RAC3 more than a nuclear receptor coactivator: A key inhibitor of senescence that is down-regulated in aging

Autores
Fernández Larrosa, Pablo Nicolás; Ruiz Grecco, Marina; Mengual Gómez, Diego Luis; Alvarado, Cecilia Viviana; Panelo, Laura Carolina; Rubio, Maria Fernanda; Alonso, Daniel Fernando; Gomez, Daniel Eduardo; Costas, Monica Alejandra
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Receptor-associated coactivator 3 (RAC3) is a nuclear receptor coactivator usually overexpressed in tumors that exerts oncogenicfunctions in the cytoplasm and the nucleus. Although as part of its oncogenic actions it was previously identified as an inhibitor ofapoptosis and autophagy, its expression is required in order to preserve the pluripotency and embryonic stem cell self-renewal. Inthis work we investigated its role in cellular senescence. We found that RAC3 overexpression in the nontumoral HEK293 cellsinhibits the premature senescence induced by hydrogen peroxide or rapamycin. The mechanism involves not only the inhibition ofautophagy early induced by these stimuli in the pathway to senescence, but also the increase in levels and nuclear localization ofboth the cell cycle suppressors p53/p21 and the longevity promoters FOXO1A, FOXO3A and SIRT1. Furthermore, we found thatRAC3 overexpression is required in order to maintain the telomerase activity. In tumoral HeLa cells its activity was inhibited bydepletion of RAC3 inducing replicative senescence. Moreover, we demonstrated that in vivo, levels of RAC3 are downregulated inthe liver from aged as compared with young rats, whereas the levels of p21 are increased, correlating with the expected senescentcell contents in aged tissues. A similar downregulation of RAC3 was observed in the premature and replicative senescence ofhuman fetal WI-38 cells and premature senescence of hepatocyte HepG2 cell line. Taken together, all these results demonstratethat RAC3 is an inhibitor of senescence whose downregulation in aged individuals could be probably a tumor suppressormechanism, avoiding the clonal expansion of risky old cells having damaged DNA.
Fil: Fernández Larrosa, Pablo Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Ruiz Grecco, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Mengual Gómez, Diego Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Alvarado, Cecilia Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Panelo, Laura Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Rubio, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Gomez, Daniel Eduardo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Costas, Monica Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Materia
NUCLEAR RECEPTOR COACTIVATOR
RAC3
AIB1
SENESCENCE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/43537
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/43537
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling RAC3 more than a nuclear receptor coactivator: A key inhibitor of senescence that is down-regulated in agingFernández Larrosa, Pablo NicolásRuiz Grecco, MarinaMengual Gómez, Diego LuisAlvarado, Cecilia VivianaPanelo, Laura CarolinaRubio, Maria FernandaAlonso, Daniel FernandoGomez, Daniel EduardoCostas, Monica AlejandraNUCLEAR RECEPTOR COACTIVATORRAC3AIB1SENESCENCEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Receptor-associated coactivator 3 (RAC3) is a nuclear receptor coactivator usually overexpressed in tumors that exerts oncogenicfunctions in the cytoplasm and the nucleus. Although as part of its oncogenic actions it was previously identified as an inhibitor ofapoptosis and autophagy, its expression is required in order to preserve the pluripotency and embryonic stem cell self-renewal. Inthis work we investigated its role in cellular senescence. We found that RAC3 overexpression in the nontumoral HEK293 cellsinhibits the premature senescence induced by hydrogen peroxide or rapamycin. The mechanism involves not only the inhibition ofautophagy early induced by these stimuli in the pathway to senescence, but also the increase in levels and nuclear localization ofboth the cell cycle suppressors p53/p21 and the longevity promoters FOXO1A, FOXO3A and SIRT1. Furthermore, we found thatRAC3 overexpression is required in order to maintain the telomerase activity. In tumoral HeLa cells its activity was inhibited bydepletion of RAC3 inducing replicative senescence. Moreover, we demonstrated that in vivo, levels of RAC3 are downregulated inthe liver from aged as compared with young rats, whereas the levels of p21 are increased, correlating with the expected senescentcell contents in aged tissues. A similar downregulation of RAC3 was observed in the premature and replicative senescence ofhuman fetal WI-38 cells and premature senescence of hepatocyte HepG2 cell line. Taken together, all these results demonstratethat RAC3 is an inhibitor of senescence whose downregulation in aged individuals could be probably a tumor suppressormechanism, avoiding the clonal expansion of risky old cells having damaged DNA.Fil: Fernández Larrosa, Pablo Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Ruiz Grecco, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Mengual Gómez, Diego Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Alvarado, Cecilia Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Panelo, Laura Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Rubio, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Gomez, Daniel Eduardo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Costas, Monica Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaNature Publishing Group2015-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/43537Fernández Larrosa, Pablo Nicolás; Ruiz Grecco, Marina; Mengual Gómez, Diego Luis; Alvarado, Cecilia Viviana; Panelo, Laura Carolina; et al.; RAC3 more than a nuclear receptor coactivator: A key inhibitor of senescence that is down-regulated in aging; Nature Publishing Group; Cell Death and Disease; 6; 10-2015; 1-12; e19021476-54032041-4889CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.nature.com/cddis/index.htmlinfo:eu-repo/semantics/altIdentifier/doi/10.1038/cddis.2015.218info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T12:11:17Zoai:ri.conicet.gov.ar:11336/43537instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 12:11:18.213CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv RAC3 more than a nuclear receptor coactivator: A key inhibitor of senescence that is down-regulated in aging
title RAC3 more than a nuclear receptor coactivator: A key inhibitor of senescence that is down-regulated in aging
spellingShingle RAC3 more than a nuclear receptor coactivator: A key inhibitor of senescence that is down-regulated in aging
Fernández Larrosa, Pablo Nicolás
NUCLEAR RECEPTOR COACTIVATOR
RAC3
AIB1
SENESCENCE
title_short RAC3 more than a nuclear receptor coactivator: A key inhibitor of senescence that is down-regulated in aging
title_full RAC3 more than a nuclear receptor coactivator: A key inhibitor of senescence that is down-regulated in aging
title_fullStr RAC3 more than a nuclear receptor coactivator: A key inhibitor of senescence that is down-regulated in aging
title_full_unstemmed RAC3 more than a nuclear receptor coactivator: A key inhibitor of senescence that is down-regulated in aging
title_sort RAC3 more than a nuclear receptor coactivator: A key inhibitor of senescence that is down-regulated in aging
dc.creator.none.fl_str_mv Fernández Larrosa, Pablo Nicolás
Ruiz Grecco, Marina
Mengual Gómez, Diego Luis
Alvarado, Cecilia Viviana
Panelo, Laura Carolina
Rubio, Maria Fernanda
Alonso, Daniel Fernando
Gomez, Daniel Eduardo
Costas, Monica Alejandra
author Fernández Larrosa, Pablo Nicolás
author_facet Fernández Larrosa, Pablo Nicolás
Ruiz Grecco, Marina
Mengual Gómez, Diego Luis
Alvarado, Cecilia Viviana
Panelo, Laura Carolina
Rubio, Maria Fernanda
Alonso, Daniel Fernando
Gomez, Daniel Eduardo
Costas, Monica Alejandra
author_role author
author2 Ruiz Grecco, Marina
Mengual Gómez, Diego Luis
Alvarado, Cecilia Viviana
Panelo, Laura Carolina
Rubio, Maria Fernanda
Alonso, Daniel Fernando
Gomez, Daniel Eduardo
Costas, Monica Alejandra
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv NUCLEAR RECEPTOR COACTIVATOR
RAC3
AIB1
SENESCENCE
topic NUCLEAR RECEPTOR COACTIVATOR
RAC3
AIB1
SENESCENCE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Receptor-associated coactivator 3 (RAC3) is a nuclear receptor coactivator usually overexpressed in tumors that exerts oncogenicfunctions in the cytoplasm and the nucleus. Although as part of its oncogenic actions it was previously identified as an inhibitor ofapoptosis and autophagy, its expression is required in order to preserve the pluripotency and embryonic stem cell self-renewal. Inthis work we investigated its role in cellular senescence. We found that RAC3 overexpression in the nontumoral HEK293 cellsinhibits the premature senescence induced by hydrogen peroxide or rapamycin. The mechanism involves not only the inhibition ofautophagy early induced by these stimuli in the pathway to senescence, but also the increase in levels and nuclear localization ofboth the cell cycle suppressors p53/p21 and the longevity promoters FOXO1A, FOXO3A and SIRT1. Furthermore, we found thatRAC3 overexpression is required in order to maintain the telomerase activity. In tumoral HeLa cells its activity was inhibited bydepletion of RAC3 inducing replicative senescence. Moreover, we demonstrated that in vivo, levels of RAC3 are downregulated inthe liver from aged as compared with young rats, whereas the levels of p21 are increased, correlating with the expected senescentcell contents in aged tissues. A similar downregulation of RAC3 was observed in the premature and replicative senescence ofhuman fetal WI-38 cells and premature senescence of hepatocyte HepG2 cell line. Taken together, all these results demonstratethat RAC3 is an inhibitor of senescence whose downregulation in aged individuals could be probably a tumor suppressormechanism, avoiding the clonal expansion of risky old cells having damaged DNA.
Fil: Fernández Larrosa, Pablo Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Ruiz Grecco, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Mengual Gómez, Diego Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Alvarado, Cecilia Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Panelo, Laura Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Rubio, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Gomez, Daniel Eduardo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Costas, Monica Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
description Receptor-associated coactivator 3 (RAC3) is a nuclear receptor coactivator usually overexpressed in tumors that exerts oncogenicfunctions in the cytoplasm and the nucleus. Although as part of its oncogenic actions it was previously identified as an inhibitor ofapoptosis and autophagy, its expression is required in order to preserve the pluripotency and embryonic stem cell self-renewal. Inthis work we investigated its role in cellular senescence. We found that RAC3 overexpression in the nontumoral HEK293 cellsinhibits the premature senescence induced by hydrogen peroxide or rapamycin. The mechanism involves not only the inhibition ofautophagy early induced by these stimuli in the pathway to senescence, but also the increase in levels and nuclear localization ofboth the cell cycle suppressors p53/p21 and the longevity promoters FOXO1A, FOXO3A and SIRT1. Furthermore, we found thatRAC3 overexpression is required in order to maintain the telomerase activity. In tumoral HeLa cells its activity was inhibited bydepletion of RAC3 inducing replicative senescence. Moreover, we demonstrated that in vivo, levels of RAC3 are downregulated inthe liver from aged as compared with young rats, whereas the levels of p21 are increased, correlating with the expected senescentcell contents in aged tissues. A similar downregulation of RAC3 was observed in the premature and replicative senescence ofhuman fetal WI-38 cells and premature senescence of hepatocyte HepG2 cell line. Taken together, all these results demonstratethat RAC3 is an inhibitor of senescence whose downregulation in aged individuals could be probably a tumor suppressormechanism, avoiding the clonal expansion of risky old cells having damaged DNA.
publishDate 2015
dc.date.none.fl_str_mv 2015-10
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/43537
Fernández Larrosa, Pablo Nicolás; Ruiz Grecco, Marina; Mengual Gómez, Diego Luis; Alvarado, Cecilia Viviana; Panelo, Laura Carolina; et al.; RAC3 more than a nuclear receptor coactivator: A key inhibitor of senescence that is down-regulated in aging; Nature Publishing Group; Cell Death and Disease; 6; 10-2015; 1-12; e1902
1476-5403
2041-4889
CONICET Digital
CONICET
url http://hdl.handle.net/11336/43537
identifier_str_mv Fernández Larrosa, Pablo Nicolás; Ruiz Grecco, Marina; Mengual Gómez, Diego Luis; Alvarado, Cecilia Viviana; Panelo, Laura Carolina; et al.; RAC3 more than a nuclear receptor coactivator: A key inhibitor of senescence that is down-regulated in aging; Nature Publishing Group; Cell Death and Disease; 6; 10-2015; 1-12; e1902
1476-5403
2041-4889
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.nature.com/cddis/index.html
info:eu-repo/semantics/altIdentifier/doi/10.1038/cddis.2015.218
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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