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

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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.