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Elucidation of the mechanism of DNA degradation during keratinocyte terminal differentiation and analysis of associated factors in diseased skin with parakeratosis

Research Project

Project/Area Number 24791180
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Dermatology
Research InstitutionTokyo Medical University

Principal Investigator

YAMAMOTO-TANAKA Mami  東京医科大学, 医学部, 助教 (60421062)

Project Period (FY) 2012-04-01 – 2014-03-31
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2012: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Keywords表皮角化細胞 / カスパーゼ‐14 / メソトリプシン / フィラグリン / 不全角化 / カスパーゼ-14
Research Abstract

Loss of the nucleus is a critical step during keratinocyte terminal differentiation. However, the mechanism of denucleation is still not fully understood. In this study, we showed that at least two pathways are involved in the denucleation process, that is, profilaggrin N-terminal fragment-dependent and caspase-14-mediated CAD-dependent DNA degradation pathways. Epidermal mesotrypsin liberated a 55-kDa N-terminal fragment of profilaggrin (FLG-N) and FLG-N was translocated into the nucleus. These cells became TUNEL positive. On the other hand, caspase-14 caused limited proteolysis of ICAD, followed by accumulation of caspase activated DNase (CAD), resulting in TUNEL-positive nuclei. Both mesotrypsin and caspase-14 were absent in the parakeratotic area of the skin with atopic dermatitis and psoriasis. These results indicate that multiple pathways are likely to be involved in keratinocyte DNA degradation and the maintenance of the barrier function of epidermis.

Report

(3 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Research-status Report
  • Research Products

    (34 results)

All 2014 2013 2012 Other

All Journal Article (9 results) (of which Peer Reviewed: 9 results,  Open Access: 1 results) Presentation (23 results) Book (2 results)

  • [Journal Article] Multiple pathways are involved in DNA degradation during keratinocyte terminal differentiation.2014

    • Author(s)
      Yamamoto-Tanaka M, Makino T, Motoyama A, Miyai M, Tsuboi R, Hibino T.
    • Journal Title

      Cell Death Dis.

      Volume: 5 Issue: 4 Pages: e1181-e1181

    • DOI

      10.1038/cddis.2014.145

    • Related Report
      2013 Annual Research Report 2013 Final Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Keratinocyte-specific mesotrypsin contributes to desquamation process via kallikrein activation and LEKTI degradation2014

    • Author(s)
      Miyai M, Matsumoto Y, Yamanishi H, Yamamoto-Tanaka M, Tsuboi R, Hibino T
    • Journal Title

      J Invest Dermatol

      Volume: 134 Pages: 1665-1674

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Keratinocyte-specific mesotrypsin contributes to desquamation process via kallikrein activation and LEKTI degradation.2014

    • Author(s)
      Miyai M, Matsumoto Y, Yamanishi H, Yamamoto-Tanaka M, Tsuboi R, Hibino T
    • Journal Title

      Journal of Investigative Dermatology

      Volume: 134 Issue: 6 Pages: 1665-1674

    • DOI

      10.1038/jid.2014.3

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Kallikrein-related peptidase 5 functions in proteolytic processing of profilaggrin in cultured human keratinocytes2013

    • Author(s)
      Sakabe JI, Yamamoto M, Hirakawa S, Motoyama A, Ohta I, Tatsuno K, Ito T, Kabashima K, Hibino T, Tokura Y
    • Journal Title

      J Biol Chem

      Volume: 288 Pages: 17179-17189

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] S100A9 is a novel ligand of EMMPRIN that promotes melanoma metastasis2013

    • Author(s)
      Hibino T, Sakaguchi M, Miyamoto S, Yamamoto M, Motoyama A, Hosoi J, Shimokata T, Ito T, Tsuboi R, Huh NH
    • Journal Title

      Cancer Res

      Volume: 73 Pages: 172-183

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Kallikrein-related peptidase 5 functions in proteolytic processing of profilaggrin in cultured human keratinocytes.2013

    • Author(s)
      Sakabe JI, Yamamoto M, Hirakawa S, Motoyama A, Ohta I, Tatsuno K, Ito T, Kabashima K, Hibino T, Tokura Y
    • Journal Title

      The Journal of Biological Chemistry

      Volume: 288 Issue: 24 Pages: 17179-17189

    • DOI

      10.1074/jbc.m113.476820

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] S100A9 is a novel ligand of EMMPRIN that promotes melanoma metastasis.2013

    • Author(s)
      Hibino T, Sakaguchi M, Miyamoto S, Yamamoto M, Motoyama A, Hosoi J, Shimokata T, Ito T, Tsuboi R, Huh NH
    • Journal Title

      Cancer Research

      Volume: 73 Pages: 172-183

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Kallikrein-related peptidase-7 regulates caspase-14 maturation during keratinocyte terminal differentiation by generating an intermediate form2012

    • Author(s)
      Yamamoto M, Miyai M, Matsumoto Y, Tsuboi R, Hibino T
    • Journal Title

      J Biol Chem

      Volume: 287 Pages: 32825-32834

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Kallikrein-related peptidase-7 regulates caspase-14 maturation during keratinocyte terminal differentiation by generating an intermediate form.2012

    • Author(s)
      Yamamoto M, Miyai M, Matsumoto Y, Tsuboi R, Hibino T
    • Journal Title

      The Journal of Biological Chemistry

      Volume: 287 Pages: 32825-32834

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Presentation] 表皮ケラチノサイトの最終分化における脱核には複数の経路が協調的に関係している2013

    • Author(s)
      田中(山本)真実, 牧野輝彦, 本山晃, 宮井雅史, 坪井良治, 日比野利彦
    • Organizer
      第36回 日本分子生物学会
    • Place of Presentation
      神戸
    • Year and Date
      2013-12-05
    • Related Report
      2013 Final Research Report
  • [Presentation] Multiple pathways are involved in DNA degradation during keratinocyte terminal differentiation2013

    • Author(s)
      Yamamoto-Tanaka M, Makino T, Motoyama A, Tsuboi R, Hibino T
    • Organizer
      第27回表皮細胞研究会
    • Place of Presentation
      山梨
    • Year and Date
      2013-11-23
    • Related Report
      2013 Final Research Report
  • [Presentation] アトピー性皮膚炎におけるS100A8/A9 の役割-新規レセプターの発見とその機能2013

    • Author(s)
      田中(山本)真実, 阪口政清, 本山晃, 許南浩, 日比野利彦, 坪井良治
    • Organizer
      第90回東京医科大学・東京薬科大学・免疫アレルギー研究会
    • Place of Presentation
      東京
    • Year and Date
      2013-11-05
    • Related Report
      2013 Final Research Report
  • [Presentation] S100A9-EMMPRIN とinflammasome はアトピー性皮膚炎の病態に関与する2013

    • Author(s)
      山本真実, 本山晃, 桃井隆, 坪井良治, 日比野利彦
    • Organizer
      第112回 日本皮膚科学会総会
    • Place of Presentation
      横浜
    • Year and Date
      2013-06-15
    • Related Report
      2013 Final Research Report
  • [Presentation] Activation of inflammasome is related to S100A9 induction and is involved in chronic inflammation of the skin with atopic dermatitis2013

    • Author(s)
      Yamamoto M, Inoue K, Sawane M, Maeda T, Tsuboi R, Hibino T
    • Organizer
      International Investigative Dermatology
    • Place of Presentation
      Edinburgh, Scotland
    • Year and Date
      2013-05-09
    • Related Report
      2013 Final Research Report
  • [Presentation] 表皮ケラチノサイトの最終分化における脱核には複数の経路が協調的に関係している.2013

    • Author(s)
      田中(山本)真実, 牧野輝彦, 本山晃, 宮井雅史, 坪井良治, 日比野利彦
    • Organizer
      第36回 日本分子生物学会年会
    • Place of Presentation
      神戸
    • Related Report
      2013 Annual Research Report
  • [Presentation] ケラチノサイト特異的メソトリプシンは、Kallikrein活性化とLEKTIの分解を介して角層剥離関与している2013

    • Author(s)
      宮井雅史, 松元有羽子, 山西治代, 田中(山本)真実, 坪井良治, 日比野利彦
    • Organizer
      第36回 日本分子生物学会年会
    • Place of Presentation
      神戸
    • Related Report
      2013 Annual Research Report
  • [Presentation] S100A9-EMMPRINとinflammasomeはアトピー性皮膚炎の病態に関与する.2013

    • Author(s)
      山本真実, 本山晃, 桃井隆, 坪井良治, 日比野利彦
    • Organizer
      第112回 日本皮膚科学会総会
    • Place of Presentation
      横浜
    • Related Report
      2013 Annual Research Report
  • [Presentation] 表皮角化細胞の脱核のプロセスには複数の経路が関与する2012

    • Author(s)
      山本真実, 牧野輝彦, 本山晃, 坪井良治, 日比野利彦
    • Organizer
      第111回 日本皮膚科学会総会
    • Place of Presentation
      京都
    • Year and Date
      2012-06-02
    • Related Report
      2013 Final Research Report
  • [Presentation] Identification of a novel receptor for S100A8 and its possible involvement in abnormal proliferation2012

    • Author(s)
      Yamamoto M, Sakaguchi M, Motoyama M, Huh N, Tsuboi R, Hibino T
    • Organizer
      The 37th Annual Meeting of the Japanese Society for Investigative Dermatology
    • Place of Presentation
      Okinawa, Japan
    • Related Report
      2013 Final Research Report
  • [Presentation] KLK7 participates in activation of caspase-14 during keratinocyte terminal differentiation2012

    • Author(s)
      Yamamoto M, Miyai M, Matsumoto Y, Tsuboi R, Hibino T
    • Organizer
      The 72nd Annual Meeting of the Society for Investigative Dermatology
    • Place of Presentation
      Raleigh, North Carolina
    • Related Report
      2013 Final Research Report
  • [Presentation] Identification of a novel receptor for S100A8 and its possible involvement in abnormal proliferation.2012

    • Author(s)
      Yamamoto M, Sakaguchi M, Motoyama M, Huh NH, Tsuboi R, Hibino T
    • Organizer
      The 37th Annual Meeting of the Japanese Society for Investigative Dermatology,
    • Place of Presentation
      Okinawa, Japan
    • Related Report
      2012 Research-status Report
  • [Presentation] Keratinocyte-specific PRSS3 participates in the desquamation process via degradation of LEKTI.2012

    • Author(s)
      Miyai M, Yamanishi H, Matsumoto Y, Yamamoto M, Hibino T
    • Organizer
      The 37th Annual Meeting of the Japanese Society for Investigative Dermatology
    • Place of Presentation
      Okinawa, Japan
    • Related Report
      2012 Research-status Report
  • [Presentation] 表皮バリア機能関連因子プロフィラグリンのプロセッシングにおけるKLK5の関与.2012

    • Author(s)
      坂部純一, 山本真実, 本山晃, 太田 勲, 平川聡史, 日比野利彦, 戸倉新樹
    • Organizer
      第17回日本病態プロテアーゼ学会
    • Place of Presentation
      浜松
    • Related Report
      2012 Research-status Report
  • [Presentation] 表皮角化細胞の脱核のプロセスには複数の経路が関与する.2012

    • Author(s)
      山本真実, 牧野輝彦, 本山晃, 坪井良治, 日比野利彦
    • Organizer
      第111回 日本皮膚科学会総会
    • Place of Presentation
      京都
    • Related Report
      2012 Research-status Report
  • [Presentation] KLK7 participates in activation of caspase-14 during keratinocyte terminal differentiation.2012

    • Author(s)
      Yamamoto M, Miyai M, Matsumoto Y, Tsuboi R, Hibino T
    • Organizer
      The 72nd Annual Meeting of the Society for Investigative Dermatology
    • Place of Presentation
      Raleigh, North Carolina
    • Related Report
      2012 Research-status Report
  • [Presentation] Mandatory role of kallikrein 5 in profilaggrin maturation and possible association of its impairment with atopic dermatitis.2012

    • Author(s)
      Sakabe J, Yamamoto M, Motoyama A, Hirakawa S, Kobayashi M, Nakamura M, Hibino T, Tokura Y
    • Organizer
      The 72nd Annual Meeting of the Society for Investigative Dermatology
    • Place of Presentation
      Raleigh, North Carolina
    • Related Report
      2012 Research-status Report
  • [Presentation] Analysis of profilaggrin N-terminal fragment function in keratinocyte terminal differentiation.2012

    • Author(s)
      Makino T, Yamamoto M, Yamakoshi T, Rehman MU, Hibino T, Shimizu T
    • Organizer
      The 72nd Annual Meeting of the Society for Investigative Dermatology
    • Place of Presentation
      Raleigh, North Carolina
    • Related Report
      2012 Research-status Report
  • [Presentation] Multiple pathways are involved in DNA degradation during keratinocyte terminal differentiation.

    • Author(s)
      Yamamoto-Tanaka M, Makino T, Motoyama A, Tsuboi R, Hibino T
    • Organizer
      第27回表皮細胞研究会
    • Place of Presentation
      山梨
    • Related Report
      2013 Annual Research Report
  • [Presentation] アトピー性皮膚炎におけるS100A8/A9の役割-新規レセプターの発見とその機能.

    • Author(s)
      田中(山本)真実, 阪口政清, 本山晃, 許南浩, 日比野利彦, 坪井良治
    • Organizer
      第90回東京医科大学・東京薬科大学・免疫アレルギー研究会
    • Place of Presentation
      東京
    • Related Report
      2013 Annual Research Report
  • [Presentation] Activation of inflammasome is related to S100A9 induction and is involved in chronic inflammation of the skin with atopic dermatitis.

    • Author(s)
      Yamamoto M, Inoue K, Sawane M, Maeda T, Tsuboi R, Hibino T
    • Organizer
      International Investigative Dermatology
    • Place of Presentation
      Edinburgh, Scotland
    • Related Report
      2013 Annual Research Report
  • [Presentation] Involvement of kallilrein-related peptidase 5 in profilaggrin processing.

    • Author(s)
      Sakabe J, Yamamoto M, Motoyama A, Ohta I, Hirakawa S, Hibino T, Tokura Y
    • Organizer
      International Investigative Dermatology
    • Place of Presentation
      Edinburgh, Scotland
    • Related Report
      2013 Annual Research Report
  • [Presentation] Keratinocyte-specific PRSS3 effectively actives KLKs and degrades LEKTI - a hidden mechanism of desquamation.

    • Author(s)
      Miyai M, Matsumoto Y, Yamanishi H, Yamamoto M, Tsuboi R, Hibino T
    • Organizer
      International Investigative Dermatology
    • Place of Presentation
      Edinburgh, Scotland
    • Related Report
      2013 Annual Research Report
  • [Book] Caspase-14 protocols. In; Methods in Molecular Biology 11332014

    • Author(s)
      Yamamoto-Tanaka M, Hibino T(edited by P. Bozhov and G. Salvesen)
    • Publisher
      New York : Humana Press
    • Related Report
      2013 Final Research Report
  • [Book] Caspase, Paracaspases, and Metacaspases2014

    • Author(s)
      Yamamoto-Tanaka M, Hibino T
    • Total Pages
      266
    • Publisher
      Springer New York
    • Related Report
      2013 Annual Research Report

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Published: 2013-05-31   Modified: 2019-07-29  

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