Fig. 2

p53 is a critical inhibitor in induced pluripotent stem cells (iPSCs). iPSC generation in normal fibroblasts with intact p53 requires the strong effects of four transcription factors, and leaky outcomes are observed. In contrast, iPSC generation coupled with p53 loss requires only two factors and exhibits markedly higher efficiency. a During normal development, totipotent stem cells at the top of the developmental hill gradually descend to become somatic cells at the bottom of the hill. A model of human iPSCs is provided in the upper-left corner. A model of human fibroblast cells is presented in the lower-left corner. Under normal conditions, with an intact p53 signaling pathway, the four transcription factors Oct4 (O), Sox2 (S), c-Myc (M), and Klf (K), which are represented by thick arrows from the top of the hill, promote the reprogramming of fibroblast cells into iPSCs. However, p53 dramatically attenuates the effects of these factors into much weaker forces, which are depicted as thin lines. In particular, iPSC generation across the p53 shield occurs only in certain cases at a low rate of approximately 0.01–0.1%, as reported previously [1–3]. b A markedly higher rate of 20% [38] suggests that cell identities shift nearly freely and reversibly between iPSCs and fibroblast cells under conditions of p53 loss. Furthermore, only Oct4 and Sox2 are sufficient for iPSC generation in this situation