The functional role of a superoxide generating gene Nox1 in Ras oncogene-induced transformation and human tumor development

• Project/Area Number: 16590242
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Shinshu University School of Medicine
• Principal Investigator: KAMATA Tohru Shinshu University, School of medicine, professor, 医学部, 教授 (40056304)
• Co-Investigator(Kenkyū-buntansha): ADACHI Yoshifumi Shinshu University, School of medicine, Associated professor, 医学部, 助教授 (50201893) ; SHINOHARA Masahiro Shinshu University, School of medicine, Research Associate, 医学部, 助手 (60345733)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 2004: ¥2,500,000 (Direct Cost: ¥2,500,000)
• Keywords: Nox1 / Ras / reactive oxygen species / redox signaling / cancer / pancreatic cancer / melanoma / Nox4 / MAP Kinase / 癌 / RNAi / MAPkinase / 転移 / 情報伝達

Research Abstract

The aim of our study is to elucidate the functional role of reactive oxygen species (ROS) -generating Nox1 family genes in development of human cancers by utilizing Ras-transformation as a model system and lay a foundation for treatment and diagnosis of human cancers. We previously found that Ras oncogene upregulates Nox1 expression via Raf-MEK-MAPK pathway and Nox1 generated-ROS are required for oncogenic Ras transformation. This implicates an important role as a new limiting factor for Nox1 in oncogenesis. In the current study, we demonstrated that Nox4-generated ROS confer cell survival activity to pancreatic cancer cells through the AKT-ASK1 pathway and inhibit cell growth of melanoma cells by deregulating cell cycle. Furthermore, we identified ER proteins, PDI family proteins as potential downstream targets for Nox1-generated ROS whose Cys-SH residues are selectively oxidized by ROS. In the future study, we will further analyze what activity associated with these redox proteins is essential for Nox1-mediated cell transformation process. Our discovery accelerates the dissection of Nox-redox signaling pathway and provides a novel insight into its functional role in cancer development.

Research Products

• [Journal Article] Inhibition of NADPHoxidase4 activates apoptosis via the AKT/apoptosis signal-regulating kinasel pathway in pancreatic cancer PANC-1 cells. (2006)
  • Author(s): Mochizuki, T. et al.
  • Journal Title: Oncogene (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A reducing and denaturing step maximizes the immunoprecipitation of m-calpain : an approach toward antibodies that do not work well in immunoprecipitation. (2006)
  • Author(s): Chen, W., Nishikimi, A., Kamata, T., Adachi, Y.
  • Journal Title: J.Biochem.Biophysics Methods. (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inhibition of NADPHoxidase 4 activates apoptosis via the AKT/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells. (2006)
  • Author(s): Mochizuki, T., Furuta, S., Mitsushita, J., Shang, W.H., Yamaura, M., Ishizone, S., Nakayama, J., Konagai, A., Hirose, K., Kiyosawa, K., Kamata, T.
  • Journal Title: Oncogene. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inhibition of NADPHoxidase4 activates apoptosis via the AKT/apoptosis signal-regulating kinasel pathway in pancreatic cancer PANC-1 cells. (2006)
  • Author(s): Mochizuki, T. et al.
  • Journal Title: Oncogene in press
• [Journal Article] Development of a direct and sensitive detection method for DNA-binding proteins based on electrophoretic mobility shift assay and iodoacetamide derivative labeling. (2005)
  • Author(s): Adachi, Y., Chen, W., Shang, W.H., Kamata, T.
  • Journal Title: Anal.Biochem. 342 Pages: 348-351
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 活性酸素は癌化に寄与しうるか? NADPHoxidase ファミリーによる新しい癌化機構 (2005)
  • Author(s): 鎌田徹, 満下淳地
  • Journal Title: 信州医学雑誌 52 Pages: 265-270
  • NAID: 130005074312
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Do reactive oxygen species contribute to cancer? -A novel mechanism of cancer development mediated by the NADPHoxidase family- (2005)
  • Author(s): Kamata, T., Mitsushita, J.
  • Journal Title: The Shinshu Medical Journal 52 Pages: 265-270
  • NAID: 130005074312
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The superoxide-generating oxidase Nox1 is functionally required for Ras oncogene transfprmation. (2004)
  • Author(s): Mitsushita, J., Lambeth, D., Kamata, T.
  • Journal Title: Cancer Res. 64 Pages: 3580-3585
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulation of Amphiphysinl by Mitogen-activated protein kinase. (2004)
  • Author(s): Shang, W.H., Adachi, Y., Nakamura, A., Copeland, T., Kim, SP., Kamata, T.
  • Journal Title: J.Biol.Chem. 279 Pages: 2004-2004
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The superoxide-generating oxidase Nox1 is functionally required for Ras oncogene transformation. (2004)
  • Author(s): Mitsushita, J., Lambeth, D., Kamata, T.
  • Journal Title: Cancer Res. 64 Pages: 3580-3585
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regulation of Amphiphysin1 by Mitogen-activated protein kinase. (2004)
  • Author(s): Shang, W.H., Adachi, Y., Nakamura, A., Copeland, T., Kim, SP., Kamata, T.
  • Journal Title: J.Biol.Chem. 279 Pages: 40890-40896
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The superoxide-generating oxidase Nox1 is functionally required for Ras oncogene transformation. (2004)
  • Author(s): Mitsushita.J., Lambeth, D., kamata, T
  • Journal Title: Cancer Research 64 Pages: 3580-3585
• [Journal Article] Regulation of Amphiphysinl by Mitogen-activated protein kinase. (2004)
  • Author(s): Shang, W.H, Adachi, Y., Nakamura, A., Copeland, T., Kim, SP., Kamata, T.
  • Journal Title: The Journal of Biological Chemistry 279 Pages: 40890-40896
• [Journal Article] Ras is involved in the negative control of autophagy through the class I PI3-kinase. (2004)
  • Author(s): Furuta, S., Hidaka, R, Ogata, A., Yokota, S., Kamata, T.
  • Journal Title: Oncogene 23 Pages: 3898-3904
• [Journal Article] A reducing and denaturing step maximizes the immunoprecipitation of m-calpain : an approach toward antibodies that do not work well in immunoprecipitation.
  • Author(s): Chen, W., Nishikimi, A., Kamata, T., Adachi, Y.
  • Journal Title: Anal.Biochem. in press
• [Book] タンパク質科学イラストレイテッド (2005)
  • Author(s): 竹縄忠臣 編集
  • Total Pages: 332
  • Publisher: 羊土社