Regulation and Function of p53 in Embryonic Stem Cells

Abstract

The p53 protein is one of the most well-known tumor suppressor proteins, and it plays a variety of functions in somatic cells. Once activated, p53 induces cell cycle arrest and inhibits cell proliferation. Since it was found that p53 is highly expressed in murine embryonic stem cells, a cell type that proliferates very fast because of a shortened G1 phase, it remained a mystery whether p53 is active in this cell type. I observed that a significant part of p53 is localized in the nucleus of murine embryonic stem cells and that the majority of this nuclear p53 is bound to DNA. In addition, 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. This high amount of MDMX is most likely due to exclusion of exon 7 of the MDMX RNA during retinoic acid induced differentiation. MDMX co-eluted with p53 from sucrose gradient assays and downregulation of MDMX in mESCs increased MDM2 abundance, a transcriptional target of p53, indicating that MDMX controls p53’s transcriptional activity in stem cells. P53 is posttranslationally modified in mESCs and these modifications endow a neutral isoelectric point (pI) of a fraction of the p53 protein that is only present in stem cells. Moreover, according to its nuclear localization in mESCs, p53 influences the transcriptome of mESCs. However, in contrast to 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. Chromatin-Immunoprecipitation showed that p53 binds to the responsive element of these proto-oncogenes. 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.