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Research on inhibitors for autocrine and cross-induction mechanism in human keratinocytes

Research Project

Project/Area Number 13557071
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Dermatology
Research InstitutionEhime University

Principal Investigator

HASHIMOTO Koji  Ehime University, Faculty of Medicine, Professor, 医学部, 教授 (00110784)

Co-Investigator(Kenkyū-buntansha) YAMASAKI Kenshi  Ehime University, Faculty of Medicine, Professor, 医学部, 助手 (40294798)
SHIRAKATA Yuji  Ehime University, Faculty of Medicine, Instructor, 医学部, 助手 (50226320)
SAYAMA Koji  Ehime University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (80187286)
YOSHINO Kouichirou  Nippon Organon Inc.Principle Investigator, 医薬研究所・研究開発本部, 研究部長
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥12,300,000 (Direct Cost: ¥12,300,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥10,500,000 (Direct Cost: ¥10,500,000)
Keywordskeratinocytes / autocrine / HB-EGF / ADAM / MMP / conditional knockout mouse / adenovirus vector / real time PCR / adenovirus vector / adnovirus vector
Research Abstract

It has been reported that several EGF family are autocrine gowth factors in normal human keratinocytes (NHEK) and can induce the other EGF family known as cross-induction mechanism. To elucidate autocrine and cross-induction mechanism, we investigated the signal transduction pathways of auto- and cross-induction by HB-EGF. HB-EGF phosphorylated EGFR after 5 min, and induction of HB-EGF was inhibited by the addition of AG1483, an EGFR inhibitor. ERK, p38, and JNK were phosphorylated by the addition of HB-EGF after 10 min, suggesting the activation of all three pathways by HB-EGF. NHEK were treated with various signal transduction inhibitors ; then, the induction of EGF family mRNA was examined by RPA. The auto- and cross-induction of HB-EGF was completely blocked by treatment with curcumin, a natural JNK inhibitor, but not by p38 or MEK inhibitors. These results demonstrate that the auto- and cross-induction mechanisms of HB-EGF are mediated by the EGFR and JNK pathways. For cutaneous w … More ound healing, the most important growth factor is EGF family. HB-EGF, an autocrine growth factor in NHEK, is thought to play an important role in skin wound healing, although there have been no study about an involvement of HB-EGF in in vivo skin wound healing using mouse model. Since germline targeting of the HB-EGF gene resulted in embryonic lethality, we generated keratinocyte specific HB-EGF deficient mice (KS-HB-EGF-/-mice) using Cre/loxP technology in combination with keratin 5 promoter. A cutaneous wound was made on the mouse back skin using 6-mm punch biopsy and wound closure was measured by migration of epidermal edge stained by anti-keratin antibody. Wound closure was markedly retarded in KS-HB-EGF-/-mice compared to wild type mice on day 9. To further clarify the role of HB-EGF in cutaneous wound healing, we performed scraping wound assay using NHEK. HB-EGF mRNA was rapidly induced at 2 h after scraping, although the slight increase of TGF-alpha, amphiregulin and epiregulin m RNA was observed. Taking together, HB-EGF plays an important role in skin wound healing by accelerating keratinocyte migration. Less

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (38 results)

All Other

All Publications (38 results)

  • [Publications] Iwamoto R, Yamazaki S.Asakura M, Takashima S, Hasuwa H, Miyado K, Adachi S, Kitakaze M, Hashimoto K, Raab G, Klagsbrun M, Nanba D, Higashiyama S, Hori M, Mekada E: "HB-EGF and ErbB signaling is essential for heart function"Proc Natl Acad Sci. (In press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sayama K, Yamasaki K, Hanakawa Y, Shirakata Y, Tokumaru S, Ijuin T, Takenawa T, Hashimoto K: "Phosphatidyl inositol 3 kinase is a key regulator of early phase differentiation in keratinocytes"J Biol Chem. 277. 40390-40396 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Li G, Schaider H, Satyamoorthy K, Hanakawa Y, Hashimoto K, Herlyn M: "Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development"Oncogene. 20. 8125-8135 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shouda T, Yoshida T, Hanada T, Wakioka T, Oishi M, Miyoshi K, Komiya S, Kosai K, Hanakawa Y, Hashimoto K, Nagata K, Yoshimura A: "Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis"J Clin Invest. 1781-1788 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sayama K, Hanakawa Y, Shirakata Y, Yamasaki K, Sawada Y, Sun L, Yamanishi K, Ichijo H, Hashimoto K: "Apoptosis signal regulating kinase 1 (ASK1) is an intracellular inducer of keratino cyte differentiation"J Biol Chem. 276. 999-1004 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hanakawa Y, Amagai M, Shirakata Y, Yahata Y, Tokumaru S, Yamasaki K, Tohyama M, Sayama K, Hashimoto K: "Differentiatl effects of desmoglein 1 and desmoglein 3 on desmosome formation"J Invest Dermatol. 119. 1231-1236 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tohyama M, Shirakara Y, Yamasaki K, Sayama K, Hashimoto K: "Differentiated keratinocytes are responsible for TNF-alpha regulated production of macrophage inflammatory protein 3alpha/CCL20, a potent chemokine for Langerhans cells"J Dermatol Sci. 27. 130-139 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hamada K, Shinomiya H, Asano Y, Kihana T, Iwamoto M, Hanakawa Y, Hashimoto K, Hirose S, Kyo S, Ito M.: "Molecular cloning of human squamous cell carcinoma antigen 1 gene and characterization of its promoter"Biochim Biophys Acta. 19. 124-131 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hamada K, Hanakawa Y, Hashimoto K, Iwamoto M, Kihana T, Hirose S, Nakamura M, Ito M.: "Gene expression of human squamous cell carcinoma antigens 1 and 2 in human cell lines"Oncol Rep. 8. 347-354 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kobayashi M, Amagai M, Kuroda-Kinoshita K, Hashimoto T, Shirakata Y, Hashimoto_K, Nishikawa T: "BP180 ELISA using bacterial recombinant NC16a protein as a diagnostic and monitoring tool for bullous pemphigoid"J Dermatol Sci. 30. 224-232 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hattori N, Komine M, Yano S, Kaneko T, Hanakawa Y, Hashimoto K, Tamaki K.: "Interferon-gamma, a strong suppressor of cell proliferation, induces upregulation of keratin K6, one of the inflammatory-and proliferation-associated keratins"J Invest Dermatol.. 119. 403-410 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tsuda T, Thoyama M, Yamasaki K, Shirakata Y, Yahata Y, Tokumaru S, Sayama K, Hashimoto K: "Lack of evidence for TARC/CCL17 production by normal human keratinocytes in vitro"J Dermatol Sci. (In press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Wada T, Shirakata Y, Takahashi H, Murakami S, Iizuka H, Suzuki H, Hashimoto K: "A Japanese Case of Segmental Darier's Disease Caused by Mosaicism for the ATP2A2 Mutation"Br J Dermatol. (In press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shirakata Y, Tamai K, Nakaoka H, Tokumaru S, Sayama K, Murakami S, Hashimoto K: "Severe Palmo-plantar Hyperkeratosis in Koebner Epidermolysis Bullosa Simplex"J Dermatol. (In press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tohyama M, Shirakara Y, Yamasaki K, Sayama K, Hashimoto K: "Differentiated keratinocytes are responsible for TNF-alpha regulated production of macrophage inflammatory protein 3alpha/CCL20, a potent chemokine for Langerhans cells"J Dermatol Sci. 27(2). 130-139 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sayama K, Hanakawa Y, Shirakata Y, Yamasaki K, Sawada Y, Sun L, Yamanishi K, Ichijo H, Hashimoto K: "Apoptosis signal regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation"J Biol Chem. 276. 999-1004 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shouda T, Yoshida T, Hanada T, Wakioka T, Oishi M, Miyoshi K, Komiya S, Kosai K, Hanakawa Y, Hashimoto K, Nagata K, Yoshimura A: "Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis"J Clin Invest. 108(12). 1781-1788 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Li G, Schaider H, Satyamoorthy K, Hanakawa Y, Hashimoto K, Herlyn M: "Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development"Oncogene. 20(56). 8125-8135 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hamada K, Shinomiya H, Asano Y, Kihana T, Iwamoto M, Hanakawa Y, Hashimoto K, Hirose S, Kyo S, Ito M: "Molecular cloning of human squamous cell carcinoma antigen 1 gene and characterization of its promoter"Biochim Biophys Acta. 19 ; 1518(1-2). 124-131 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hamada K, Hanakawa Y, Hashimoto K, Iwamoto M, Kihana T, Hirose S, Nakamura M, Ito M: "Gene expression of human squamous cell carcinoma antigens 1 and 2 in human cell lines"Oncol Rep. 8(2). 347-354 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sayama K, Yamasaki K, Hanakawa Y, Shirakata Y, Tokumaru S, Ijuin T, Takenawa T, Hashimoto K: "Phosphatidyl inositol 3 kinase is a key regulator of early phase differentiation in keratinocytes"J Biol Chem. 277. 40390-40396 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hanakawa Y, Amagai M, Shirakata Y, Yahata Y, Tokumaru S, Yamasaki K, Tohyama M, Sayama K, Hashimoto K: "Differentiatl effects of desmoglein 1 and desmoglein 3 on desmosome formation"J Invest Dermatol. 119. 1231-1236 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kobayashi M, Amagai M, Kuroda-Kinoshita K, Hashimoto T, Shirakata Y, Hashimoto K, Nishikawa T: "BP180 ELISA using bacterial recombinant NC16a protein as a diagnostic and monitoring tool for bullous pemphigoid"J Dermatol Sci. 30. 224-232 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hattori N, Komine M, Yano S, Kaneko T, Hanakawa Y, Hashimoto K, Tamaki K: "Interferon-gamma, a strong suppressor of cell proliferation, induces upregulation of keratin K6, one of the inflammatory- and proliferation-associated keratins"J Invest Dermatol. 119(2). 403-410 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tsuda T, Thoyama M, Yamasaki K, Shirakata Y, Yahata Y,Tokumaru S, Sayama K, Hashimoto K: "Lack of evidence for TARC/CCL17 production by normal human keratinocytes in vitro"J Dermatol Sci. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Wada T, Shirakata Y, Takahashi H, Murakami S, lizuka H, Suzuki H, Hashimoto K: "A Japanese Case of Segmental Darier's Disease Caused by Mosaicism for the ATP2A2 Mutation"Br J Dermatol. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwamoto R, Yamazaki S, Asakura M, Takashima S, Hasuwa H, Miyado K, Adachi S, Kitakaze M, Haahimoto K, Raab G, Klagsbrun M, Nanba D, Higashiyama S, Hori M, Mekada E: "HB-EGF and ErbB signaling is essential for heart function"Proc Natl Acad Sci. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shirakata Y, Tamai K, Nakaoka H, Tokumaru S, Sayama K, Murakami S, Hashimoto K: "Severe Palmo-plantar Hyperkeratosis in Koebner Epidermolysis Bullosa Simplex"J Dermatol. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwamoto R, Yamazaki S, Asakura M, Takashima S, Hasuwa H, Miyado K, Adachi S, Kitakaze M, Hashimoto K, Raab G, Klagsbrun M, Nanba D, Higashiyama S. Hori M, Mekada E: "HB-EGF and ErbB signaling is essential for heart function"Proc Natl Acad Sci. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sayama K, Yamasaki K, Hanakawa Y, Shirakata Y, Tokumaru S, Ijuin T, Takenawa T, Hashimoto K: "Phosphatidyl inositol 3 kinase is a key regulator of early phase differentiation in keratinocyles"J Biol Chem. 277. 40390-40396 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hanakawa Y, Amagai M, Shirakata Y, Yahata Y, Tokumaru S, Yamasaki K, Tohyama M, Sayama K, Hashimoto K: "Differentiatl effects of desmoglein 1 and desmoglein 3 on desmosome formation"J Invest Dermatol. 119. 1231-1236 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hattori N, Komine M, Yano S, Kaneko T, Hanakawa Y, Hashimoto K, Tamaki K: "Interferon-gamma, a strong suppressor of cell proliferation, induces upregulation of keratin K6, one of the inflammatory-and proliferation-associated keratins"J Invest Dermatol. 119. 403-410 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tsuda T, Thoyama M, Yamasaki K, Shirakata Y, Yahata Y, Tokumaru S, Sayama K, Hashimoto K: "Lack of evidence for TARC/CCL17 production by normal human keratinocytes in vitro"J Dermatol Sci. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shouda T, Yoshida T, Hanada T, Wakioka T, Oishi M, Miyoshi K, Komiya S, Kosai K, Hanakawa Y, Hshimoto K, Nagata K, Yoshimura A: "Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis"J Clin Invest. 108(12). 1781-1788 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Li G, Schaider H, Satyamoorthy K, Hanakawa Y, Hashimoto K, Herlyn M: "Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development"Oncogene. 20(56). 8125-8135 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hamada K, Shinomiya H, Asano Y, Kihana T, Iwamoto M, Hanakawa Y, Hashimoto K, Hirose S, Kyo S, Ito M: "Molecular cloning of human squamous cell carcinoma antigen 1 gene and characterization of its promoter"Biochim Biophys Acta.. 1518(1-2). 124-131 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sayama K, Hanakawa Y, Shirakata Y, Yamasaki K, Sawada Y, Sun L, Yamanishi K, Ichijo H, Hashimoto K: "Apoptosis signal regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation"J Biol Chem.. 276. 999-1004 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tohyama M, Shirakara Y, Yamasaki K, Sayama K, Hashimoto K: "Differentiated keratinocytes are responsible for TNF-alpha regulated production of macrophage inflammatory protein 3alpha/CCL20, a potent chemokine for Langerhans cells"J Dermatol Sci.. 27(2). 130-139 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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