期刊
CELL DEATH AND DIFFERENTIATION
卷 21, 期 8, 页码 1185-1197出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2014.34
关键词
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资金
- National Research Foundation (NRF)
- Ministry of Science, ICT and Future Planning, Korean government, through its National Nuclear Technology Program [2012M2A2A7035878, 2012M2B2B1055639]
- National Research Foundation of Korea [2012M2A2A7035878, 2012M2B2B1055639] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Reactive oxygen species (ROS) are well known to be involved in oncogene-mediated cellular transformation. However, the regulatory mechanisms underlying ROS generation in oncogene-transformed cells are unclear. In the present study, we found that oncogenic K-Ras induces ROS generation through activation of NADPH oxidase 1 (NOX1), which is a critical regulator for the K-Ras-induced cellular transformation. NOX1 was activated by K-Ras-dependent translocation of p47(phox), a subunit of NOX1 to plasma membrane. Of note, PKC delta, when it was activated by PDPK1, directly bound to the SH3-N domain of p47(phox) and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47(phox) C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation. Notably, oncogenic K-Ras activated all MAPKs (JNK, ERK and p38); however, only p38 was involved in p47(phox)-NOX1-dependent ROS generation and consequent transformation. Importantly, K-Ras-induced activation of p38 led to an activation of PDPK1, which then signals through PKC delta, p47(phox) and NOX1. In agreement with the mechanism, inhibition of p38, PDPK1, PKC delta, p47(phox) or NOX1 effectively blocked K-Ras-induced ROS generation, anchorage-independent colony formation and tumor formation. Taken together, our findings demonstrated that oncogenic K-Ras activates the signaling cascade p38/PDPK1/PKC delta/p47(phox)/NOX1 for ROS generation and consequent malignant cellular transformation.
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