Role of post-transcriptional regulation in cellular senescence

• Project/Area Number: 24590368
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: National Center for Geriatrics and Gerontology
• Principal Investigator: SUGIMOTO Masataka 独立行政法人国立長寿医療研究センター, 老化細胞研究プロジェクトチーム, プロジェクトリーダー (50426491)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 細胞老化 / RNA結合タンパク質 / HuR / SASP / 翻訳制御 / ARF / 翻訳

Outline of Final Research Achievements

Upon stress, cells undergo irreversible growth arrest called cellular senescence. Cellular senescence acts as potent anti-tumor barrier, and recent observations suggest it is also involved in aging-associated disorders. Numerous studies have been performed to elucidate the mechanisms regulating senescence, but little is known about how post-transcriptional regulation contributes to it. In this study, we focused on the role of HuR in cellular senescence.
HuR level declined during cellular senescence. HuR knockdown induced senescence with concomitant expression of ARF protein. In addition, these cells show several senescence-associated features including the induction of cytokine induction. Moreover, adipose-specific deletion of HuR gene induced senescence in early age, which is accompanied by reduced insulin sensitivity. Together, these findings demonstrate HuR-mediated post-transcriptional regulation plays essential roles in the induction and maintenance of senescence phenotypes.

Research Products

• [Journal Article] ATM regulates adipocyte differentiation and contributes to glucose homeostasis. (2015)
  • Author(s): Takagi M., Uno M., Nishii R., Sugimoto M., Hasegawa S., Piao J., Ihara N., Kanai S., Kakei S., Tamura Y., Suganami T., Kamei Y., Shimizu T., Yasuda A., Ogawa Y., Mizutani S.
  • Journal Title: Cell Reports Volume: 10 Issue: 6 Pages: 957-967
  • DOI: 10.1016/j.celrep.2015.01.027
  • Peer Reviewed / Open Access
• [Journal Article] Loss of HuR leads to senescence-like cytokine induction in rodent fibroblasts by activating NF-κB. (2014)
  • Author(s): Hashimoto M, Tsugawa T, Kawagishi H, Asai A, Sugimoto M.
  • Journal Title: Biochim Biophys Acta. Volume: 1840 Issue: 10 Pages: 3079-3087
  • DOI: 10.1016/j.bbagen.2014.07.005
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] HuR maintains replicative lifespan by suppressing ARF tumor suppressor. (2013)
  • Author(s): Kawagishi, H., Hashimoto, M., Nakamura, H., Tsugawa, T., Watanabe, A., Kontoyiannis, D. L., and Sugimoto, M.
  • Journal Title: Molecular and Cellular Biology Volume: 33 Issue: 10 Pages: 1886-1900
  • DOI: 10.1128/mcb.01277-12
  • Peer Reviewed
• [Journal Article] Autoimmunity and persistent RAS- mutated clones long after the spontaneous regression of JMML (2013)
  • Author(s): Takagi M, Imai C, et al
  • Journal Title: Leukemia Volume: 27 Issue: 9 Pages: 1926-1928
  • DOI: 10.1038/leu.2013.82
  • Peer Reviewed
• [Journal Article] Artemis-dependent DNA double-strand break formation at stalled replication forks. (2013)
  • Author(s): Unno J, Takagi M, Piao J, Sugimoto M, Honda F, Maeda D, Masutani M, Kiyono T, Watanabe F, Morio T, Teraoka H, Mizutani S.
  • Journal Title: Cancer Sci. Volume: 104 Issue: 6 Pages: 703-10
  • DOI: 10.1111/cas.12144
  • Peer Reviewed
• [Presentation] HuR maintains replicative lifespan by repressing ARF tumor suppressor. (2012)
  • Author(s): Sugimoto,M, Kawagishi,H., Tsugawa,T., and Hashimoto,M.
  • Organizer: Keystone Symposia Aging and Diseases of Aging
  • Place of Presentation: Tokyo, Japan
• [Presentation] RNA結合タンパク質HuRは癌抑制タンパク質ARFを抑制することにより細胞の分裂寿命を維持する (2012)
  • Author(s): 杉本昌隆、川岸裕幸、津川貴行、中村英亮
  • Organizer: 日本基礎老化学会第35回大会
  • Place of Presentation: 東邦大学
• [Presentation] HuR regulates senescence-associated secretory phenotype through DNA damage response pathway. (2012)
  • Author(s): Tsugawa,T, Michihiro,H., Kawagishi,H, and Sugimoto,M.
  • Organizer: 第35回大会 日本分子生物学会年会（ワークショップ）
  • Place of Presentation: 福岡国際会議場
• [Presentation] 転写後発現調節機構を介した細胞老化の制御
  • Author(s): 杉本昌隆
  • Organizer: 第65回日本細胞生物学会
  • Place of Presentation: 名古屋
  • Invited
• [Presentation] 転写後発現調節機構を介した細胞老化の制御
  • Author(s): 橋本理尋、川岸裕幸、杉本昌隆
  • Organizer: 日本基礎老化学会第35回大会
  • Place of Presentation: 大阪
• [Presentation] Regulation of senescence-associated phenotypes by RNA-binding protein HuR.
  • Author(s): Tusugawa,T., Hashimoto,M., Kawagishi,H., and Sugimoto,M.
  • Organizer: Salk Symposia Mechanisms and Models of Cancer
  • Place of Presentation: La Jolla (米国)