Details

Autor(en) / Beteiligte

• Weyemi, U
• Lagente-Chevallier, O
• Boufraqech, M
• Prenois, F
• Courtin, F
• Caillou, B
• Talbot, M
• Dardalhon, M
• Al Ghuzlan, A
• Bidart, J-M
• Schlumberger, M
• Dupuy, C

Titel

ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescence

Ist Teil von

• Oncogene, 2012-03, Vol.31 (9), p.1117-1129

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2012

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.