Functions of p53 in the differentiation of human and mouse ESCs Functions of p53 in the differentiation of human and mouse ESCs. A schematic of p53 signaling and functions in human (left) and mouse (right) ESCs is shown. Functions of p53 in the differentiation of human and mouse ESCs. A schematic of p53 signaling and functions in human (left) and mouse (right) ESCs is shown. In response to retinoic acid (RA) in human ESCs, and in response to either RA or DNA damage in mouse ESCs, p53 becomes stabilized by post-translational modifications (such as acetylation and phosphorylation). Aurora kinase-mediated phosphorylation and inactivation of p53 (at Ser212 and Ser312) is specific to mouse ESCs, whereas the inactivation of p53 in human ESCs is mediated by SIRT1, an NAD+-dependent deacetylase that deacetylates p53. By contrast, the RA-induced acetylation of p53 by CBP/p300 in human ESCs, and the phosphorylation of p53 by CDK in mouse ESCs, leads to p53 activation. Once stabilized, p53 directly transcriptionally activates its target genes, which encode a variety of developmental genes and transcription factors. In parallel, p53 either directly represses the expression of pluripotency genes (such as Nanog in mouse ESCs) or activates genes that encode non-coding RNAs (such as miRNAs and lncRNAs in human ESCs), which fine-tune the activity of p53 to achieve sustained repression of pluripotency in ESCs. All members of the p53 family (*) are involved in the activation of mesendodermal genes. HOTAIRM1, Hox transcript antisense RNA, myeloid-specific 1; LIF, leukemia inhibitory factor; LncPRESS1, p53-regulated and ESC-associated 1; TUNA, Tcl1 upstream neuron-associated. Abhinav K. Jain, and Michelle Craig Barton Development 2018;145:dev158360 © 2018. Published by The Company of Biologists Ltd