DNA damage and oxidant stress activate p53 through differential upstream signaling pathways.
Free Radic Biol Med
; 172: 298-311, 2021 08 20.
Article
en En
| MEDLINE
| ID: mdl-34144191
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 H2O2. When cells are exposed to exogenously added H2O2, ATR/CHK1 and ATM/CHK2 dependent DNA damage signaling is switched on, suggesting that H2O2 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, H2O2 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteína p53 Supresora de Tumor
/
Proteínas de Ciclo Celular
Límite:
Humans
Idioma:
En
Revista:
Free Radic Biol Med
Asunto de la revista:
BIOQUIMICA
/
MEDICINA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Países Bajos
Pais de publicación:
Estados Unidos