Molecular bases and the counteracting strategy for the detrimental phenotype of Max-null ES cells

• Project/Area Number: 25670147
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• 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): KATANO Miyuki 埼玉医科大学, 医学部, 助手 (60521060)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: ES細胞 / 癌細胞 / アポトーシス / c-Myc / Nanog / Myc

Outline of Final Research Achievements

We have previously demonstrated that homozygous knockout of Max gene encoding indispensable partner protein for MYC family protein in ES cells leads to loss of pluripotent properties and extensive cell death. Furthermore, we have also demonstrated that such detrimental phenotypes of Max-null ES cells can be eased by the forced expression of Nanog encoding one of pluripotency marker proteins. In this research project, we have uncovered a part of the molecular mechanisms underscoring the phenotypes associated with ablation of Max expression in ES cells and the rescue effect attained by Nanog overexpression on Max-null ES cells.

Research Products

• [Journal Article] Functional crosstalk between Myc and PI3K signaling for supporting unlimited self-renewal of embryonic stem cells (2015)
  • Author(s): Hishida T, Nakachi Y, Mizuno Y, Katano M, Okazaki Y, Ema M, Takahashi S, Hirasaki M, Suzuki A, Ueda A, Nishimoto M, Hishida-Nozaki Y, Vazquez-Ferrer E, Sancho-Martinez I, Izpisua Belmonte JC, Okuda A.
  • Journal Title: STEM CELLS Volume: 33 Issue: 3 Pages: 713-725
  • DOI: 10.1002/stem.1893
  • Peer Reviewed / Open Access
• [Journal Article] Forced expression of Nanog or Esrrb preserves the ESC status in the absence of nucleostemin expression (2015)
  • Author(s): Katano M, Ema M, Nakachi Y, Mizuno Y, Hirasaki M, Suzuki A, Ueda A, Nishimoto M, Takahashi S, Okazaki, Okuda A.
  • Journal Title: STEM CELLS Volume: 33 Issue: 4 Pages: 1089-1101
  • DOI: 10.1002/stem.1918
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of Ccr4-Not complex components as regulators of transition from partial to genuine induced pluripotent stem cells (2014)
  • Author(s): Kamon M, Katano M, Hiraki K, Hishida T, Nakachi Y, Mizuno Y, Okazaki Y, Suzuki A, Hirasaki M, Ueda A, Nishimoto M, Kato H, Okuda A.
  • Journal Title: Stem Cells and Development Volume: 23 Issue: 18 Pages: 2170-2179
  • DOI: 10.1089/scd.2013.0326
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Genomic Aspects of Common Diseases (2014)
  • Author(s): Muramatsu M, Okuda A, and Okazaki Y.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 452 Pages: 211-212
  • Peer Reviewed
• [Journal Article] Establishment of a novel model of chondrogenesis using murine embryonic stem cells carrying fibrodysplasia ossificans progressiva-associated mutant ALK2. (2014)
  • Author(s): Fujimoto M, Ohte S, Shin M, Yoneyama K, Osawa K, Miyamoto A, Tsukamoto S, Mizuta T, Kokabu S, Machiya A, Okuda A, Suda N, Katagiri T.
  • Journal Title: Biochmical and Biophysical Research Communications Volume: 455 Issue: 3-4 Pages: 347-352
  • DOI: 10.1016/j.bbrc.2014.11.012
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Striking similarity in the gene expression levels of individual Myc module members among ESCs, EpiSCs, and partial iPSCs. (2013)
  • Author(s): Masataka Hirasaki, Keiko Hiraki-Kamon, Masayoshi Kamon, Ayumu Suzuki, Miyuki Katano, Masazumi Nishimoto, Akihiko Okuda.
  • Journal Title: PLoS One Volume: 8
  • Peer Reviewed
• [Journal Article] In vivo function and evolution of the eutherian-specific pluripotency marker UTF1. (2013)
  • Author(s): Nishimoto M, Katano M, Yamagishi T, Hishida T, Kamon M, Nabeshima Y, Nabeshima Y, Katsura Y, Satta Y, Deakin J E, Graves J A M, Kuroki Y, Ono R, Ishino F, Okazaki Y, Kato H and Okuda A.
  • Journal Title: PLoS One Volume: 8 Issue: 7 Pages: 68119-68119
  • DOI: 10.1371/journal.pone.0068119
  • Peer Reviewed
• [Journal Article] Abundant nucleostemin expression supports the undifferentiated properties of germ cell tumors (2013)
  • Author(s): Uema, N., Ooshio, T., Harada, K., Naito, M., Naka, K., Hoshii, T., Tadokoro, Y., Ohta, K., Ali, M.A., Katano, M., Soga, T., Nakanuma, Y., Okuda, A., Hirao, A.
  • Journal Title: Am. J. Pathol. Volume: 183 Issue: 2 Pages: 592-603
  • DOI: 10.1016/j.ajpath.2013.04.018
  • 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
• [Presentation] マウスES細胞においてNucleosteminノックアウトによる未分化性の消失はNanogもしくはEsrrbタンパク質強制発現により回避される (2014)
  • Author(s): 片野 幸、水野洋介、仲地 豊、平崎正孝、鈴木 歩、西本正純、岡崎康司、奥田晶彦
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 神奈川県横浜市 （パシフィコ横浜）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] 真獣類の発生過程におけるPer2とCKIの発現は概日リズム形成に重要である (2014)
  • Author(s): 西本正純、奥田晶彦、大西芳秋
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 神奈川県横浜市 （パシフィコ横浜）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] ミトコンドリア呼吸鎖異常症の原因遺伝子の包括的大規模解析 (2014)
  • Author(s): 木下善仁、徳澤佳美、神田将和、森山陽介、水野洋介、菅原（山下）泉、田丸俊輔、栃木秀乃、上原奈津美、仲地豊、八塚由紀子、入月浩美、鈴木聡美、Nurun Nahar Borna、平田智子、的場奈々、加藤英政、奥田晶彦、森雅人、安嶋まさみ、原嶋宏子、山崎太郎、村山圭、大竹明、岡崎康司
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 神奈川県横浜市 （パシフィコ横浜）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Jarid2 improves the kinetics and efficiency of transcription-based reprogramming (2013)
  • Author(s): Hiroyoshi Iseki,Yutaka Nakachi, Tomoaki Hishida, Yoko Tanimoto,Fumihiko Sugiyama, Ken-ichi Yagami, Akihiko Okuda, Yasushi Okazaki
  • Organizer: 11th annual meeting of ISSCR
  • Place of Presentation: Boston, USA
• [Presentation] Underlying the molecular bases of cell death phenotype of Max-null embryonic stem cells (2013)
  • Author(s): Akihiko Okuda
  • Organizer: Small RNAs to Stem Cells & Epigenetic Reprogramming Asia-2013 Meeting
  • Place of Presentation: 東京都文京区
• [Presentation] Mycモジュール遺伝子メンバーのほとんどが、ES細胞とEpiblast幹細胞の両者で同レベルの発現を示す (2013)
  • Author(s): 平崎正孝、片野 幸、鈴木 歩、西本正純、奥田晶彦
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸市
• [Presentation] MaxノックアウトES細胞の激しい細胞死はヌクレオチド欠乏に伴う複製ストレスにより引き起こされる (2013)
  • Author(s): 鈴木 歩、菱田友昭、平崎正孝、曽我朋義、奥田晶彦
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸市
• [Presentation] ヒト分化多能性細胞の分化の改善 (2013)
  • Author(s): 加藤英政、平木啓子、栄徳勝光、清澤秀孔、奥田晶彦
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸市
• [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/