p53 regulates cell cycle and microRNAs to promote differentiation of human embryonic stem cells.

Multiple studies show that tumor suppressor p53 is a barrier to dedifferentiation; whether this is strictly due to repression of proliferation remains a subject of debate. Here, we show that p53 plays an active role in promoting differentiation of human embryonic stem cells (hESCs) and opposing self...

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Autores principales:	Abhinav K Jain, Kendra Allton, Michelina Iacovino, Elisabeth Mahen, Robert J Milczarek, Thomas P Zwaka, Michael Kyba, Michelle Craig Barton
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/95383081643b4342828fa9dca7f7709b
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spelling	oai:doaj.org-article:95383081643b4342828fa9dca7f7709b2021-11-18T05:36:45Zp53 regulates cell cycle and microRNAs to promote differentiation of human embryonic stem cells.1544-91731545-788510.1371/journal.pbio.1001268https://doaj.org/article/95383081643b4342828fa9dca7f7709b2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22389628/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Multiple studies show that tumor suppressor p53 is a barrier to dedifferentiation; whether this is strictly due to repression of proliferation remains a subject of debate. Here, we show that p53 plays an active role in promoting differentiation of human embryonic stem cells (hESCs) and opposing self-renewal by regulation of specific target genes and microRNAs. In contrast to mouse embryonic stem cells, p53 in hESCs is maintained at low levels in the nucleus, albeit in a deacetylated, inactive state. In response to retinoic acid, CBP/p300 acetylates p53 at lysine 373, which leads to dissociation from E3-ubiquitin ligases HDM2 and TRIM24. Stabilized p53 binds CDKN1A to establish a G(1) phase of cell cycle without activation of cell death pathways. In parallel, p53 activates expression of miR-34a and miR-145, which in turn repress stem cell factors OCT4, KLF4, LIN28A, and SOX2 and prevent backsliding to pluripotency. Induction of p53 levels is a key step: RNA-interference-mediated knockdown of p53 delays differentiation, whereas depletion of negative regulators of p53 or ectopic expression of p53 yields spontaneous differentiation of hESCs, independently of retinoic acid. Ectopic expression of p53R175H, a mutated form of p53 that does not bind DNA or regulate transcription, failed to induce differentiation. These studies underscore the importance of a p53-regulated network in determining the human stem cell state.Abhinav K JainKendra AlltonMichelina IacovinoElisabeth MahenRobert J MilczarekThomas P ZwakaMichael KybaMichelle Craig BartonPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 10, Iss 2, p e1001268 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Abhinav K Jain Kendra Allton Michelina Iacovino Elisabeth Mahen Robert J Milczarek Thomas P Zwaka Michael Kyba Michelle Craig Barton p53 regulates cell cycle and microRNAs to promote differentiation of human embryonic stem cells.
description	Multiple studies show that tumor suppressor p53 is a barrier to dedifferentiation; whether this is strictly due to repression of proliferation remains a subject of debate. Here, we show that p53 plays an active role in promoting differentiation of human embryonic stem cells (hESCs) and opposing self-renewal by regulation of specific target genes and microRNAs. In contrast to mouse embryonic stem cells, p53 in hESCs is maintained at low levels in the nucleus, albeit in a deacetylated, inactive state. In response to retinoic acid, CBP/p300 acetylates p53 at lysine 373, which leads to dissociation from E3-ubiquitin ligases HDM2 and TRIM24. Stabilized p53 binds CDKN1A to establish a G(1) phase of cell cycle without activation of cell death pathways. In parallel, p53 activates expression of miR-34a and miR-145, which in turn repress stem cell factors OCT4, KLF4, LIN28A, and SOX2 and prevent backsliding to pluripotency. Induction of p53 levels is a key step: RNA-interference-mediated knockdown of p53 delays differentiation, whereas depletion of negative regulators of p53 or ectopic expression of p53 yields spontaneous differentiation of hESCs, independently of retinoic acid. Ectopic expression of p53R175H, a mutated form of p53 that does not bind DNA or regulate transcription, failed to induce differentiation. These studies underscore the importance of a p53-regulated network in determining the human stem cell state.
format	article
author	Abhinav K Jain Kendra Allton Michelina Iacovino Elisabeth Mahen Robert J Milczarek Thomas P Zwaka Michael Kyba Michelle Craig Barton
author_facet	Abhinav K Jain Kendra Allton Michelina Iacovino Elisabeth Mahen Robert J Milczarek Thomas P Zwaka Michael Kyba Michelle Craig Barton
author_sort	Abhinav K Jain
title	p53 regulates cell cycle and microRNAs to promote differentiation of human embryonic stem cells.
title_short	p53 regulates cell cycle and microRNAs to promote differentiation of human embryonic stem cells.
title_full	p53 regulates cell cycle and microRNAs to promote differentiation of human embryonic stem cells.
title_fullStr	p53 regulates cell cycle and microRNAs to promote differentiation of human embryonic stem cells.
title_full_unstemmed	p53 regulates cell cycle and microRNAs to promote differentiation of human embryonic stem cells.
title_sort	p53 regulates cell cycle and micrornas to promote differentiation of human embryonic stem cells.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/95383081643b4342828fa9dca7f7709b
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p53 regulates cell cycle and microRNAs to promote differentiation of human embryonic stem cells.

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