Hydroxyurea induces a hypersensitive apoptotic response in mouse embryonic stem cells through p38-dependent acetylation of p53.
While hydroxyurea (HU) is well known to deplete dNTP pools and lead to replication fork arrest in the cell, the mechanisms by which it exerts a cell response are poorly understood. Here, our results suggest that mouse embryonic stem cells (mESCs), unlike terminally differentiated cells such as mouse embryonic fibroblasts (MEFs), rapidly respond to low concentrations of HU by p53 acetylation, leading to activation of the caspase-dependent apoptotic pathway. We show that HU treatment induces the production of nitric oxide (NO), which plays a central role in the rapid induction of apoptosis in mESCs. By contrast, reactive oxygen species, which are expressed at significantly higher levels in mESCs compared with MEFs, are not related to the HU response. Furthermore, on exposure to HU, the p38 signaling pathway becomes activated in a dose-dependent manner, and chemical inhibition of the p38 pathway attenuates HU-dependent apoptosis in mESCs. Our data reveal that acetylation of p53 as a result of HU-dependent NO production plays a key role in the induction of the apoptotic response in mESCs. Finally, p38 signaling appears to be the main pathway underlying the activation of apoptosis in mESCs in response to HU exposure.
1 Department of Biomedical Science, College of Life Science, CHA University , Seoul, Korea.
Sun-Hee
SH
Heo
Young
Y
Cha
Kyung-Soon
KS
Park
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000986:Antisickling Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006918:Hydroxyurea / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000986:Antisickling Agents; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D048051:p38 Mitogen-Activated Protein Kinases; D006918:Hydroxyurea