DNA damage and oxidant stress activate p53 through differential upstream signaling pathways.

Autor: Shi T; Center for Molecular Medicine, Molecular Cancer Research, the Netherlands., van Soest DMK; Center for Molecular Medicine, Molecular Cancer Research, the Netherlands., Polderman PE; Center for Molecular Medicine, Molecular Cancer Research, the Netherlands., Burgering BMT; Center for Molecular Medicine, Molecular Cancer Research, the Netherlands; Oncode Institute, University Medical Center Utrecht, Universiteitsweg, 100 3584, CG, Utrecht, the Netherlands., Dansen TB; Center for Molecular Medicine, Molecular Cancer Research, the Netherlands. Electronic address: t.b.dansen@umcutrecht.nl.
Jazyk: angličtina
Zdroj: Free radical biology & medicine [Free Radic Biol Med] 2021 Aug 20; Vol. 172, pp. 298-311. Date of Electronic Publication: 2021 Jun 16.
DOI: 10.1016/j.freeradbiomed.2021.06.013
Abstrakt: Stabilization and activation of the p53 tumor 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 also induces signaling through stress-activated kinases (SAPK, e.g., JNK and p38 MAPK) 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 oxidative signaling to stimulate p53 without inducing collateral DNA damage, thereby limiting mutation accumulation in both healthy and tumor tissues.
(Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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