ERF deletion rescues RAS deficiency in mouse embryonic stem cells

MEK inhibition in combination with a glycogen synthase kinase-3β (GSK3β) inhibitor, referred as the 2i condition, favors pluripotency in embryonic stem cells (ESCs). However, the mechanisms by which the 2i condition limits ESC differentiation and whether RAS proteins are involved in this phenomenon...

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Autores: Mayor-Ruiz, Cristina, Olbrich, Teresa, Drosten, Matthias, Lecona, Emilio, Vega-Sendino, Maria, Ortega Jimenez, Sagrario, Dominguez, Orlando, Barbacid, Mariano, Ruiz, Sergio, Fernandez-Capetillo, Oscar
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/8360
Acceso en línea:http://hdl.handle.net/20.500.12105/8360
Access Level:acceso abierto
Palabra clave:Animals
Cell Differentiation
Cell Line
Embryonic Stem Cells
Enhancer Elements, Genetic
Gene Deletion
Mice
Mice, Nude
Repressor Proteins
Teratoma
Genes, ras
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oai_identifier_str oai:repisalud.isciii.es:20.500.12105/8360
network_acronym_str ES
network_name_str España
repository_id_str
spelling ERF deletion rescues RAS deficiency in mouse embryonic stem cellsMayor-Ruiz, CristinaOlbrich, TeresaDrosten, MatthiasLecona, EmilioVega-Sendino, MariaOrtega Jimenez, SagrarioDominguez, OrlandoBarbacid, MarianoRuiz, SergioFernandez-Capetillo, OscarAnimalsCell DifferentiationCell LineEmbryonic Stem CellsEnhancer Elements, GeneticGene DeletionMiceMice, NudeRepressor ProteinsTeratomaGenes, rasMEK inhibition in combination with a glycogen synthase kinase-3β (GSK3β) inhibitor, referred as the 2i condition, favors pluripotency in embryonic stem cells (ESCs). However, the mechanisms by which the 2i condition limits ESC differentiation and whether RAS proteins are involved in this phenomenon remain poorly understood. Here we show that RAS nullyzygosity reduces the growth of mouse ESCs (mESCs) and prohibits their differentiation. Upon RAS deficiency or MEK inhibition, ERF (E twenty-six 2 [Ets2]-repressive factor), a transcriptional repressor from the ETS domain family, translocates to the nucleus, where it binds to the enhancers of pluripotency factors and key RAS targets. Remarkably, deletion of Erf rescues the proliferative defects of RAS-devoid mESCs and restores their capacity to differentiate. Furthermore, we show that Erf loss enables the development of RAS nullyzygous teratomas. In summary, this work reveals an essential role for RAS proteins in pluripotency and identifies ERF as a key mediator of the response to RAS/MEK/ERK inhibition in mESCs.Cold Spring Harbor Laboratory PressFundación La CaixaBoehringer Ingelheim FondsBotín FoundationBanco SantanderUnión Europea. Comisión Europea. European Research Council (ERC)Ministerio de Economía y Competitividad (España)Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)Fundación La Marató TV3Howard Hughes Medical Institute20192019-09-2020182018-04-0120182018-04-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/pdfvideo/quicktimehttp://hdl.handle.net/20.500.12105/8360reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengES SAF2014-57791-REDC Not availableES SAF2011-23753 Not availableES SAF2013-49147-P Not availableES SAF2016-80874-P Not availableEuropean Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 617840open accesshttp://purl.org/coar/access_right/c_abf2Atribución-NoComercial-CompartirIgual 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/83602026-06-12T12:43:37Z
dc.title.none.fl_str_mv ERF deletion rescues RAS deficiency in mouse embryonic stem cells
title ERF deletion rescues RAS deficiency in mouse embryonic stem cells
spellingShingle ERF deletion rescues RAS deficiency in mouse embryonic stem cells
Mayor-Ruiz, Cristina
Animals
Cell Differentiation
Cell Line
Embryonic Stem Cells
Enhancer Elements, Genetic
Gene Deletion
Mice
Mice, Nude
Repressor Proteins
Teratoma
Genes, ras
title_short ERF deletion rescues RAS deficiency in mouse embryonic stem cells
title_full ERF deletion rescues RAS deficiency in mouse embryonic stem cells
title_fullStr ERF deletion rescues RAS deficiency in mouse embryonic stem cells
title_full_unstemmed ERF deletion rescues RAS deficiency in mouse embryonic stem cells
title_sort ERF deletion rescues RAS deficiency in mouse embryonic stem cells
dc.creator.none.fl_str_mv Mayor-Ruiz, Cristina
Olbrich, Teresa
Drosten, Matthias
Lecona, Emilio
Vega-Sendino, Maria
Ortega Jimenez, Sagrario
Dominguez, Orlando
Barbacid, Mariano
Ruiz, Sergio
Fernandez-Capetillo, Oscar
author Mayor-Ruiz, Cristina
author_facet Mayor-Ruiz, Cristina
Olbrich, Teresa
Drosten, Matthias
Lecona, Emilio
Vega-Sendino, Maria
Ortega Jimenez, Sagrario
Dominguez, Orlando
Barbacid, Mariano
Ruiz, Sergio
Fernandez-Capetillo, Oscar
author_role author
author2 Olbrich, Teresa
Drosten, Matthias
Lecona, Emilio
Vega-Sendino, Maria
Ortega Jimenez, Sagrario
Dominguez, Orlando
Barbacid, Mariano
Ruiz, Sergio
Fernandez-Capetillo, Oscar
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fundación La Caixa
Boehringer Ingelheim Fonds
Botín Foundation
Banco Santander
Unión Europea. Comisión Europea. European Research Council (ERC)
Ministerio de Economía y Competitividad (España)
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Fundación La Marató TV3
Howard Hughes Medical Institute
dc.subject.none.fl_str_mv Animals
Cell Differentiation
Cell Line
Embryonic Stem Cells
Enhancer Elements, Genetic
Gene Deletion
Mice
Mice, Nude
Repressor Proteins
Teratoma
Genes, ras
topic Animals
Cell Differentiation
Cell Line
Embryonic Stem Cells
Enhancer Elements, Genetic
Gene Deletion
Mice
Mice, Nude
Repressor Proteins
Teratoma
Genes, ras
description MEK inhibition in combination with a glycogen synthase kinase-3β (GSK3β) inhibitor, referred as the 2i condition, favors pluripotency in embryonic stem cells (ESCs). However, the mechanisms by which the 2i condition limits ESC differentiation and whether RAS proteins are involved in this phenomenon remain poorly understood. Here we show that RAS nullyzygosity reduces the growth of mouse ESCs (mESCs) and prohibits their differentiation. Upon RAS deficiency or MEK inhibition, ERF (E twenty-six 2 [Ets2]-repressive factor), a transcriptional repressor from the ETS domain family, translocates to the nucleus, where it binds to the enhancers of pluripotency factors and key RAS targets. Remarkably, deletion of Erf rescues the proliferative defects of RAS-devoid mESCs and restores their capacity to differentiate. Furthermore, we show that Erf loss enables the development of RAS nullyzygous teratomas. In summary, this work reveals an essential role for RAS proteins in pluripotency and identifies ERF as a key mediator of the response to RAS/MEK/ERK inhibition in mESCs.
publishDate 2018
dc.date.none.fl_str_mv 2018
2018-04-01
2018
2018-04-01
2019
2019-09-20
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/8360
url http://hdl.handle.net/20.500.12105/8360
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv ES SAF2014-57791-REDC Not available
ES SAF2011-23753 Not available
ES SAF2013-49147-P Not available
ES SAF2016-80874-P Not available
European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 617840
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución-NoComercial-CompartirIgual 4.0 Internacional
http://creativecommons.org/licenses/by-nc-sa/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución-NoComercial-CompartirIgual 4.0 Internacional
http://creativecommons.org/licenses/by-nc-sa/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
video/quicktime
dc.publisher.none.fl_str_mv Cold Spring Harbor Laboratory Press
publisher.none.fl_str_mv Cold Spring Harbor Laboratory Press
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869416985916342272
score 15.811543

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