Regulation of INK4a/ARF gene locus and its role in cellular senescence

• Project/Area Number: 17013064
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Japanese Foundation For Cancer Research (2008-2009); The University of Tokushima (2005-2007)
• Principal Investigator: HARA Eiji Japanese Foundation For Cancer Research, 癌研究所がん生物部, 部長 (80263268)
• Project Period (FY): 2005 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥49,600,000 (Direct Cost: ¥49,600,000); Fiscal Year 2009: ¥10,700,000 (Direct Cost: ¥10,700,000); Fiscal Year 2008: ¥10,700,000 (Direct Cost: ¥10,700,000); Fiscal Year 2007: ¥9,400,000 (Direct Cost: ¥9,400,000); Fiscal Year 2006: ¥9,400,000 (Direct Cost: ¥9,400,000); Fiscal Year 2005: ¥9,400,000 (Direct Cost: ¥9,400,000)
• Keywords: p16^<INK4a> / p53 / イメージング / 細胞老化 / 癌抑制 / 加齢 / INK4A / ARF遺伝子座 / 染色体 / 発癌ストレス / P16^<INK4a> / 可視化 / p14^<ARF> / ルシフェラーゼ / 転写調節 / 発癌 / 細胞周期 / インビボ・イメージング

Research Abstract

We developed a bioluminescence imaging system for non-invasive and real-time analysis of p16^<Ink4a> expression in living mice. Using this system, we show that various oncogenic insults provoke epigenetic de-repression of p16^<Ink4a> expression through reduction of DNMT1 levels in vivo. This pathway is accelerated in the absence of p53, indicating that p53 normally holds the p16^<Ink4a> response in check. These results unveil a backup tumor suppressor role for p16^<Ink4a>in the event of p53 inactivation, expanding our understanding of how tumor suppression mechanism is regulated.

Research Products

• [Journal Article] Normal proliferation and tumorigenesis but impaired pancreatic function in mice lacking cell cycle regulator Seil (2010)
  • Author(s): Pablo J. Fernandez-Marcos
  • Journal Title: PLOS one 5-1 e8744 Pages: 1-12
  • Peer Reviewed
• [Journal Article] Real-time in vivo imaging of p16^<Ink4a> expression : a new approach to study senescence stress signaling in living animals (2010)
  • Author(s): Naoko Ohtani
  • Journal Title: Cell Division 5:1 Pages: 1-8
  • Peer Reviewed
• [Journal Article] Real-time in vivo imaging of p16Ink4a reveals cross-talk with p5 (2009)
  • Author(s): Yamakoshi, K., Takahashi, A., Hirota, F., Nakayama, R., Ishimaru, N., Kubo, Y., Mann, D.J., Ohmura, M., Hirao, A., Saya, H., Arase, S., Hayashi, Y., Nakao, K., Matsumoto, M., Ohtani, N., Hara, E.
  • Journal Title: J. Cell Biol. 186 Pages: 393-407
  • Peer Reviewed
• [Journal Article] Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation (2009)
  • Author(s): Inomata, K., Aoto, T., Binh, N.T., Okamoto, N., Tanimura, S., Wakayama, T., Iseki, S., Hara, E., Masunaga, T., Shimizu, H., Nishimura, E.K.
  • Journal Title: Cell 137 Pages: 1088-1099
  • Peer Reviewed
• [Journal Article] Real-time in vivo imaging of p16^<Ink4a> reveals cross talk with p53 (2009)
  • Author(s): Kimi Yamakoshi
  • Journal Title: The Journal of Cell Biology 186 Pages: 393-407
  • Peer Reviewed
• [Journal Article] Cellular senescence: Its role in tumor suppression and aglng. (2009)
  • Author(s): Naoko Ohtani
  • Journal Title: Cancer Science 100 Pages: 792-797
  • Peer Reviewed
• [Journal Article] Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation (2009)
  • Author(s): Ken Inomata,
  • Journal Title: Cell (印刷中)
  • Peer Reviewed
• [Journal Article] Visualizing the dynamics of p21Waf1/Cip1 cyclin-dependent kinase inhibitor expression in living animals (2007)
  • Author(s): Ohtani, N., Imamura, Y., Yamakoshi, K., Hirota, F., Nakayama, R., Kubo, Y., Ishimaru, N., Takahashi, A., Hirao, A., Shimizu, T., Mann, D.J., Saya, H., Hayashi, Y., Arase, S., Matsumoto, M., Nakao, K., Hara, E.
  • Journal Title: Proc. Natl. Acad. Sci. USA 104 Pages: 15034-15039
  • Peer Reviewed
• [Journal Article] Visualizing teh dynamics of P21^<Waf1/Cip1>cyclin-dependent kinase inhibitor expression in living animals. (2007)
  • Author(s): Naoko Ohtani
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America 104 Pages: 15034-15039
  • Peer Reviewed
• [Journal Article] Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence (2006)
  • Author(s): Takahashi, A., Ohtani, N., Yamakoshi, K., Iida, S., Tahara, H., Nakayama, K., Nakayama, K.I., Ide, T., Saya, H., Hara, E.
  • Journal Title: Nature Cell Biol. 8 Pages: 1291-1297
  • Peer Reviewed
• [Journal Article] Mitogenic signalling and the p16^<INK4a>/Rb pathway cooperate to enforce irreversible cellular senescence (2006)
  • Author(s): Akiko Takahashi
  • Journal Title: Nature Cell Biology 8 Pages: 1291-1297
• [Journal Article] Site-specific DNA methylation by a complex of PU.1. and Dnmt3a/b (2006)
  • Author(s): Mitsuhiro Suzuki
  • Journal Title: Oncogene 25 Pages: 2477-2488
• [Journal Article] The expression of p16(INK4a) tumor suppressor is upregulated by human cytomegalovirus infection and required for optimal viral replication. (2006)
  • Author(s): Claudia Zannetti
  • Journal Title: Virology 349 Pages: 79-86
• [Journal Article] Transforming activity of Fbxo7 is mediated specifically through regulation of cyclinD/cdk6 (2005)
  • Author(s): Laman, H., Funes, J., Ye, H., Henderson, S., Galinanes-Garcia, L., Hara, E., Knowles, P., McDonald, N., Boshoff, C.
  • Journal Title: EMBO J. 24 Pages: 3104-3116
  • Peer Reviewed
• [Journal Article] Reduction of total E2F/DP activity induces senescence-like cell cycle arrest in cancer cells lacking functional pRB and p53 (2005)
  • Author(s): Maehara, K., Yamakoshi, K., Ohtani, N., Kubo, Y., Takahashi, A., Arase, S., Jones, N., Hara, E.
  • Journal Title: J. Cell Biol. 167 Pages: 553-560
  • Peer Reviewed
• [Journal Article] Transforming activity of Fbxo7 is mediated specifically through regulation of cyclin D/cdk6 (2005)
  • Author(s): Heike Laman
  • Journal Title: The EMBO Journal 24 Pages: 3104-3116
• [Journal Article] Reduction of total E2F/DP activity induces senescence-like cell cycle arrest in cancer cells lacking functional pRB and p53 (2005)
  • Author(s): Kayoko Maehara
  • Journal Title: The Journal of Cell Biology 168 Pages: 553-560
• [Journal Article] Hepatocyte growth factor induces redistribution of p21 and p27 through ERK-dependent p16 up-regulation, leading to cell cycle arrest at G1 in HepG2 hepatoma cells (2005)
  • Author(s): Han Junhong
  • Journal Title: The Journal of Biological Chemistry 280 Pages: 31548-31556
• [Presentation] Visualizing the dynamics of Oncogenic stress response in living mice. (2009)
  • Author(s): Naoko Ohtani
  • Organizer: American Association for cancer Research conference on Mouse Models of Cancer
  • Place of Presentation: 米国サンフランンシスコ
  • Year and Date: 2009-01-13
• [Presentation] Real-time in vivo imaging of p16Ink4a unveils a cross talk between p53 and p16Ink4a (2009)
  • Author(s): Eiji Hara
  • Organizer: IMCB Symposium on Cell Cycle Regulation & Tumorigenesis
  • Place of Presentation: シンガポール
• [Presentation] Real-time in vivo imaging of p16Ink4a unveils a cross talk between p53 and p16Ink4a (2009)
  • Author(s): Kimi Yamakoshi, Akiko Takahashi, Naoko Ohtani, Eiji Hara
  • Organizer: The Salk Institute Meeting on Maechanisms and Models of Cancer
  • Place of Presentation: ラホヤ、アメリカ
• [Presentation] Real-time in vivo imaging of p16^<Ink4a> unveils a cross talk between p53 and p16^<Ink4a> (2009)
  • Author(s): Eiji Hara
  • Organizer: IMCB Symposium on Cell Cycle Regulation & Tumorigenesis
  • Place of Presentation: シンガポールシンガポール市
• [Presentation] Real-time imaging of p16^<1NK4a> expression visualizes the dynamics of senescence slgnaling in living mice. (2008)
  • Author(s): Eiji Hara
  • Organizer: 日本分子生物学会・日本生化学会合同大会
  • Place of Presentation: 神戸市ポートアイランド
  • Year and Date: 2008-12-10
• [Presentation] Real-time in vivo imaging of p16 tumor suppressor gene expression (2007)
  • Author(s): 原 英二
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-10-05
• [Presentation] The role of p16Ink4a CDK inhibitor in cell cycle control and cellular senescence. (2007)
  • Author(s): Eiji Hara
  • Organizer: Gene & Cancer Meeting
  • Place of Presentation: ウォーリック、イギリス
• [Presentation] Mitogenic signaling and p16/Rb-pathway cooperate to enforce irreversible cellular senescence through activating ROS/PKC-δ signaling pathway (2007)
  • Author(s): Akiko Takahashi, Naoko Ohtani, Kimi Yamakoshi, Eiji Hara
  • Organizer: Keystone Symposium
  • Place of Presentation: ウィスラー、カナダ
• [Book] 細胞周期アッセイ法がん分子標的治療研究マニュアル (2009)
  • Author(s): 高橋暁子、原英二
  • Publisher: 金芳堂
• [Remarks]
  • URL: http://www.jfcr.or.jp/tci/canbio/index.html
• [Remarks]
  • URL: http://www.jfcr.or.jp/tci/canbio/index.html