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p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression

Nature Cell Biology volume 7, pages 165–171 (2005)Cite this article

Abstract

The tumour suppressor p53 becomes activated in response to upstream stress signals, such as DNA damage, and causes cell-cycle arrest or apoptosis1. Here we report a novel role for p53 in the differentiation of mouse embryonic stem cells (ESCs). p53 binds to the promoter of Nanog, a gene required for ESC self-renewal2,3, and suppresses Nanog expression after DNA damage. The rapid down-regulation of Nanog mRNA during ESC differentiation correlates with the induction of p53 transcriptional activity and Ser 315 phosphorylation. The importance of Ser 315 phosphorylation was revealed by the finding that induction of p53 activity is impaired in p53S315A knock-in ESCs during differentiation, leading to inefficient suppression of Nanog expression. The decreased inhibition of Nanog expression in p53S315A ESCs during differentiation is due to an impaired recruitment of the co-repressor mSin3a to the Nanog promoter. These findings indicate an alternative mechanism for p53 to maintain genetic stability in ESCs, by inducing the differentiation of ESCs into other cell types that undergo efficient p53-dependent cell-cycle arrest and apoptosis.

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Figure 1: p53-dependent suppression of Nanog expression.
Figure 2: p53 binds to the Nanog promoter.
Figure 3: p53 activation and phosphorylation during retinoic-acid-induced ESC differentiation.
Figure 4: p53 stability and activity in p53hki and p53hkiS315A ESCs during retinoic-acid-induced differentiation.
Figure 5: Recruitment of co-repressor mSin3a to the Nanog promoter.

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Acknowledgements

This work was supported by a National Institutes of Health grant (CA94254) to Y.X. We thank M. Hollstein for the humanized p53 knock-in construct and H. Niwa for the episomal expression vector that expresses in ESC.

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Authors and Affiliations

  1. Division of Biological Sciences, Section of Molecular Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0322, CA, USA

    Tongxiang Lin, Connie Chao & Yang Xu

  2. Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, USA

    Shin'ichi Saito, Sharlyn J. Mazur & Ettore Appella

  3. Department of Pharmacology, Fox Chase Cancer Center, 333 Cottman Avenue, 19111, PA, USA

    Maureen E. Murphy

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  1. Tongxiang Lin
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Correspondence to Yang Xu.

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Lin, T., Chao, C., Saito, S. et al. p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol 7, 165–171 (2005). https://doi.org/10.1038/ncb1211

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