Mechanism of premature senescence induction through DNA damage responses

• Project/Area Number: 23240124
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Carcinogenesis
• Research Institution: Nagoya City University
• Principal Investigator: NAKANISHI Makoto 名古屋市立大学, 医学(系)研究科(研究院), 教授 (40217774)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥49,400,000 (Direct Cost: ¥38,000,000、Indirect Cost: ¥11,400,000); Fiscal Year 2013: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000); Fiscal Year 2012: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000); Fiscal Year 2011: ¥20,800,000 (Direct Cost: ¥16,000,000、Indirect Cost: ¥4,800,000)
• Keywords: 癌 / ゲノム / シグナル伝達 / 発現抑制 / 老化

Research Abstract

Senescence is a state of permanent growth arrest and is a pivotal part of the anti-tumorigenic barrier in vivo. Although the tumor suppressor activities of p53 and pRb family proteins are essential for the induction of senescence, molecular mechanisms by which these proteins induce senescence are still not clear. Using time-lapse live-cell imaging, we demonstrate here that normal human diploid fibroblasts (HDFs) exposed to various senescence-inducing stimuli undergo a mitosis skip before entry into permanent cell cycle arrest. This mitosis skip is mediated by both p53-dependent premature activation of APC/CCdh1 and pRb family protein-dependent transcriptional suppression of mitotic regulators. Importantly, mitotic skipping is necessary and sufficient for senescence induction. Our findings provide decisive evidence for the molecular basis underlying the induction and maintenance of cellular senescence.

Research Products

• [Journal Article] Necessary and sufficient role for a mitosis skip in senescence induction (2014)
  • Author(s): Johumra 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: (in press)
  • Peer Reviewed
• [Journal Article] Mammalian-specific H2A variant, H2ABbd, is Involved in Apoptotic Induction via Activation of NF-κB Signaling Pathway. (2014)
  • Author(s): Goshima T, Shimada M, Sharif J, Matsuo H, Misaki T, Johmura Y, Murata K, Koseki H, Nakanishi M.
  • Journal Title: J Biol Chem. Volume: 未定 Issue: 17 Pages: 11656-66
  • DOI: 10.1074/jbc.m113.541664
  • Peer Reviewed
• [Journal Article] Necessary and sufficient role for a mitosis skip in senescence induction (2014)
  • Author(s): Johumra 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: 未定
• [Journal Article] Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication (2013)
  • Author(s): Nishiyama, A
  • Journal Title: Nature Volume: 502 Issue: 7470 Pages: 249-253
  • DOI: 10.1038/nature12488
  • Peer Reviewed
• [Journal Article] Increased protein stability of CDKN1C causes a gain-of-function phenotype in patients with IMAGe syndrome. (2013)
  • Author(s): Hamajima N, Johmura Y, Suzuki S, Nakanishi M, Saitoh S.
  • Journal Title: PLoS One. Volume: 8(9) Issue: 9 Pages: e75137-e75137
  • DOI: 10.1371/journal.pone.0075137
  • Peer Reviewed
• [Journal Article] Involvement of ribonucleotide reductase-M1 in 5-fluorouracil induced DNA damage in esophageal cancer cell lines. (2013)
  • Author(s): Aoki Y, Sakogawa K, Hihara J, Emi M, Hamai Y, Kono K, Shi L, Sun J, Kitao H, Ikura T, Niida H, Nakanishi M, Okada M, Tashiro S.
  • Journal Title: Int J Oncol. Volume: 42(6) Issue: 6 Pages: 1951-60
  • DOI: 10.3892/ijo.2013.1899
  • Peer Reviewed
• [Journal Article] Mitotic phosphorylation of MPP8 by cyclin-dependent kinases regulates chromatin dissociation (2013)
  • Author(s): Nishigaki M, Kawada Y, Misaki T, Murata K, Goshima T, Hirokawa T, Yamada C, Shimada M, Nakanishi M
  • Journal Title: Biochem Biophys Res Commun Volume: 432(4) Issue: 4 Pages: 654-9
  • DOI: 10.1016/j.bbrc.2013.02.027
  • Peer Reviewed
• [Journal Article] Response to DNA damage : why do we need to focus on protein phosphatases? (2013)
  • Author(s): Shimada M, Nakanishi M
  • Journal Title: Front Oncol Volume: 3 Pages: 8-8
  • DOI: 10.3389/fonc.2013.00008
  • Peer Reviewed
• [Journal Article] Chkl phosphorylates the tumor suppressor Mig-6, regulating the activation of EGF signaling. (2012)
  • Author(s): Liu, N., et al.
  • Journal Title: EMBO J. Volume: 31 Issue: 10 Pages: 2365-2377
  • DOI: 10.1038/emboj.2012.88
  • Peer Reviewed
• [Journal Article] Histone H1 expression in human prostate cancer tissues and cell lines (2012)
  • Author(s): Sato S, Takahashi S, Asamoto M, Nakanishi M, Wakita T, Ogura Y, Yatabe Y, Shirai T
  • Journal Title: Pathol Int Volume: 62(2) Issue: 2 Pages: 84-92
  • DOI: 10.1111/j.1440-1827.2011.02755.x
  • NAID: 10031185172
  • Peer Reviewed
• [Journal Article] TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2 (2012)
  • Author(s): Delhase M, Kim SY, Lee H, Naiki-Ito A, Chen Y, Ahn ER, Murata K, Kim SJ, Lautsch N, Kobayashi KS, Shirai T, Karin M, Nakanishi M
  • Journal Title: Proc Natl Acad Sci Volume: 109(4) Issue: 4 Pages: 177-86
  • DOI: 10.1073/pnas.1119296109
  • Peer Reviewed
• [Journal Article] Organ differences in the impact of p27(kip1) deficiency on carcinogenesis induced by N-methyl-N-nitrosourea (2011)
  • Author(s): Ogawa K, Murasaki T, Sugiura S, Nakanishi M, Shirai T
  • Journal Title: J Appl Toxicol Volume: (In press) Issue: 6 Pages: 471-9
  • DOI: 10.1002/jat.1770
  • Peer Reviewed
• [Journal Article] Genetic variation of the IL-28B promoter affecting gene expression (2011)
  • Author(s): Sugiyama M, Tanaka Y, Wakita T, Nakanishi M, Mizokami M
  • Journal Title: PLoS One Volume: 6(10) Issue: 10 Pages: e26620-e26620
  • DOI: 10.1371/journal.pone.0026620
  • Peer Reviewed
• [Journal Article] (2011)
  • Author(s): Nakanishi M
  • Journal Title: Cell cycle. Rinsho Ketsueki Volume: 52(10) Pages: 1660-8
  • Peer Reviewed
• [Journal Article] Easy-to-use phylogenetic analysis system for hepatitis B virus infection (2011)
  • Author(s): Sugiyama M, Inui A, Shin-IT, Komatsu H, Mukaide M, Masaki N, Murata K, Ito K, Nakanishi M, Fujisawa T, Mizokami M
  • Journal Title: Hepatol Res Volume: 41(10) Issue: 10 Pages: 936-945
  • DOI: 10.1111/j.1872-034x.2011.00859.x
  • NAID: 10031144168
  • Peer Reviewed
• [Journal Article] Identification of a checkpoint modulator with synthetic lethality to p53 mutants. (2011)
  • Author(s): Harada N, Watanabe Y, Yoshimura Y, Sakumoto H, Makishima F, Tsuchiya M, Nakanishi K, Nakanishi M, Aoki Y. et al.
  • Journal Title: Anticancer Drugs Volume: 22(10) Issue: 10 Pages: 986-94
  • DOI: 10.1097/cad.0b013e328349dd43
  • Peer Reviewed
• [Journal Article] Nuclear Chk1 prevents premature mitotic entry (2011)
  • Author(s): Matsuyama, M., Goto, H., Kasahara, K., Kawakami, Y., Nakanishi, M., Kiyono, T., Goshima, N., Inagaki, M.
  • Journal Title: J. Cell Sci. Volume: 124 Issue: 13 Pages: 2113-2119
  • DOI: 10.1242/jcs.086488
  • Peer Reviewed
• [Journal Article] SYCP3 mutation may not be associated with recurrent miscarriage caused by aneuploidy (2011)
  • Author(s): Mizutani E, Suzumori N, Ozaki Y, Oseto K, Yamada-Namikawa C, Nakanishi M, Sugiura-Ogasawara M
  • Journal Title: Hum Reprod Volume: 26(5) Issue: 5 Pages: 1259-66
  • DOI: 10.1093/humrep/der035
  • Peer Reviewed
• [Journal Article] Novel findings for the development of drug therapy for various liver diseases : Genetic variation in IL-28B is associated with response to the therapy for chronic hepatitis C (2011)
  • Author(s): Sugiyama M, Tanaka Y, Nakanishi M, Mizokami M
  • Journal Title: J Pharmacol Sci Volume: 115(3) Pages: 263-9
  • NAID: 10029892326
  • Peer Reviewed
• [Journal Article] Cell cycle (2011)
  • Author(s): Nakanishi M
  • Journal Title: Rinsho Ketsueki Volume: 52(10) Pages: 1660-8
  • NAID: 10029769432
  • Peer Reviewed
• [Presentation] 2013 Translational Epigenomics (2013)
  • Author(s): 中西 真
  • Organizer: The 10th Nikko International Symposium
  • Place of Presentation: 栃木県自治医科大学
  • Year and Date: 2013-10-17
• [Presentation] Ubiquitylation/deubiquitylation circuit of histone H3 at K23 couples maintenance DNA methylation with DNA (2013)
  • Author(s): 中西 真
  • Organizer: 第3回日仏がんワークショップ
  • Place of Presentation: フランストゥールーズ
• [Presentation] Uhrf1-dependent ubiquitination of histone H3 at lysine 23 couples maintenance DNA methylation and DNA replication (2013)
  • Author(s): 中西 真
  • Organizer: he 10th Nikko International Symposium 2013 Translational Epigenomics
  • Place of Presentation: 自治医大 栃木県
  • Invited
• [Presentation] Ubiquitylation/deubiquitylation circuit of histone H3 at K23 couples maintenance DNA methylation with DNA (2013)
  • Author(s): 中西 真
  • Organizer: 第３回日仏がんワークショップ
  • Place of Presentation: トゥルーズ フランス
  • Invited
• [Presentation] Role of DNA damage responses in induction of premature senescence (2012)
  • Author(s): 中西 真
  • Organizer: Hallym-NCGG-ExtendedSymposium
  • Place of Presentation: Anyang 市(韓国)
• [Presentation] Maintaining the integrity of genomic information by cell cycle checkpoints (2012)
  • Author(s): 中西 真
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
• [Presentation] Role of DNA damage responses in induction of premature senescence (2012)
  • Author(s): 中西 真
  • Organizer: 3R シンポジウム
  • Place of Presentation: 鳴門市 淡路島
• [Presentation] Novel histone modifications couple maintenance DNA methylation with DNA replication (2012)
  • Author(s): 中西 真
  • Organizer: 日仏がん学会
  • Place of Presentation: 鳴門市淡路島
• [Presentation] Role of DNA damage responses in induction of premature senescence (2012)
  • Author(s): 中西 真
  • Organizer: Hallym-NCGG-Extended Symposium
  • Place of Presentation: Hallym University(韓国Anyang市）
  • Invited
• [Presentation] Maintaining the integrity of genomic information by cell cycle checkpoints. (2012)
  • Author(s): 中西 真
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（札幌市）
  • Invited
• [Presentation] Role of DNA damage responses in induction of premature senescence. (2012)
  • Author(s): 中西 真
  • Organizer: 3Rシンポジウム
  • Place of Presentation: 淡路夢舞台国際会議場（淡路市）
  • Invited
• [Presentation] Novel histone modifications couple maintenance DNA methylation with DNA replication (2012)
  • Author(s): 中西 真
  • Organizer: 日仏がん学会
  • Place of Presentation: グランドエクシブ鳴門（鳴門市）
  • Invited
• [Presentation] Molecular mechanisms of dNTPs supply at DNA damage sites in mammals (2011)
  • Author(s): 中西 真
  • Organizer: 第70回日本癌学会総会
  • Place of Presentation: 名古屋国際会議場
• [Presentation] Molecular mechanisms of dNTPs supply at DNA damage sites in mammals (2011)
  • Author(s): 中西真
  • Organizer: 第70回日本癌学会総会
  • Place of Presentation: 名古屋国際会議場(愛知県)