Abstract
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 H 2 O 2. Knocking down the NADPH oxidase with small interference RNA decreases H-RasV12-induced DNA-damage response detected by γ-H2A.X foci analysis. Using HyPer, a specific probe for H 2 O 2, we detected an increase in H 2 O 2 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, HP1Β 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.
Original language | English (US) |
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Pages (from-to) | 1117-1129 |
Number of pages | 13 |
Journal | Oncogene |
Volume | 31 |
Issue number | 9 |
DOIs | |
State | Published - Mar 1 2012 |
Externally published | Yes |
Keywords
- DNA damage
- NADPH oxidase NOX4
- ROS
- oncogenic H-RasV12
- senescence
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research