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Mechanism of cytokine-induced cellular senescence

Research Project

Project/Area Number 21590316
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionOsaka City University

Principal Investigator

KOJIMA Hirotada  大阪市立大学, 大学院・医学研究科, 講師 (40336772)

Co-Investigator(Kenkyū-buntansha) NAKAJIMA Koichi  大阪市立大学, 大学院・医学研究科, 教授 (00227787)
Project Period (FY) 2009 – 2011
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywordsサイトカイン / 細胞老化 / がん / シグナル伝達
Research Abstract

Normal cells undergo senescence in response to various stresses, such as DNA damage and certain cytokines. One such cytokine, interleukin-6 (IL-6), a multifunctional cytokine, can act on multiple lineages of cells combination with soluble IL-6 receptor α (sIL-6Rα) to induce cell proliferation, differentiation and even promotion of tumorigenesis. We studied the molecular mechanisms by which IL-6 and sIL-6Rα cause premature senescence using primary human fibroblasts. Stimulation of fibroblasts cells with IL-6/sIL-6Rα sequentially caused generation of reactive oxygen species (ROS) as early as day 1, followed by DNA damage, p53 accumulation, and finally senescence. STAT3 was required for the early and late events leading to senescence, including the early-phase increase of ROS and senescence-associated secretary phenotype occurring 4 days after IL-6/sIL-6Ra stimulation. Interestingly, Insulin-like growth factor-binding protein 5 (IGFBP-5) secreted into the supernatants was identified as the STAT3-downstream molecule responsible for the IL-6/STAT3-induced ROS generation and premature senescence. IGFBP-5 was consistently expressed from the initial phase through the entire senescence process, the profile being quite different from that of senescence-associated secretary phenotype. Thus, IL-6/sIL-6R? forms a senescence-inducing circuit involving the STAT3?IGFBP5 axis as a key triggering and reinforcing component.

Report

(4 results)
  • 2011 Annual Research Report   Final Research Report ( PDF )
  • 2010 Annual Research Report
  • 2009 Annual Research Report
  • Research Products

    (19 results)

All 2013 2012 2011 2010 2009 Other

All Journal Article (9 results) (of which Peer Reviewed: 8 results) Presentation (8 results) Book (1 results) Remarks (1 results)

  • [Journal Article] The STAT3-IGFBP5 axis is critical for IL-6/gp130-induced premature senescence in human fibroblasts2012

    • Author(s)
      Kojima H, Kunimoto H, Inoue T, Nakajima K
    • Journal Title

      Cell Cycle

      Volume: 11 Issue: 4 Pages: 730-739

    • DOI

      10.4161/cc.11.4.19172

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] SIRT2 down-regulation in HeLa can induce p53 accumulation via p38 MAPK activation-dependent p300 decrease, eventually leading to apoptosis2011

    • Author(s)
      Li Y, Matsumori H, Nakayama Y, Osaki M, Kojima H,, Kurimasa A, Ito H, Mori S, Katoh M, Oshimura M, Inoue T
    • Journal Title

      Genes Cells

      Volume: 16 Issue: 1 Pages: 34-45

    • DOI

      10.1111/j.1365-2443.2010.01460.x

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Identification of functional domains and novel binding partners of STIM proteins2011

    • Author(s)
      Saitoh N, Oritani K, Saito K, Yokota T, Ichii M, Sudo T, Fujita N, Nakajima K, Okada M, Kanakura Y
    • Journal Title

      J Cell Biochem

      Volume: 112 Issue: 1 Pages: 147-156

    • DOI

      10.1002/jcb.22910

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Phospho-Ser727 of STAT3 regulates STAT3 activity by enhancing dephosphory-lation of phospho-Tyr705 largely through TC452011

    • Author(s)
      Ryohei Wakahara, Hiroyuki Kunimoto, Kanae Tanino, Hirotada Kojima, Akira Inoue, Haruo Shintaku and Koichi Nakajima
    • Journal Title

      Genes to Cells

      Volume: 17 Issue: 2 Pages: 132-145

    • DOI

      10.1111/j.1365-2443.2011.01575.x

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] SIRT2 down-regulation in HeLa can induce p53 accumulation via p38 MAPK activation-dependent p300 decrease, eventually leading to apoptosis.2011

    • Author(s)
      Li Y, Matsumori H, Nakayama Y, Osaki M, Kojima H, Kurimasa A, ItoH, Mori S, Katoh M, Oshimura M, Inoue T.
    • Journal Title

      Genes Cells.

      Volume: 16 Pages: 34-45

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of functional domains and novel binding partners of STIM proteins.2011

    • Author(s)
      Saitoh N, Oritani K, Saito K, Yokota T, Ichii M, Sudo T, Fujita N, Nakajima K, Okada M, Kanakura Y.
    • Journal Title

      J Cell Biochem.

      Volume: 112 Pages: 147-156

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 【サイトカインと疾患 : あらたな病態モデルから治療へ】サイトカインシグナル伝達機構 JAK-STATの標準経路と非標準経路モデル2010

    • Author(s)
      中嶋弘一, 小島裕正
    • Journal Title

      医学のあゆみ

      Volume: 234(5) Pages: 325-330

    • Related Report
      2011 Final Research Report
  • [Journal Article] Laminin-511, inducer of hair growth, is down-regulated and its suppressor in hair growth, laminin-332 up-regulated in chemotherapy-induced alopecia2010

    • Author(s)
      Imanishi H, Tsuruta D, , Tateishi C, Sugawara K, Paus R, Tsuji T, Ishii M, Ikeda K, Kunimoto H, Nakajima K, Jones JC, Kobayashi H
    • Journal Title

      J Dermatol Sci

      Volume: 58 Issue: 1 Pages: 43-54

    • DOI

      10.1016/j.jdermsci.2010.02.005

    • NAID

      10027400358

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] GANP suppresses the arginine methyltransferase PRMT5 regulating IL-4-mediated STAT6-signaling to IgE production in B cells2009

    • Author(s)
      Igarashi H, Kuwahara K, Yoshida M, Xing Y, Maeda K, Nakajima K and Sakaguchi N
    • Journal Title

      Mol Immunol

      Volume: 6 Issue: 6 Pages: 1031-41

    • DOI

      10.1016/j.molimm.2008.08.272

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Presentation] Phospho-Ser727 of STAT3 shortens the duration of STAT3 activity by enhancing the dephosphorylation of pY705 through nuclear TC452011

    • Author(s)
      Wakahara R, Kunimoto H, Kojima H, Nakajima K
    • Organizer
      第40回日本免疫学会学術集会
    • Place of Presentation
      千葉市
    • Year and Date
      2011-11-29
    • Related Report
      2011 Final Research Report
  • [Presentation] Phospho-Ser727 of STAT3 shortens the duration of STAT3 activity by enhancing the dephosphorylation of pY705 through nuclear TC452011

    • Author(s)
      Wakahara R, Kunimoto H, Kojima H, Nakajima K
    • Organizer
      第40回日本免疫学会学術集会
    • Place of Presentation
      幕張メッセ(千葉市)
    • Year and Date
      2011-11-29
    • Related Report
      2011 Annual Research Report
  • [Presentation] gp130-Stat3 signaling induces premature cellular senescence2010

    • Author(s)
      Kojima H, Kunimoto H, Nakajima K
    • Organizer
      第33回日本分子生物学会・第83回日本生化学会大会合同年会
    • Place of Presentation
      神戸市
    • Year and Date
      2010-12-10
    • Related Report
      2011 Final Research Report
  • [Presentation] gp130-Stat3 signaling induces premature cellular senescence2010

    • Author(s)
      小島裕正, 國本浩之, 中嶋弘一
    • Organizer
      第33回日本分子生物学会年会・第83回日本生化学会大会 合同年会
    • Place of Presentation
      神戸ポートアイランド
    • Year and Date
      2010-12-10
    • Related Report
      2010 Annual Research Report
  • [Presentation] Prolonged stimulation of gp130 leads to premature senescence of human diploid fibroblasts2010

    • Author(s)
      Kojima H, Kunimoto H, Nakajima K
    • Organizer
      14^<th> International Congress of Immunology
    • Place of Presentation
      Kobe, Japan
    • Year and Date
      2010-08-27
    • Related Report
      2011 Final Research Report
  • [Presentation] Prolonged stimulation of gp130 leads to premature senescence of human diploid fibroblasts2010

    • Author(s)
      Kojima H, Kunimoto H, Nakajima K
    • Organizer
      14th International Congress of Immunology
    • Place of Presentation
      Kobe, Japan
    • Year and Date
      2010-08-27
    • Related Report
      2010 Annual Research Report
  • [Presentation] Prolonged stimulation of gp130 leads to premature senescence of human diploid fibroblasts2009

    • Author(s)
      Kojima H, Kunimoto H, Nakajima K
    • Organizer
      第32回日本分子生物学会年会
    • Place of Presentation
      横浜市
    • Year and Date
      2009-12-17
    • Related Report
      2011 Final Research Report
  • [Presentation] Prolonged stimulation of gp130 leads to premature senescence of human diploid fibroblasts2009

    • Author(s)
      小島裕正
    • Organizer
      第32回日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜 (神奈川)
    • Year and Date
      2009-12-17
    • Related Report
      2009 Annual Research Report
  • [Book] Tumor Dormancy and Cellular Quiescence and Senescence, Cancer, and Noncancer Pathologies : Interleukin-6 Induces Premature Senescence Involving the STAT3 and Insulin-Like Growth Factor-Binding Protein 52013

    • Author(s)
      Kojima H, Kunimoto H, Inoue T, Nakajima K.Aging
    • Publisher
      (in press)
    • Related Report
      2011 Final Research Report
  • [Remarks]

    • URL

      http://www.med.osaka-cu.ac.jp/immune/.

    • Related Report
      2011 Final Research Report

URL: 

Published: 2009-04-01   Modified: 2016-04-21  

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