Suppression of Induced Pluripotent Stem Cell Generation by the p53-p21 Pathway

Nature. 2009 Aug 27;460(7259):1132-5. doi: 10.1038/nature08235. Epub 2009 Aug 9.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Differentiation
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Embryo, Mammalian / cytology
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression Profiling
  • Gene Silencing
  • Genes, myc
  • Humans
  • Male
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • Plasmids / genetics
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / metabolism*
  • T-Lymphocytes / cytology
  • Transfection
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • Tumor Suppressor Protein p53

Associated data

  • GEO/GSE13365