuda A, Okochi H, Inoue T,Suzuki A, Masui S.
  • Journal Title: Proc Natl Acad Sci USA Volume: 110巻 Pages: 6412-6417
  • NAID: 120005244176
  • Peer Reviewed
• [Journal Article] Transcription factors interfering with dedifferentiation induce cell type-specific transcriptional profiles. (2013)
  • Author(s): Hikichi T, Matoba R, Ikeda T, Watanabe A, Yamamoto T, Yoshitake S, Tamura-Nakano M, Kimura T, Kamon M, Shimura M, Kawakami K, Okuda A, Okochi H, Inoue T, Suzuki A, Masui S.
  • Journal Title: Proceeding of the National Academy of Sciences of USA Volume: 110 Issue: 16 Pages: 6412-6417
  • DOI: 10.1073/pnas.1220200110
  • NAID: 120005244176
  • Peer Reviewed
• [Journal Article] Max is a repressor of germ-cell-related gene expression in mouse embryonic stem cells (2013)
  • Author(s): Maeda, I., Okamura, D., Tokitake, Y., Ikeda, M, Kawaguchi, H., Mise, N., Abe, K., Noce, T., Okuda, A, Matsui, Y
  • Journal Title: Nature Communications Volume: 4 Issue: 1 Pages: 1754-1754
  • DOI: 10.1038/ncomms2780
  • Peer Reviewed
• [Journal Article] Sirt1, p53 and p38MAPK are crucial regulators of detrimental phenotypes of ESCs with Maxexpression ablation. (2012)
  • Author(s): Hishida T, Nozaki Y, Nakachi Y, Mizuno Y, Iseki H, Katano M, Kamon M, Hirasaki M, Nishimoto M, Okazaki Y, Okuda A.
  • Journal Title: Stem Cells Volume: 30巻 Pages: 1634-1644
  • Peer Reviewed
• [Journal Article] Zappavigna V, Nicolis, SK. Emx2 is a dose-dependent negative regulator of Sox2 telencephalic enhancers (2012)
  • Author(s): Mariani J, Favaro R, Lancini C, Vaccari G, Ferri ALM, Bertolini J, Tonoli D, Latorre E, Caccia R, Ronchi A, Ottolenghi S, Miyagi S, Okuda A
  • Journal Title: Nucleic Acids Res. Volume: 40巻 Pages: 6461-6476
  • Peer Reviewed
• [Journal Article] Emx2 is a dose-dependent negative regulator of Sox2 telencephalic enhancers. (2012)
  • Author(s): Mariani J, Favaro R, Lancini C, Vaccari G, Ferri ALM, Bertolini J, Tonoli D, Latorre E, Caccia R, Ronchi A, Ottolenghi S, Miyagi S, Okuda A, Zappavigna V, Nicolis SK.
  • Journal Title: Nucleic Acids Research Volume: 40 Issue: 14 Pages: 6461-6476
  • DOI: 10.1093/nar/gks295
  • Peer Reviewed
• [Journal Article] Indefinite self-renewal of ESCs through Myc/Max transcriptional complex-independent mechanisms. (2011)
  • Author(s): Hishida T, Nozaki Y, Nakachi Y, Mizuno Y, Okazaki Y, Ema M, Takahashi S, Nishimoto M, Okuda A.
  • Journal Title: Cell Stem Cell Volume: 9巻 Pages: 37-49
  • Peer Reviewed
• [Journal Article] Indefinite self-renewal of ES cells through Myc/Max transcriptional complexes-independent mechanisms (2011)
  • Author(s): Hishida T, Nozaki Y, Nakachi Y, Mizuno Y, Okazaki Y, Ema M, Takahashi S, Nishimoto M, Okuda A
  • Journal Title: Cell Stem Cell Volume: 9 Issue: 8 Pages: 37-49
  • DOI: 10.1002/stem.1147
  • Peer Reviewed
• [Journal Article] Indefinite self-renewal of ESCs through Myc/Max transcriptional complex-independent mechanisms (2011)
  • Author(s): Tomoaki Hishida
  • Journal Title: Cell stem Cell Volume: 9 Pages: 37-49
  • Peer Reviewed
• [Journal Article] Integration of exogenous DNA into mouse embryonic stem cell chromosome shows preference into genes and frequent modification at junctions. (2010)
  • Author(s): Suzuki K, Ohbayashi F, Nikaido I, Okuda A, Takaki H, Okazaki Y, Mitani K.
  • Journal Title: Chromosome Res. Volume: 18巻 Pages: 191-201
  • Peer Reviewed
• [Journal Article] Integration of exogenous DNA into mouse embryonic stem cell chromosome shows preference into genes and frequent modification at junctions (2010)
  • Author(s): Keiichiro Suzuki
  • Journal Title: Chromosome Research Volume: 18 Pages: 191-201
  • Peer Reviewed
• [Journal Article] mx2 is a dose-dependent negative regulator of Sox2 telencephal ic enhancer
  • Author(s): Jessica Mariani
  • Journal Title: Nucleic Acids Research Volume: (in press)
  • Peer Reviewed
• [Presentation] Unlimited self-renewal of mouse ES cells without Myc/Max complexes under 2i condition. (2012)
  • Author(s): 奥田晶彦
  • Organizer: 10th annual meeting of ISSCR
  • Place of Presentation: 横浜
• [Presentation] Reprogramming human cells into a humanized ground state (2011)
  • Author(s): Yosuke Moriyama, Hidemasa Kato, Keiko Hiraki, Shizuka Funayama, Yasushi Okazaki, Akihiko Okuda.
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜、パシフィコ横浜
  • Year and Date: 2011-12-13
• [Presentation] Context-dependent requirement of Myc/Max complexes for the maintenance of the indefinite self-renewal of ES cells (2011)
  • Author(s): Tomoaki Hishida, Yuriko Nozaki, Yutaka Nakachi, Yosuke Mizuno, Yasushi Okazaki, Masatsugu Ema, Satoru Takahashi, Masazumi Nishimoto, Akihiko Okuda
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜、パシフィコ横浜
  • Year and Date: 2011-12-13
• [Presentation] Eutherian-specific UTF1 gene is critical for the placental growth (2011)
  • Author(s): Masazumi Nishimoto, Miyuki Katano, Toshiyuki Yamagishi, Tomoaki Hishida, Masayoshi Kamon, Yoko Nabeshima, Yo-ichi Nabeshima, Yoko Kuroki, Ryuichi Ono, Fumitoshi Ishino, Hidemasa Kato, Akihiko Okuda.
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜、パシフィコ横浜
  • Year and Date: 2011-12-13
• [Presentation] Partial iPS 細胞を真の iPS 細胞へと変換する能力を持つ遺伝子のゲノムワイドスクリーニングによる同定 (2011)
  • Author(s): 加門正義、菱田友昭、平木啓子、片野 幸、西本正純、加藤英政、奥田晶彦
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜、パシフィコ横浜
  • Year and Date: 2011-12-13
• [Presentation] iPS 細胞誘導過程、 及びpluripotency 獲得後における c-Myc/Max転写複合体の役割 (2011)
  • Author(s): 奥田晶彦
  • Organizer: 再生医療実現化プロジェクト 第4回夏のワークショップ
  • Place of Presentation: 大阪市 TKP 大阪梅田ビジネスセンター
  • Year and Date: 2011-07-08
• [Presentation] Ground state condition renders Myc activity redundant in ES cells for their indefinite self-renewal (2011)
  • Author(s): Tomoaki Hishida, Akihiko Okuda
  • Organizer: 第9回幹細胞シンポジウム
  • Place of Presentation: 東京都港区 泉ガーデンギャラリー
  • Year and Date: 2011-05-14
• [Presentation] Ground state condition renders Mye activity redundant in ES cells for their indefinite self-renewal (2011)
  • Author(s): 菱田友昭
  • Organizer: 第9回幹細胞シンポジウム
  • Place of Presentation: 東京都港区六本木
  • Year and Date: 2011-05-14
• [Presentation] Myc/Max転写複合体非存在下におけるES細胞の無限の自己増殖性 (2011)
  • Author(s): 奥田晶彦
  • Organizer: 第10回再生医療学会
  • Place of Presentation: 東京都新宿区
  • Year and Date: 2011-03-02
• [Presentation] The Nexus between Nucleostemin and Nanog for the maintenance of ES cell pluripotency (2010)
  • Author(s): Miyuki Katano, Hidemasa Kato, Jun Nomura, Akihiko Okuda
  • 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: 神戸市 神戸ポートアイランド
  • Year and Date: 2010-12-10
• [Book] 第8章 幹細胞と癌細胞で発現するNucleostemin 遺伝子の役割: 細胞周期フロンティア (2010)
  • Author(s): 片野 幸、加藤英政、奥田晶彦
  • Publisher: 共立出版
• [Book] 細胞周期フロンティア (2010)
  • Author(s): 片野幸
  • Publisher: 共立出版
• [Remarks] 2011 年 7 月 8 日の Cell Stem Cell への論文発表(雑誌論文 No. 5)に伴い、産経新聞全国版(ES 細胞がん遺伝子不要 -高品質 iPS 細胞作製も-)を筆頭に、各種新聞で取り上げられた。
• [Remarks] 埼玉医科大学ゲノム医学研究センター
  • URL: http://www.saitama-med.ac.jp/genome/
• [Remarks]
  • URL: http://www.saitama-med.ac.jp/genome/
• [Remarks]
  • URL: http://www.saitama-med.ac.jp/genome/
• [Patent(Industrial Property Rights)] 人工多能性幹細胞の製造方法 (2011)
  • Inventor(s): 菱田友昭
  • Industrial Property Rights Holder: 学校法人 埼玉医科大学
  • Filing Date: 2011-02-15
  • Overseas