DNA damage and oxidizing conditions activate p53 through differential upstream signaling pathways

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Abstract
Stabilization and activation of the p53 tumour suppressor are triggered in response to various cellular stresses, including DNA damaging agents and elevated Reactive Oxygen Species (ROS) like H 2 O 2 . When cells are exposed to exogenously added H 2 O 2 , ATR/CHK1 and ATM/CHK2 dependent DNA damage signaling is switched on, suggesting that H 2 O 2 induces both single and double strand breaks. These collective observations have resulted in the widely accepted model that oxidizing conditions lead to DNA damage that subsequently mediates a p53-dependent response like cell cycle arrest and apoptosis. However, H 2 O 2 induces signaling through stress-activated kinases (SAPK, e.g., JNK and p38MAPK) that can activate p53. Here we dissect to what extent these pathways contribute to functional activation of p53 in response to oxidizing conditions. Collectively, our data suggest that p53 can be activated both by SAPK signaling and the DDR independently of each other, and which of these pathways is activated depends on the type of oxidant used. This implies that it could in principle be possible to modulate redox signaling to stimulate p53 without inducing collateral DNA damage, thereby limiting mutation accumulation in both healthy and tumor tissues.
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