Molecular bases of apoptotic phenotype provoked by c-Myc which is liberated from Max control

• Project/Area Number: 25860244
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Saitama Medical University
• Principal Investigator: Hirasaki Masataka 埼玉医科大学, 医学部, 助教 (10522154)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ES細胞 / c-Myc / N-Myc / mouse ES / Max / Nanog / アポトーシス

Outline of Final Research Achievements

In 2011, our lab reported that extinction of Max gene expression in ES cells provoke cell death. In this study, we found that Nanog is co-precipitated with N-Myc and c-Myc proteins in a Max protein independent manner. Next we performed the experiments with Myc-ER fusion protein and found that activation of Myc activities in ESCs provokes apoptosis like that observed with Max-null ES cells. Indeed, we found that c-Myc-ER stable transfectants of wild-type ESCs show extensive apoptotic phenotype by the addition of 4-hydroxytamoxifen. Based on these findings, we hypothesize that Myc proteins liberated from Max control in Max-KO ESCs attribute to apoptotic phenotype of Max-KO ESCs and Nanog can neutralize apoptosis-promoting activity of Myc proteins by interacting with them.

Academic Significance and Societal Importance of the Research Achievements

ES細胞においてMax欠損状態では、生物学的な機能を持たないであろうと考えられていたc-Mycが、アポトーシスを誘導するという思いもよらない現象を引き起こした。そこで申請者は、この現象を規定している分子メカニズムを解明する事は、c-Myc に関して全く新しい分子指標を見出すことに繋がるのではないかと考えている。そして、この研究は、c-Myc を標的としたES 細胞のアポトーシス誘導による、未分化状態の細胞を優先的に死滅させる創薬や排除させるシステムの構築の指針なると考えている。

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] The protein phosphatase Siw14 controls caffeine-induced nuclear localization and phosphorylation of Gln3 via the type 2A protein phosphatases Pph21 and Pph22 in Saccharomyces cerevisiae. (2015)
  • Author(s): Numamoto M, Sasano Y, Hirasaki M, Sugiyama M, Maekawa H, Harashima S.
  • Journal Title: J. Biochem. Volume: 157 Issue: 1 Pages: 53-64
  • DOI: 10.1093/jb/mvu055
  • NAID: 40020325374
  • 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] 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 Issue: 12 Pages: e83769-e83769
  • DOI: 10.1371/journal.pone.0083769
  • 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
• [Presentation] Does Nanog neutralize the apoptosis-promoting activity of c-Myc liberated from Max control? (2014)
  • Author(s): Masataka Hirasaki, Atsushi Ueda, Miyuki Katano, Ayumu Suzuki, Masazumi Nishimoto, Akihiko Okuda
  • Organizer: 第12回RCGMフロンティアシンポジウム
  • Place of Presentation: 埼玉県日高市・埼玉医科大学 30周年記念講堂
  • Year and Date: 2014-10-31 – 2014-11-01
• [Presentation] Nanog は、Max非結合型Mycによるアポトーシスを抑圧するか？ (2014)
  • Author(s): 平崎 正孝、上田 篤、 片野 幸、 鈴木 歩、 西本 正純、 奥田 晶彦
  • Organizer: 4.「人工多能性幹細胞（iPS 細胞）作製・制御等の医療基盤技術」研究領域 平成２６年度領域ミーティング
  • Place of Presentation: 兵庫県淡路島市・兵庫県立淡路夢舞台国際会議場
  • Year and Date: 2014-10-28 – 2014-10-29
• [Presentation] Strict conservation of expression levels of individual Myc module genes between ESCs and EpiSCs (2013)
  • Author(s): Masataka Hirasaki, Miyuki Katano, Ayumu Suzuki, Masazumi Nishimoto, Akihiko Okuda
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 兵庫県神戸市・神戸ポートアイランド
• [Presentation] Mycモジュール遺伝子群はES細胞とEpiblast幹細胞の両者で高い発現の類似性を示す (2013)
  • Author(s): 平崎 正孝、片野 幸、 鈴木 歩、 西本 正純、 奥田 晶彦
  • Organizer: 第11回RCGMフロンティアシンポジウム
  • Place of Presentation: 埼玉県日高市・埼玉医科大学 ３０周年記念講堂