Nature 460, 1132-1135 (27 August 2009) | doi:10.1038/nature08235; Received 8 September 2008; Accepted 30 June 2009; Published online 9 August 2009

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

Hyenjong Hong1,2, Kazutoshi Takahashi1, Tomoko Ichisaka1,3, Takashi Aoi1, Osami Kanagawa4, Masato Nakagawa1,2, Keisuke Okita1 & Shinya Yamanaka1,2,3,5

  1. Center for iPS Cell Research and Application (CiRA), Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan
  2. Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
  3. Yamanaka iPS Cell Special Project, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
  4. Laboratory for Autoimmune Regulation, RIKEN Center for Allergy and Immunology, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
  5. Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA

Correspondence to: Shinya Yamanaka1,2,3,5 Correspondence and requests for materials should be addressed to S.Y. (Email: yamanaka@frontier.kyoto-u.ac.jp).

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 mouse1, 2, 3, 4 and in human5, 6, 7, 8. The efficiency of this process, however, is low9. Pluripotency can be induced without c-Myc, but with even lower efficiency10, 11. A p53 (also known as TP53 in humans and Trp53 in mice) short-interfering RNA (siRNA) was recently shown to promote human iPS cell generation12, 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.


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