Elucidation of the mechanisms underlying in vivo carcinogenesis by comprehensive analyses of cellular senescence

• Project/Area Number: 17H01398
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: The University of Tokyo
• Principal Investigator: Nakanishi Makoto 東京大学, 医科学研究所, 教授 (40217774)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥42,640,000 (Direct Cost: ¥32,800,000、Indirect Cost: ¥9,840,000); Fiscal Year 2019: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000); Fiscal Year 2018: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000); Fiscal Year 2017: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
• Keywords: 細胞老化 / p53 / シングルセル解析 / 個体老化 / 発がん / DNA損傷応答 / 老化細胞 / メタボローム / Glutaminolysis / TCA回路 / 癌 / 老化 / 細胞・組織

Outline of Final Research Achievements

We found that there are many protein aggregates in lysosomes during senescence induction. These aggregates triggers activation of CaMKII-p38MAPK-IL-1 alpha-NF-kB axis, leading to the induction of SASP. Survival of senescent cells depends on activation of glutaminolysis and its inhibition induces mortality specifically in senescent cells. We develop mouse model in which senescent cells are visualized and can be analyzed at a single cell level. We also develop mouse model in which senescence induction can be regulated. Interestingly, aging process appears to be accelerated in these mouse after induction of senescence.

Academic Significance and Societal Importance of the Research Achievements

本研究により老化細胞特異的な除去技術のシーズが開発された。この技術により個体レベルで加齢性変化を改善することができた。現在日本は超高齢社会を迎えて加齢性変化を改善する技術が社会実装されれば社会全体に大きな貢献を果たすことは間違いない。

Research Products

• [Journal Article] Enhanced processivity of Dnmt1 by monoubiquitinated histone H3 (2020)
  • Author(s): Y. Mishima, L. Brueckner, S. Takahashi, T. Kawakami, J. Otani, A. Shinohara, K. Takeshita, R. G. Garvilles, M. Watanabe, N. Sakai, H. Takeshima, C. Nachtegael, A. Nishiyama, M. Nakanishi, K. Arita, K. Nakashima, H. Hojo, I. Suetake
  • Journal Title: Genes Cells Volume: 25 Issue: 1 Pages: 22-32
  • DOI: 10.1111/gtc.12732
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation (2020)
  • Author(s): A. Nishiyama, C. Mulholland, S. Bultmann, S. Kori, A. Endo, Y. Saeki, W. Qin, C. Trummer, Y. Chiba, H. Yokoyama, S. Kumamoto, T. Kawakami, H. Hojo, G. Nagae, H. Aburatani, K. Tanaka, K. Arita, H. Leonhardt, M. Nakanishi
  • Journal Title: Nat. Commun. Volume: 11 Issue: 1 Pages: 1222-1222
  • DOI: 10.1038/s41467-020-15006-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cdk1-mediated DIAPH1 phosphorylation maintains metaphase cortical tension and inactivates the spindle assembly checkpoint at anaphase. (2019)
  • Author(s): Nishimura K, Johmura Y, Deguchi K, Jiang Z, Uchida KSK, Suzuki N, Shimada M, Chiba Y, Hirota T, Yoshimura SH, Kono K, Nakanishi M.
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1-10
  • DOI: 10.1038/s41467-019-08957-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Isozyme-Specific Role of SAD-A in Neuronal Migration During Development of Cerebral Cortex (2018)
  • Author(s): Nakanishi Keiko、Niida Hiroyuki、Tabata Hidenori、Ito Tsuyoshi、Hori Yuki、Hattori Madoka、Johmura Yoshikazu、Yamada Chisato、Ueda Takashi、Takeuchi Kosei、Yamada Kenichiro、Nagata Koh-ichi、Wakamatsu Nobuaki、Kishi Masashi、Pan Y Albert、Ugawa Shinya、Shimada Shoichi、Sanes Joshua R、Higashi Yujiro、Nakanishi Makoto
  • Journal Title: Cerebral Cortex Volume: 160 Issue: 9 Pages: 721-721
  • DOI: 10.1093/cercor/bhy253
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fbxo22-mediated KDM4B degradation determines selective estrogen receptor modulator activity in breast cancer. (2018)
  • Author(s): Johmura Y, Maeda I, Suzuki N, Wu W, Goda A,Morita M, Yamaguchi K, Yamamoto M, Nagasawa S, Kojima Y, Tsugawa K, Inoue N, Miyoshi Y, Osako T Akiyama F, Maruyama R, Inoue JI, Fukukawa Y, Ohta T, Nkanishi M.
  • Journal Title: J Clin Invest. Volume: 128 Issue: 12 Pages: 5603-5619
  • DOI: 10.1172/jci121679
  • Peer Reviewed / Open Access
• [Journal Article] Usp7-dependent histone H3 deubiquitylation regulates maintenance of DNA methylation. (2017)
  • Author(s): Yamaguchi L, Nishiyama A, Misaki T, Johmura Y, Ueda J, Arita K, Nagao K, Obuse C, Nakanishi M
  • Journal Title: Scientific reports Volume: 7 Issue: 1 Pages: 1-12
  • DOI: 10.1038/s41598-017-00136-5
  • Peer Reviewed / Open Access
• [Journal Article] Structure of the Dnmt1 Reader Module Complexed with a Unique Two-Mono-Ubiquitin Mark on Histone H3 Reveals the Basis for DNA Methylation Maintenance. (2017)
  • Author(s): Ishiyama, S., Nishiyama, A., Saeki, Y., Moritsugu, K., Morimoto, D., Yamaguchi, L., Arai, N., Matsumura, R., Kawakami, T., Mishima, Y., Hojo, H., Shimamura, S., Ishikawa, F., Tajima, S., Tanaka, K., Ariyoshi, M., Shirakawa, M., Ikeguchi, M., Kidera, A., Suetake, I., Arita, K. and Nakanishi M.
  • Journal Title: Mol Cell Volume: 68 Pages: 350-360
  • Peer Reviewed
• [Journal Article] Exon 7 splicing variant of estrogen receptor α is associated with pathological invasiveness in smoking-independent lung adenocarcinoma. (2017)
  • Author(s): Suzuki, A., Okuda, K., Yano, M., Oda, R., Sakane, T., Kawano, O., Haneda, H., Moriyama, S., Nakanishi, M. and Nakanishi, R.
  • Journal Title: Oncol Lett Volume: 14 Issue: 1 Pages: 891-898
  • DOI: 10.3892/ol.2017.6216
  • Peer Reviewed / Open Access
• [Journal Article] The G2 checkpoint inhibitor CBP-93872 increases the sensitivity of colorectal and pancreatic cancer cells to chemotherapy. (2017)
  • Author(s): Iwata T, Uchino T, Koyama A, Johmura Y, Koyama K, Saito T, Ishiguro S, Arikawa T, Komatsu S, Miyachi M, Sano T, Nakanishi M, Shimada M.
  • Journal Title: Plos one Volume: 12 Issue: 5 Pages: 1-13
  • DOI: 10.1371/journal.pone.0178221
  • Peer Reviewed / Open Access
• [Journal Article] A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly. (2017)
  • Author(s): Negishi Y, Miya F, Hattori A, Johmura Y, Nakagawa M, Ando N, Hori I, Togawa T, Aoyama K, Ohashi K, Fukumura S, Mizuno S, Umemura A, Kishimoto Y, Okamoto N, Kato M, Tsunoda T, Yamasaki M, Kanemura Y, Kosaki K, Nakanishi M, Saitoh S.
  • Journal Title: BMC Med Genet. Volume: 18 Issue: 1 Pages: 4-4
  • DOI: 10.1186/s12881-016-0363-6
  • Peer Reviewed / Open Access
• [Presentation] 細胞老化の代謝的特性とSenolysis (2019)
  • Author(s): 中西 真
  • Organizer: 第28回 日本Cell Death学会学術集会
  • Invited
• [Presentation] 細胞老化と加齢性疾患 (2019)
  • Author(s): 中西 真
  • Organizer: 第81回 日本血液学会学術集会
  • Invited
• [Presentation] Metabolic vulnerability in senescent cells (2019)
  • Author(s): 中西 真
  • Organizer: 第42回 日本分子生物学会年会
  • Invited
• [Presentation] DNA維持メチル化とDNA複製の共役機構 (2018)
  • Author(s): 中西 真、西山 敦哉、有田 恭平
  • Organizer: 第12回 エピジェネティクス研究会年会
• [Presentation] 脂質代謝異常による老化細胞蓄積と老年病発症機序の解明 (2018)
  • Author(s): 中西 真
  • Organizer: 第29回研究成果発表会 第1回早石修記念賞記念式典・記念講演
• [Presentation] ゲノムストレスによる細胞老化誘導と個体老化における役割 (2018)
  • Author(s): 中西 真
  • Organizer: ゲノム創薬・医療フォーラム 第10回談話会
• [Presentation] Role of Cellular Senescence in Carcinogenesis. (2018)
  • Author(s): Makoto Nakanishi
  • Organizer: 第37回 札幌国際がんシンポジウム
  • Int'l Joint Research
• [Presentation] Molecular coupling between DNA methylation maintenance and DNA replication. (2018)
  • Author(s): Makoto Nakanishi
  • Organizer: EMBO Workshop Cellular signaling and cancer therapy.
  • Int'l Joint Research
• [Presentation] 発がんにおける細胞老化の役割 (2018)
  • Author(s): 中西 真
  • Organizer: 日本癌学会学術総会
• [Presentation] ゲノムストレスによる細胞老化誘導と個体老化 (2018)
  • Author(s): 中西 真
  • Organizer: 第13回 臨床ストレス応答学会大会シンポジウム
• [Presentation] Role of Cellular Senescence in Carcinogenesis. (2018)
  • Author(s): Makoto Nakanishi
  • Organizer: Genoproteomic Signature of Human Diseases.
  • Int'l Joint Research
• [Presentation] 人はなぜ老化するの？ (2018)
  • Author(s): 中西 真
  • Organizer: 豊明市民公開講座
  • Invited
• [Presentation] 老化とがん (2018)
  • Author(s): 中西 真
  • Organizer: 先端医学研究交流セミナー in Sapporo がん・白血病-先端研究の現状
  • Invited
• [Presentation] 老化細胞特有の代謝特性と形質維持 (2018)
  • Author(s): 中西 真
  • Organizer: 第29回 フォーラム・イン・ドージン
  • Invited
• [Presentation] Molecular coupling between DNA methylation maintenance and DNA replication. (2017)
  • Author(s): Makoto Nakanishi
  • Organizer: L'Institut Curie
  • Int'l Joint Research / Invited
• [Presentation] Molecular coupling between DNA methylation maintenance and DNA replication. (2017)
  • Author(s): Makoto Nakanishi
  • Organizer: University of Copenhagen
  • Int'l Joint Research / Invited
• [Presentation] Mechanism of senescence induction and maintenance and their role in aging (2017)
  • Author(s): Makoto Nakanishi
  • Organizer: 東北大学研究推進・支援基地の創出センター/Aging Science: from Molecules to Society
  • Int'l Joint Research
• [Presentation] エピゲノム修飾を介したオートファジー制御とがん (2017)
  • Author(s): 中西 真
  • Organizer: がんシリーズ第６回 エピゲノム情報に基づくがんの制御
• [Presentation] 細胞老化と前立腺疾患 (2017)
  • Author(s): 中西 真
  • Organizer: 第２０回 UPTシンポジウム
• [Book] アンチ・エイジング医学-日本抗加齢医学雑誌 (2018)
  • Author(s): 城村 由和、中西 真
  • Total Pages: 8
  • Publisher: メディカルレビュー社
  • ISBN: 9784779221606
• [Book] 実験医学 2017年9月号 (2017)
  • Author(s): 城村 由和 中西 真
  • Total Pages: 6
  • Publisher: 羊土社
  • ISBN: 9784758101677
• [Patent(Industrial Property Rights)] がんの予後判定方法 (2018)
  • Inventor(s): 中西 真
  • Industrial Property Rights Holder: 中西 真
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-177864
  • Filing Date: 2018
  • Acquisition Date: 2018
• [Patent(Industrial Property Rights)] 老化細胞を除去する方法、および老化細胞の調整方法 (2018)
  • Inventor(s): 中西 真
  • Industrial Property Rights Holder: 中西 真
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-210300
  • Filing Date: 2018
  • Acquisition Date: 2018