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2007 Fiscal Year Final Research Report Summary

The analysis of molecular mechanism for IRS-1 ubiquitination by nitric oxide

Research Project

Project/Area Number 18591517
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionKumamoto University

Principal Investigator

SUGITA Hiroki  Kumamoto University, University Hospital, Lecturer (30398218)

Co-Investigator(Kenkyū-buntansha) BABA Hideo  Kumamoto University, Faculty of Medical and Pharmaceutical Sciences, Professor (20240905)
Project Period (FY) 2006 – 2007
Keywordsnitric oxide / TRS(insulin receptor substrate)-1 / IGF(insulin like growth factor)-1 / insulin / ubiquitin / Akt / pancreatic cancer / GSK(glvcogen svnthase kinase)-3
Research Abstract

(1) The effects of nitric oxide on IGF-R/1RS-1 /PI3-K/Akt pathway and MAPK pathway in cancer cells.
Nitric oxide (NO) donor down-regulated insulin/IGF signal including IRS-1, Akt, and GSK-3 in MIAPaCa-2 cells (derived from pancreatic cancer). On the other hand, NO donor up-regulated the phosphorylation of Erk 1/2.
(2) IRS-1 ubiquitination by NO donor
Protease inhibitor completely inhibited the degradation of IRS-1 protein by NO in MIAPaCa-2. The result suspected that NO regulated the ubiquitination and the degradation of IRS-1 protein in MIAPaCa-2. We produced the some constructs of IRS-1 delation mutants, and made the MIAPaCa-2 express them. Then, we found out the important site for IRS-I protein degradation by NO.
(3) The effects of NO on cancer proliferation
NO down-regulated the cell growth in some cancer cell lines.
We performed the cloning of stable cell lines; MIAPaCa-2 over-expressing IRS-1 wild type protein, MIAPaCa-2 over-expressing IRS-1 dominant negative. The cell line, over-expressing IRS-1 wild type protein, show high seed for cell growth, and greater sensitivity for NO. On the other hand, cell line, over-expressing IRS-1 dominant negative, show low speed of cell growth, and smaller sensitivity for NO. These results indicates that NO down-regulates IGF signal by the depression of IRS-1 protein. That may be one of the mechanisms for the down-regulation of cancer proliferation by NO.

  • Research Products

    (13 results)

All 2008 2007 2006

All Journal Article (9 results) (of which Peer Reviewed: 4 results) Presentation (4 results)

  • [Journal Article] Combined radical retropubic prostatectomy and abdominoperineal excision of the rectum for locally invasive rectal cancer as a less invasive surgery:report of a case2008

    • Author(s)
      Sugita H.
    • Journal Title

      Int.J.Surg. 92

      Pages: 249-251

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] radical retropubic prostatectomy and abdominoperineal excision of the rectum for locally invasive rectal cancer as a less invasive surgery : report of a case.2008

    • Author(s)
      Sugita, H., Egami, H., Yokoyama, Y., Suyama, K, Ogawa
    • Journal Title

      Int. J. Surg. 92(5)

      Pages: 249-251

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Farnesyltransferase inhibitor,manumycin a,prevents atherosclerosis development and reduces oxidative stress in apolipoprotein E-deficient mice2007

    • Author(s)
      Sugita M
    • Journal Title

      Arterioscler Thromb Vasc Biol. 27

      Pages: 1390-13905

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] 進行胆道癌におけるIrinotecan+low-dose CDDP(I/low-P)療法2007

    • Author(s)
      杉田 裕樹
    • Journal Title

      肝胆膵 55

      Pages: 1017-1023

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Farnesyltransferase inhibitor, manumycin a, prevents atherosclerosis development and reduces oxidative stress in apolipoprotein E-deficient mice2007

    • Author(s)
      Sugita, M, Sugita, H, Kaneki, M
    • Journal Title

      Arterioscler Thromb Vase Biol 27(6)

      Pages: 1390-5

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Combined Chemotherapy of Irinotecan and Low-dose Cisplatin(I/low-P)against Metastatic Biliary Tract Cancer2006

    • Author(s)
      Sugita H.
    • Journal Title

      J Hepatobiliary Pancreat Surg 13

      Pages: 463-467

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] dipocyte apoptosis after burn injury is associated with altered fat metabolism2006

    • Author(s)
      Yasuhara S
    • Journal Title

      J Burn Care Res 27

      Pages: 367-376

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Combined Chemotherapy of Irinotecan and Low-dose Cisplatin(I/low-P) against Metastatic Biliary Tract Cancer : Report of Consecutive Three Cases2006

    • Author(s)
      Sugita, H., Hirota, M., Ichihara, A., Furuhashi, S., Kihara, S., Shimada, S.
    • Journal Title

      J Hepatobiliary Pancreat Surg 13(5)

      Pages: 463-7

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Chon JY, Tompkins RC, and Martyn. JAA dipocyte apoptosis after burn injury is associated with altered fat metabolism2006

    • Author(s)
      Yasuhara, S, Kaneki, M, Sugita, H, Sugita, M, Asai, A, Sahani, N
    • Journal Title

      J Burn Care Res 27(3)

      Pages: 367-76

    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] NOによるIRS-1蛋白分解と膵癌細胞の増殖抑制2006

    • Author(s)
      杉田 裕樹
    • Organizer
      日本消化器外科
    • Place of Presentation
      横浜
    • Year and Date
      20060713-15
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] IRS-1 protein degradation and cell growth by nitric oxide2006

    • Organizer
      annual meeting of the Japanese society of gastroenterological surgery
    • Year and Date
      20060713-15
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] The role for nitric oxide in growth signa of pancreatic cancer2006

    • Organizer
      annual meeting of the Japanese society of surgery
    • Year and Date
      20060329-31
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] 膵癌細胞の増殖シグナルにおけるNOの役割2006

    • Author(s)
      杉田 裕樹
    • Organizer
      日本外科学会
    • Place of Presentation
      東京
    • Year and Date
      20060329-30
    • Description
      「研究成果報告書概要(和文)」より

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Published: 2010-02-04  

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