TY - JOUR
T1 - DNA damage and oxidant stress activate p53 through differential upstream signaling pathways
AU - Shi, Tao
AU - van Soest, Daan M.K.
AU - Polderman, Paulien E.
AU - Burgering, Boudewijn M.T.
AU - Dansen, Tobias B.
N1 - Funding Information:
We are grateful for suggestions and input from our colleagues at the department of Molecular Cancer Research, University Medical Center Utrecht. We thank Jeroen van den Berg and René Medema for sharing their RPE Tert p53 KO cell line, and Vsevolod Belousov for sharing the HyPer7 construct. The work was made possible with grants from the China Scholarship Council ( CSC no. 201606300046) to T.S. and from the Dutch Cancer Society ( KWF UU 2014–6902) to T.B.D. B.M.T.B is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society ( KWF Kankerbestrijding ) and was funded by the gravitation program CancerGenomiCs.nl from the Netherlands Organization for Scientific Research ( NWO ).
Funding Information:
We are grateful for suggestions and input from our colleagues at the department of Molecular Cancer Research, University Medical Center Utrecht. We thank Jeroen van den Berg and Ren? Medema for sharing their RPETert p53 KO cell line, and Vsevolod Belousov for sharing the HyPer7 construct. The work was made possible with grants from the China Scholarship Council (CSC no. 201606300046) to T.S. and from the Dutch Cancer Society (KWF UU 2014?6902) to T.B.D. B.M.T.B is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society (KWF Kankerbestrijding) and was funded by the gravitation program CancerGenomiCs.nl from the Netherlands Organization for Scientific Research (NWO).
Publisher Copyright:
© 2021 The Author(s)
PY - 2021/8/20
Y1 - 2021/8/20
N2 - 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.
AB - 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.
KW - DNA damage Response
KW - Oxidative signaling
KW - p38MAPK
KW - p53 activation
KW - Stress activated protein kinases
UR - http://www.scopus.com/inward/record.url?scp=85108348139&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2021.06.013
DO - 10.1016/j.freeradbiomed.2021.06.013
M3 - Article
C2 - 34144191
AN - SCOPUS:85108348139
SN - 0891-5849
VL - 172
SP - 298
EP - 311
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -