Suppression of induced pluripotent stem cell generation by the p53-p21 pathway

• Published in: Nature (London) 2009-08, Vol.460 (7259), p.1132-1135
• Main Authors: Yamanaka, Shinya, Hong, Hyenjong, Takahashi, Kazutoshi, Ichisaka, Tomoko, Aoi, Takashi, Kanagawa, Osami, Nakagawa, Masato, Okita, Keisuke
• Format: Article
• Language: English
• Subjects: Adult; Animals; Biological and medical sciences; Cell Differentiation; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular signal transduction; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Efficiency; Embryo, Mammalian - cytology; Female; Fibroblasts; Fibroblasts - cytology; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Profiling; Gene mutations; Gene Silencing; Genes, myc; Genetic aspects; Humanities and Social Sciences; Humans; letter; Lymphocytes; Male; Mice; Molecular and cellular biology; multidisciplinary; Oligonucleotide Array Sequence Analysis; Physiological aspects; Plasmids - genetics; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; Proteins; Science; Science (multidisciplinary); Standard deviation; Stem cells; T-Lymphocytes - cytology; Transfection; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature08235

Induced pluripotent stem (iPS) cells can be generated from somatic cells by the introduction of Oct3/4 (also known as Pou5f1), Sox2, Klf4 and c-Myc, in mouse and in human. The efficiency of this process, however, is low. Pluripotency can be induced without c-Myc, but with even lower efficiency. A p53 (also known as TP53 in humans and Trp53 in mice) short-interfering RNA (siRNA) was recently shown to promote human iPS cell generation, but the specificity and mechanisms remain to be determined. Here we report that up to 10% of transduced mouse embryonic fibroblasts lacking p53 became iPS cells, even without the Myc retrovirus. The p53 deletion also promoted the induction of integration-free mouse iPS cells with plasmid transfection. Furthermore, in the p53-null background, iPS cells were generated from terminally differentiated T lymphocytes. The suppression of p53 also increased the efficiency of human iPS cell generation. DNA microarray analyses identified 34 p53-regulated genes that are common in mouse and human fibroblasts. Functional analyses of these genes demonstrate that the p53-p21 pathway serves as a barrier not only in tumorigenicity, but also in iPS cell generation.