Role of SIRT1 on regulation of senescence-associated secretory phenotype during senescence

• Project/Area Number: 24590369
• 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: MOTOYAMA NOBORU 独立行政法人国立長寿医療研究センター, 加齢健康脳科学研究部, 室長 (50277282)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 細胞老化 / SIRT1 / エピジェネティクス / アセチル化 / SASP / DNA損傷 / 細胞周期制御因子 / クロマチン / p53 / p21

Outline of Final Research Achievements

Senescent cells develop a pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). It has been thought that SASP may be a key phenomenon in linking cellular senescence with individual aging. SIRT1 is an NAD+-dependent protein deacetylase, which regulates a diverse set of biological processes. We showed that SIRT1 suppressed the expression of SASP factors. SIRT1 bound to the promoter regions of SASP components, but dissociated from them during cellular senescence. In SIRT1-depleted cells, the acetylation levels of these regions were already higher than those in control cells in the pre-senescent stage. Moreover, these acetylation levels in SIRT1-depleted cells were significantly higher than those in control cells during cellular senescence. These results suggest that SIRT1 repressed the expression of SASP factors through the deacetylation of histones in their promoter regions.

Research Products

• [Journal Article] SIRT1 suppresses the senescence-associated secretory phenotype through epigenetic gene regulation. (2015)
  • Author(s): Hayakawa T, Iwai M, Aoki S, Takimoto K, Maruyama M, Maruyama W, Motoyama N.
  • Journal Title: PLoS One. Volume: 10(1) Issue: 1 Pages: e0116480-e0116480
  • DOI: 10.1371/journal.pone.0116480
  • Peer Reviewed / Open Access
• [Journal Article] Necessary and sufficient role for a mitosis skip in senescence induction. (2014)
  • Author(s): Johmura Y, Shimada M, Misaki T, Naiki-Ito A, Miyoshi H, Motoyama N, Ohtani N, Hara E, Nakamura M, Morita A, Takahashi S, Nakanishi M.
  • Journal Title: Mol.Cell Volume: 55 Issue: 1 Pages: 73-84
  • DOI: 10.1016/j.molcel.2014.05.003
  • Peer Reviewed
• [Journal Article] Role of Gadd45a in Wip1-dependent regulation of intestinal tumorigenesis. (2012)
  • Author(s): Demidov ON, Zhu Y, Kek C, Goloudina AR, Motoyama N, Bulavin DV
  • Journal Title: Cell Death Differ Volume: 19 Issue: 11 Pages: 1761-1768
  • DOI: 10.1038/cdd.2012.57
  • Peer Reviewed
• [Journal Article] Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress (2012)
  • Author(s): Lee, I.H., Kawai, Y., Fergusson, M.M., Rovira, I.I., Bishop, A.J., Motoyama, N., Cao, L., and Finkel, T
  • Journal Title: Science Volume: 336 Issue: 6078 Pages: 225-228
  • DOI: 10.1126/science.1218395
  • Peer Reviewed
• [Presentation] SIRT1 epigenetically regulates DNA damagae-initiated pro-inflammatory response. (2014)
  • Author(s): Motoyama N, Hayakawa T, Iwai M, Aoki S, Maruyama W
  • Organizer: Molecular Biology of Aging, Cold Spring Harbor Laboratory Meeting
  • Place of Presentation: Cold Spring Harbor, NY, USA
  • Year and Date: 2014-10-01
• [Presentation] SIRT1 epigenetically regulates senescence-associated secretory phenotype during cellular senescence. (2014)
  • Author(s): Hayakawa T, Iwai M, Aoki S, Maruyama W, Motoyama N
  • Organizer: 第37回日本基礎老化学会大会
  • Place of Presentation: 大府市、愛知県
  • Year and Date: 2014-06-26 – 2014-06-27
• [Presentation] SIRT1 regulates DNA damage-mediated pro-inflammatory response. (2013)
  • Author(s): Hayakawa T, Iwai M, Aoki S, Maruyama W, Motoyama N.
  • Organizer: The 7th Symposium Mechanisms and Models of Cancer
  • Place of Presentation: La Jolla, USA
• [Presentation] SIRT1によるヒストン脱アセチル化を介したSASPのエピジェネティックな制御機構． (2013)
  • Author(s): 早川智久、岩井美佳、青木哲、丸山和佳子、本山 昇．
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] DNA損傷応答機構（DDR）による老化・がん化の制御
  • Author(s): 本山 昇
  • Organizer: 第34回日本分子生物学会
  • Place of Presentation: 福岡市
  • Invited
• [Book] 老化の分子生物学、その分子メカニズムから寿命延長まで (2014)
  • Author(s): 本山 昇
  • Publisher: 化学同人