Abstract
Since it was found that p53 is highly expressed in murine embryonic stem cells, it remained a mystery whether p53 is active in this cell type. We show that a significant part of p53 is localised in the nucleus of murine embryonic stem cells and that the majority of this nuclear p53 is bound to DNA. According to its nuclear localisation, we show that p53 alters the transcriptional program of stem cells. Nevertheless, the anti-proliferative activity of p53 is compromised in stem cells, and this control is due, at least in part, to the high amount of MdmX that is present in embryonic stem cells and bound to p53. Instead of the anti-proliferative activity that p53 has in differentiated cells, p53 controls transcription of pro-proliferative genes in embryonic stem cells including c-myc and c-jun. The impeded anti-proliferative activity of p53 and the induction of certain proto-oncogenes by p53 in murine embryonic stem cells can explain why stem cells proliferate efficiently despite having high levels of p53.
Highlights
The tumour suppressor protein p53 is a transcription factor that induces proliferation arrest and cell death via nuclear and cytoplasmic activities.[1,2] Under conditions with an increased risk of mutagenesis, p53 levels rise and the tumour suppressor protein becomes post-translationally modified, resulting in its activation.[3]
We show that the anti-proliferative activity of p53 is compromised in Murine embryonic stem cells (mESCs)
Results p53 is primarily nuclear in mESCs. p53 is an antiproliferative protein and highly abundant in mESCs (Supplementary Figure S1A),[8] a cell type that proliferates faster than most differentiated cell lines (Supplementary Figure S1B)
Summary
P53 is primarily nuclear in mESCs. p53 is an antiproliferative protein and highly abundant in mESCs (Supplementary Figure S1A),[8] a cell type that proliferates faster than most differentiated cell lines (Supplementary Figure S1B). We could precipitate akt[1], c-myc and c-jun DNA with an anti-p53 antibody only from lysates of p53-positive stem cells, but not from p53-negative stem cells or differentiated cells (Figure 6f, Supplementary Figure S5B). When we treated stem cells with the topoisomerase inhibitor etoposide to induce DNA strand breaks, we observed a strong induction of p53 and a p53-dependent increase in Mdm[2] and p21 (Supplementary Figure S5C). It is rather unlikely that p53 controls its 'stem cell-specific target genes' in response to DNA damage Overall, these results demonstrate that p53 alters the transcriptional program in mESCs. Most remarkably, p53 controls expression of a different set of genes in mESCs than in differentiated cells and, most strikingly, several of these genes are controlled by mutant p53 in tumour cells
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