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Linking the p53 tumor suppressor pathway to somatic cell reprogramming

Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes1–8, but the low frequency and tendency to induce malignant transformation9 compromise the clinical utility of this powerful approach. We address both issues by i...

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Autores principales: Kawamura, Teruhisa, Suzuki, Jotaro, Wang, Yunyuan V., Menendez, Sergio, Morera, Laura Batlle, Raya, Angel, Wahl, Geoffrey M., Belmonte, Juan Carlos Izpisúa
Formato: Texto
Lenguaje:English
Publicado: 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735889/
https://www.ncbi.nlm.nih.gov/pubmed/19668186
http://dx.doi.org/10.1038/nature08311
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author Kawamura, Teruhisa
Suzuki, Jotaro
Wang, Yunyuan V.
Menendez, Sergio
Morera, Laura Batlle
Raya, Angel
Wahl, Geoffrey M.
Belmonte, Juan Carlos Izpisúa
author_facet Kawamura, Teruhisa
Suzuki, Jotaro
Wang, Yunyuan V.
Menendez, Sergio
Morera, Laura Batlle
Raya, Angel
Wahl, Geoffrey M.
Belmonte, Juan Carlos Izpisúa
author_sort Kawamura, Teruhisa
collection PubMed
description Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes1–8, but the low frequency and tendency to induce malignant transformation9 compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting reprogramming efficiency in somatic cells. We show that reprogramming factors can activate the p53 pathway. Reducing signaling to p53 by expressing a mutated version of one of its negative regulators, by deleting or silencing p53 or its target gene, p21, or by antagonizing apoptosis enhanced three factor (Oct4/Sox2/Klf4)-mediated reprogramming of mouse fibroblasts. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline transmitting chimeric mice using only Oct4 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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spelling pubmed-27358892010-02-27 Linking the p53 tumor suppressor pathway to somatic cell reprogramming Kawamura, Teruhisa Suzuki, Jotaro Wang, Yunyuan V. Menendez, Sergio Morera, Laura Batlle Raya, Angel Wahl, Geoffrey M. Belmonte, Juan Carlos Izpisúa Nature Article Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes1–8, but the low frequency and tendency to induce malignant transformation9 compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting reprogramming efficiency in somatic cells. We show that reprogramming factors can activate the p53 pathway. Reducing signaling to p53 by expressing a mutated version of one of its negative regulators, by deleting or silencing p53 or its target gene, p21, or by antagonizing apoptosis enhanced three factor (Oct4/Sox2/Klf4)-mediated reprogramming of mouse fibroblasts. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline transmitting chimeric mice using only Oct4 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. 2009-08-09 2009-08-27 /pmc/articles/PMC2735889/ /pubmed/19668186 http://dx.doi.org/10.1038/nature08311 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Kawamura, Teruhisa
Suzuki, Jotaro
Wang, Yunyuan V.
Menendez, Sergio
Morera, Laura Batlle
Raya, Angel
Wahl, Geoffrey M.
Belmonte, Juan Carlos Izpisúa
Linking the p53 tumor suppressor pathway to somatic cell reprogramming
title Linking the p53 tumor suppressor pathway to somatic cell reprogramming
title_full Linking the p53 tumor suppressor pathway to somatic cell reprogramming
title_fullStr Linking the p53 tumor suppressor pathway to somatic cell reprogramming
title_full_unstemmed Linking the p53 tumor suppressor pathway to somatic cell reprogramming
title_short Linking the p53 tumor suppressor pathway to somatic cell reprogramming
title_sort linking the p53 tumor suppressor pathway to somatic cell reprogramming
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735889/
https://www.ncbi.nlm.nih.gov/pubmed/19668186
http://dx.doi.org/10.1038/nature08311
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