Linking the p53 tumour suppressor pathway to somatic cell reprogramming

On iPS cells and p53: somatic cell reprogramming This paper reports that the transcription factor p53 plays a crucial role in regulating somatic reprogramming. The authors develop an experimental protocol to reprogram somatic cells using just two factors, Oct4 and Sox2, when p53 is silenced. On the other hand, overexpression of p53 or the presence of Nutlin-3 (a p53 stabilizer) reduces reprogramming efficiency. Expression of pluripotency factors and oncogenes can reprogram somatic cells to induced pluripotent stem cells, albeit with low frequency and a tendency to induce malignant transformation. Here, reprogramming factors are shown to activate the p53 pathway, providing insights into reprogramming mechanisms. Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , but the low frequency and tendency to induce malignant transformation 9 compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting reprogramming efficiency in somatic cells. Here we show that reprogramming factors can activate the p53 (also known as Trp53 in mice, TP53 in humans) pathway. Reducing signalling to p53 by expressing a mutated version of one of its negative regulators, by deleting or knocking down p53 or its target gene, p21 (also known as Cdkn1a ), or by antagonizing reprogramming-induced apoptosis in mouse fibroblasts increases reprogramming efficiency. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline-transmitting chimaeric mice using only Oct4 (also known as Pou5f1) and Sox2. Furthermore, silencing of p53 significantly increased the reprogramming efficiency of human somatic cells. These results provide insights into reprogramming mechanisms and suggest new routes to more efficient reprogramming while minimizing the use of oncogenes.