The p53–PUMA axis suppresses iPSC generation

• Published in: Nature communications Vol. 4; no. 1; p. 2174
• Main Authors: Li, Yanxin, Feng, Haizhong, Gu, Haihui, Lewis, Dale W., Yuan, Youzhong, Zhang, Lei, Yu, Hui, Zhang, Peng, Cheng, Haizi, Miao, Weimin, Yuan, Weiping, Cheng, Shi-Yuan, Gollin, Susanne M., Cheng, Tao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2013; Nature Publishing Group
• Subjects: 631/136/532/2064/2158; 631/337; 631/80/86; Animals; Apoptosis Regulatory Proteins - deficiency; Apoptosis Regulatory Proteins - genetics; Biomarkers - metabolism; Cell Cycle - genetics; Cell Differentiation; Cell Lineage - genetics; Chromosome Aberrations; Cyclin-Dependent Kinase Inhibitor p21 - deficiency; Cyclin-Dependent Kinase Inhibitor p21 - genetics; DNA Damage; Embryo, Mammalian; Female; Fibroblasts - cytology; Fibroblasts - metabolism; Gene Deletion; Gene Expression Regulation, Developmental; Humanities and Social Sciences; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Male; Mice; Mice, Transgenic; multidisciplinary; Science; Science (multidisciplinary); Signal Transduction; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms3174

Mechanisms underlying the reprogramming process of induced pluripotent stem cells remain poorly defined. Like tumorigenesis, generation of induced pluripotent stem cells was shown to be suppressed by the Trp53 (p53) pathway, at least in part via p21 Cdkn1a (p21)-mediated cell cycle arrest. Here we examine the role of PUMA, a pro-apoptotic mediator of p53, during somatic reprogramming in comparison to p21 in the p53 pathway. Using mouse strains deficient in these molecules, we demonstrate that PUMA is an independent mediator of the negative effect of p53 on induced pluripotent stem cell induction. PUMA deficiency leads to a better survival rate associated with reduced DNA damage and fewer chromosomal aberrations in induced pluripotent stem cells, whereas loss of p21 or p53 results in an opposite outcome. Given these new findings, PUMA may serve as a distinct and more desirable target in the p53 pathway for induced pluripotent stem cell generation, thereby having important implications for potential therapeutic applications of induced pluripotent stem cells. Inhibition of the p53–p21 axis increases reprogramming efficiency of somatic cells into induced pluripotent stem cells (iPSCs). Here the authors show that depletion of the pro-apoptotic factor PUMA, acting downstream of p53, increases reprogramming efficiency, providing new insights into the roles of p53 in reprogramming.