p53 and p73 Regulate Apoptosis but Not Cell-Cycle Progression in Mouse Embryonic Stem Cells upon DNA Damage and Differentiation

• Published in: Stem cell reports 2016-12, Vol.7 (6), p.1087-1098
• Main Authors: He, Hanbing, Wang, Cheng, Dai, Qian, Li, Fengtian, Bergholz, Johann, Li, Zhonghan, Li, Qintong, Xiao, Zhi-Xiong
• Format: Article
• Language: English
• Subjects: Animals; apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Base Sequence; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Cycle Checkpoints - drug effects; Cell Cycle Checkpoints - genetics; Cell Differentiation - drug effects; Cell Differentiation - genetics; differentiation; DNA Damage; doxorubicin; Doxorubicin - pharmacology; G2/M arrest; HEK293 Cells; Humans; Mice; mouse embryonic stem cells; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - drug effects; Mouse Embryonic Stem Cells - metabolism; naive and primed state; p53; p73; Transcription, Genetic - drug effects; Tumor Protein p73 - metabolism; Tumor Suppressor Protein p53 - metabolism; Up-Regulation - drug effects; Up-Regulation - genetics
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2016.10.008

Embryonic stem cells (ESCs) are fast proliferating cells capable of differentiating into all somatic cell types. In somatic cells, it is well documented that p53 is rapidly activated upon DNA damage to arrest the cell cycle and induce apoptosis. In mouse ESCs, p53 can also be functionally activated, but the precise biological consequences are not well characterized. Here, we demonstrated that doxorubicin treatment initially led to cell-cycle arrest at G2/M in ESCs, followed by the occurrence of massive apoptosis. Neither p53 nor its target gene p73 was required for G2/M arrest. Instead, p53 and p73 were fully responsible for apoptosis. p53 and p73 were also required for differentiation-induced apoptosis in mouse ESCs. In addition, doxorubicin treatment induced the expression of retinoblastoma protein in a p53-dependent manner. Therefore, both p53 and p73 are critical in apoptosis induced by DNA damage and differentiation. •p53/p73 are key for DNA damage-induced apoptosis but not G2/M arrest in mESCs•Both p53 and p73 are required for differentiation-induced apoptosis in mESCs•Doxorubicin induces RB via p53-mediated suppression of miR-17-92 and miR-106a-363•p73 expression is induced upon differentiation in mESCs In this article, Xiao, Li, and colleagues show that p53 and p73 are pivotal for DNA-damage-induced apoptosis but not for G2/M arrest in mESCs. In addition, doxorubicin induces RB via p53-mediated suppression of miR-17-92 and miR-106a-363. During differentiation, p73, but not p53, is induced, and both p53 and p73 are critical for differentiation-induced apoptosis.