Study on the signaling patlways involvedin Nox1-mediated Ras oncogene transformation

Nox1介导的Ras癌基因转化信号通路研究

• 批准号: 18590289
• 负责人: KAMATA Tohru
• 金额: $ 2.5万
• 依托单位: Shinshu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590289/
• 关键词: Nox1; Ras; reactive oxygen species; Rho; LMW-PTP; ERp72; Adhesion-Invasion?; Cancer; Nox1; レドックスシグナリング; アポプトシス; 接着; 細胞形質

The aim of our study is to elucidate the role of reactive oxygen species(ROS) generating oxidase, Nox1 h signal transduction involved in Ras oncogene transformation Our previous study revealed that Nox1 was essential for maintenance of Ras oncogene transformation phenotypes, and that upregulation of Nox1 expression was associated with some types of human cancers. This dearly indicates an important role of Nox1 in the development of cancer. Through the two-year term effort, we have made significant progress as outlined below 1), We identified a redox protein ERp72 as a potential target for Nazi. Nox1 oxidizes ERp72 and thereby regulates its nectox activity in response to activation of EGF receptor, suggesting that Nart-ERp72 complexes are coupled to EGF receptor signafing. 2), Nox1-generated oxidants mediate down-regulation of the Rho activity in Ras-transformed cells. This involves coridalive inactivation of LMW-PTP by Nox1 and subsequent activation of RhoGAR Then, the decreased Rho activity leads to disruption of both actin stress fhers and focal adhesions. The results provide a novel insight into the molecular mechanism underlying invasion and migration of transformed cells. Our discovery has significant implications in understandng the cell transformation mechanism and the biopharmacological.modulation of Nox1 may benefit prevention of tumor expansion.

本研究的目的是阐明活性氧（reactive oxygen species，ROS）产生氧化酶、Nox 1 h信号转导在Ras癌基因转化中的作用。我们以前的研究表明，Nox 1对Ras癌基因转化表型的维持是必不可少的，并且Nox 1表达上调与某些类型的人类癌症有关。这清楚地表明了Nox 1在癌症发展中的重要作用。通过两年的长期努力，我们取得了以下重大进展1），我们确定了氧化还原蛋白ERp 72作为Nazi的潜在靶点。Nox 1氧化ERp 72，从而调节其响应EGF受体激活的nectox活性，表明Nart-ERp 72复合物与EGF受体信号传导偶联。2），Nox 1产生的氧化剂介导Ras转化细胞中Rho活性的下调。这涉及Nox 1对LMW-PTP的cordalive失活和随后的RhoGAR激活。然后，Rho活性的降低导致肌动蛋白应激因子和粘着斑的破坏。这些结果为深入了解转化细胞侵袭和迁移的分子机制提供了新的思路。我们的发现对理解细胞转化机制和生物药理学意义重大，Nox 1的调节可能有助于防止肿瘤的扩展。

项目成果

メラノーマ細胞の癌化過程における活性酸素産生遺伝子Nox4の新しい役割.

活性氧产生基因Nox4在黑色素瘤细胞癌变过程中的新作用。

• 发表时间: 2007
• 作者: 古田秀一;et. al.
• 通讯作者: et. al.

A novel role of a superoxide generating Nox4 in cell cycle progression and transforming potential of melanoma cells

产生超氧化物的 Nox4 在黑色素瘤细胞的细胞周期进程和转化潜力中的新作用

• 发表时间: 2007
• 作者: Furuta;S.;et. al.
• 通讯作者: et. al.

A redox protein ERp/72 is a target for a superoxide generating oxidase Nox1 that mediates Ras transformation

氧化还原蛋白 ERp/72 是介导 Ras 转化的超氧化物生成氧化酶 Nox1 的靶标

• 发表时间: 2006
• 作者: Wei;Chang;et. al.
• 通讯作者: et. al.

Oncogenic Ras upregulates NADPHoxidase(Nox)1 gene expression through MEK-ERK-dependent phosphorylation of GATA-6.

致癌 Ras 通过 GATA-6 的 MEK-ERK 依赖性磷酸化上调 NADPH氧化酶 (Nox)1 基因表达。

• 发表时间: 2008
• 期刊: Oncogene (in press)
• 作者: Adachi;Y.;et. al.
• 通讯作者: et. al.

Functional characterization of the Ras/ERK signaling-responsive transcriptional machinery for NADPH oxidase (Nox)1

NADPH 氧化酶 (Nox)1 的 Ras/ERK 信号响应转录机制的功能表征

• 发表时间: 2007
• 作者: Adachi;y.;et. al.
• 通讯作者: et. al.