Cited by 1,115Pluripotent Stem Cells ResearchDevelopmental Biology and Gene RegulationCancer-related Molecular Pathways

Linking the p53 tumour suppressor pathway to somatic cell reprogramming

Open access
Kawamura, Teruhisa, Suzuki, Jotaro, Wang, Yunyuan V., Menendez, Sergio, Morera, Laura Batlle, Raya, Angel, Wahl, Geoffrey M., Belmonte, Juan Carlos Izpisúa·2009·Nature

Abstract

Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes, but the low frequency and tendency to induce malignant transformation compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting reprogramming efficiency in somatic cells. Here we show that reprogramming factors can activate the p53 (also known as Trp53 in mice, TP53 in humans) pathway. Reducing signalling to p53 by expressing a mutated version of one of its negative regulators, by deleting or knocking down p53 or its target gene, p21 (also known as Cdkn1a), or by antagonizing reprogramming-induced apoptosis in mouse fibroblasts increases reprogramming efficiency. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline-transmitting chimaeric mice using only Oct4 (also known as Pou5f1) and Sox2. Furthermore, silencing of p53 significantly increased the reprogramming efficiency of human somatic cells. These results provide insights into reprogramming mechanisms and suggest new routes to more efficient reprogramming while minimizing the use of oncogenes.

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  • Reducing p53 with shRNA makes cell reprogramming more efficient.

    “Knocking down p53 by shRNA increased the efficiency of cell reprogramming.”

    From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [79]

  • Activation of p53 helps explain why induced pluripotent stem cells are produced only rarely during reprogramming.

    “Recently we, and others, showed that p53 activation contributed to the low frequency of generating induced pluripotent stem cells (iPS) during cell reprogramming [79,80].”

    From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [79]

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Authors
Kawamura, T., Suzuki, J., Wang, Y. V., Menendez, S., Morera, L. B., Raya, A., Wahl, G. M., & Belmonte, J. C. I.
Affiliations
Salk Institute for Biological Studies (US)
Corresponding author
  • Wahl, Geoffrey M.
  • Belmonte, Juan Carlos Izpisúa
Venue
Nature
Published
2009-08
Volume
460
Issue
7259
Pages
1140-1144
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2070672434
Cited by
1,115
References
40
Citations by year
2026: 13 · 2025: 12 · 2024: 30 · 2023: 34 · 2022: 31 · 2021: 36 · 2020: 29 · 2019: 41 · 2018: 55 · 2017: 60 · 2016: 65 · 2015: 77 · 2014: 96 · 2013: 111 · 2012: 136
FWCI
57.10
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R33HL088293)
  • National Cancer Institute (R01CA100845, R01CA061449)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
p53, somatic cell reprogramming, induced pluripotent stem cells, Oct4, SOX2, p21, Nutlin-3, reprogramming efficiency, malignant transformation, fibroblasts, oncogenes, apoptosis
MeSH terms
Animals, Cells, Cultured, Embryo, Mammalian, Female, Fibroblasts, Humans, Male, Mice, Inbred C57BL, Down-Regulation, Keratinocytes, Tumor Suppressor Protein p53, Pluripotent Stem Cells, Cyclin-Dependent Kinase Inhibitor p21, Mice, Cellular Reprogramming

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