p53 deficiency enhances the efficiency of somatic cell reprogramming to a pluripotent state. As p53 is usually mutated in human tumors and many mutated forms of p53 gain novel activities, here we studied the influence of mutant p53 on somatic cell reprogramming. Our data indicate a novel gain-of-function property for mutant-p53, which markedly enhanced the efficiency of the reprogramming process compared to p53 deficiency. Importantly, this novel activity of mutant p53 induced alterations in the characteristics of the reprogrammed cells; while p53-knockout cells reprogrammed with only Oct4 and Sox2 maintained their pluripotent capacity in vivo, reprogrammed cells expressing mutant p53 lost this capability, and gave rise to malignant tumors. Overall, our data show that reprogrammed cells with the capacity to differentiate into the three germ layers in vitro can form malignant tumors, suggesting that in genetically unstable cells such as those in which p53 is mutated, reprogramming may result in the generation of cells with malignant tumor-forming potential.
In an effort to elucidate the mechanism by which p53 regulates cell reprograming we that Mesenchymal-to-Epithelial Transition (MET) that was shown to be necessary and a rate-limiting step in the reprogramming of fibroblasts is restricted by p53 during the early phases of reprogramming. This effect is primarily mediated by the ability of p53 to inhibit Klf4-dependent activation of epithelial genes. We also found that the expression of E-Cadherin, an epithelial marker, negatively correlates with p53 activity in a variety of mesenchymal cells. We conclude that loss of p53 in mesenchymal cells predisposes them to the acquisition of epithelial characteristics and renders them more prone to reprogramming. Our study sheds light on a novel function by which p53 restrains reprogramming and highlights the role of p53 in the regulation of cell plasticity.
