期刊
ONCOGENE
卷 31, 期 9, 页码 1117-1129出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2011.327
关键词
oncogenic H-RasV12; ROS; NADPH oxidase NOX4; DNA damage; senescence
资金
- Electricite de France (EDF)
- Association pour la Recherche sur le Cancer (ARC)
- Ligue Contre le Cancer (comite du Val-de Marne)
- Agence Nationale de la Recherche (ANR)
Activated Ras oncogene induces DNA-damage response by triggering reactive oxygen species (ROS) production and this is critical for oncogene-induced senescence. Until now, little connections between oncogene expression, ROS-generating NADPH oxidases and DNA-damage response have emerged from different studies. Here we report that H-RasV12 positively regulates the NADPH oxidase system NOX4-p22(phox) that produces H2O2. Knocking down the NADPH oxidase with small interference RNA decreases H-RasV12-induced DNA-damage response detected by gamma-H2A.X foci analysis. Using HyPer, a specific probe for H2O2, we detected an increase in H2O2 in the nucleus correlated with NOX4-p22(phox) perinuclear localization. DNA damage response can be caused not only by H-RasV12-driven accumulation of ROS but also by a replicative stress due to a sustained oncogenic signal. Interestingly, NOX4 downregulation by siRNA abrogated H-RasV12 regulation of CDC6 expression, an essential regulator of DNA replication. Moreover, senescence markers, such as senescence-associated heterochromatin foci, PML bodies, HP1 beta foci and p21 expression, induced under H-RasV12 activation were decreased with NOX4 inactivation. Taken together, our data indicate that NADPH oxidase NOX4 is a critical mediator in oncogenic H-RasV12-induced DNA-damage response and subsequent senescence. Oncogene (2012) 31, 1117-1129; doi:10.1038/onc.2011.327; published online 15 August 2011
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