Stem Cell Reports
Volume 14, Issue 2, 11 February 2020, Pages 175-183
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Report
Critical Role for P53 in Regulating the Cell Cycle of Ground State Embryonic Stem Cells

https://doi.org/10.1016/j.stemcr.2020.01.001Get rights and content
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Highlights

  • The P53-P21 pathway is activated upon adaptation of ESCs to their pluripotent ground state.

  • P53 is required for the elongated G1-phase characteristic to 2i ESCs.

  • P53 binds the promoter and activates Rb1 expression.

Summary

Mouse embryonic stem cells (ESCs) grown in serum-supplemented conditions are characterized by an extremely short G1 phase due to the lack of G1-phase control. Concordantly, the G1-phase-specific P53-P21 pathway is compromised in serum ESCs. Here, we provide evidence that P53 is activated upon transition of serum ESCs to their pluripotent ground state using serum-free 2i conditions and that is required for the elongated G1 phase characteristic of ground state ESCs. RNA sequencing and chromatin immunoprecipitation sequencing analyses reveal that P53 directly regulates the expression of the retinoblastoma (RB) protein and that the hypo-phosphorylated, active RB protein plays a key role in G1-phase control. Our findings suggest that the P53-P21 pathway is active in ground state 2i ESCs and that its role in the G1-checkpoint is abolished in serum ESCs. Taken together, the data reveal a mechanism by which inactivation of P53 can lead to loss of RB and uncontrolled cell proliferation.

Keywords

embryonic stem cells
G1 checkpoint
P53
RB

Cited by (0)

2

Present address: Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Rd, Parkville, VIC 3052, Melbourne, Australia

3

Present address: Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands

4

Co-first author