Nature Cell Biology7, 165 - 171 (2004)
Published online: 26 December 2004; | doi:10.1038/ncb1211
p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression
Tongxiang Lin1, Connie Chao1, Shin'ichi Saito2, Sharlyn J. Mazur2, Maureen E. Murphy3, Ettore Appella2
& Yang Xu1
1
Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA.
2
Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
3
Department of Pharmacology, Fox Chase Cancer Center, 333 Cottman Avenue, PA 19111, USA.
Correspondence should be addressed to Yang Xu yangxu@ucsd.edu
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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