Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation

Autores
Grasso, Daniel Hector; Bintz, Jennifer; Lomberk, Gwen; Molejon, Maria Ines; Loncle, Celine; Garcia, Maria Noé; Lopez Millian, Maria Belen; Urrutia, Raul; Iovanna, Juan
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Nupr1 is a chromatin protein, which cooperates with Kras(G12D) to induce PanIN formation and pancreatic cancer development in mice, though the molecular mechanisms underlying this effect remain to be fully characterized. In the current study, we report that Nupr1 acts as a gene modifier of the effect of Kras(G12D)-induced senescence by regulating Dnmt1 expression and consequently genome-wide levels of DNA methylation. Congruently, 5-aza-2'-deoxycytydine, a general inhibitor of DNA methylation, reverses the Kras(G12D)-induced PanIN development by promoting senescence. This requirement of Nupr1 expression, however, is not restricted to the pancreas since in lung of Nupr1(-/-) mice the expression of Kras(G12D) induces senescence instead of transformation. Therefore, mechanistically this data reveals that epigenetic events, at least at the level of DNA methylation, modulate the functional outcome of common genetic mutations, such as Kras(G12D), during carcinogenesis. The biomedical relevance of these findings lies in that they support the rational for developing similar therapeutic interventions in human aimed at controlling either the initiation or progression of cancer.
Fil: Grasso, Daniel Hector. Centre de Recherche en Cancérologie de Marseille; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina
Fil: Bintz, Jennifer. Centre de Recherche en Cancérologie de Marseille; Francia
Fil: Lomberk, Gwen. Mayo Clinic; Estados Unidos
Fil: Molejon, Maria Ines. Centre de Recherche en Cancérologie de Marseille; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina
Fil: Loncle, Celine. Centre de Recherche en Cancérologie de Marseille; Francia
Fil: Garcia, Maria Noé. Centre de Recherche en Cancérologie de Marseille; Francia
Fil: Lopez Millian, Maria Belen. Centre de Recherche en Cancérologie de Marseille; Francia
Fil: Urrutia, Raul. Mayo Clinic; Estados Unidos
Fil: Iovanna, Juan. Centre de Recherche en Cancérologie de Marseille; Francia
Materia
PDAC
ONCOGENE-INDUCED SENESCENCE
NUPR1
DNMT1
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/47430
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/47430
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and TransformationGrasso, Daniel HectorBintz, JenniferLomberk, GwenMolejon, Maria InesLoncle, CelineGarcia, Maria NoéLopez Millian, Maria BelenUrrutia, RaulIovanna, JuanPDACONCOGENE-INDUCED SENESCENCENUPR1DNMT1https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Nupr1 is a chromatin protein, which cooperates with Kras(G12D) to induce PanIN formation and pancreatic cancer development in mice, though the molecular mechanisms underlying this effect remain to be fully characterized. In the current study, we report that Nupr1 acts as a gene modifier of the effect of Kras(G12D)-induced senescence by regulating Dnmt1 expression and consequently genome-wide levels of DNA methylation. Congruently, 5-aza-2'-deoxycytydine, a general inhibitor of DNA methylation, reverses the Kras(G12D)-induced PanIN development by promoting senescence. This requirement of Nupr1 expression, however, is not restricted to the pancreas since in lung of Nupr1(-/-) mice the expression of Kras(G12D) induces senescence instead of transformation. Therefore, mechanistically this data reveals that epigenetic events, at least at the level of DNA methylation, modulate the functional outcome of common genetic mutations, such as Kras(G12D), during carcinogenesis. The biomedical relevance of these findings lies in that they support the rational for developing similar therapeutic interventions in human aimed at controlling either the initiation or progression of cancer.Fil: Grasso, Daniel Hector. Centre de Recherche en Cancérologie de Marseille; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Bintz, Jennifer. Centre de Recherche en Cancérologie de Marseille; FranciaFil: Lomberk, Gwen. Mayo Clinic; Estados UnidosFil: Molejon, Maria Ines. Centre de Recherche en Cancérologie de Marseille; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Loncle, Celine. Centre de Recherche en Cancérologie de Marseille; FranciaFil: Garcia, Maria Noé. Centre de Recherche en Cancérologie de Marseille; FranciaFil: Lopez Millian, Maria Belen. Centre de Recherche en Cancérologie de Marseille; FranciaFil: Urrutia, Raul. Mayo Clinic; Estados UnidosFil: Iovanna, Juan. Centre de Recherche en Cancérologie de Marseille; FranciaNature Publishing Group2015-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/47430Grasso, Daniel Hector; Bintz, Jennifer; Lomberk, Gwen; Molejon, Maria Ines; Loncle, Celine; et al.; Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation; Nature Publishing Group; Scientific Reports; 5; 1754; 11-2015; 1-112045-2322CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/srep17549info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/srep17549info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-11-12T09:55:41Zoai:ri.conicet.gov.ar:11336/47430instacron: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:34982025-11-12 09:55:41.426CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation
title Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation
spellingShingle Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation
Grasso, Daniel Hector
PDAC
ONCOGENE-INDUCED SENESCENCE
NUPR1
DNMT1
title_short Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation
title_full Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation
title_fullStr Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation
title_full_unstemmed Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation
title_sort Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation
dc.creator.none.fl_str_mv Grasso, Daniel Hector
Bintz, Jennifer
Lomberk, Gwen
Molejon, Maria Ines
Loncle, Celine
Garcia, Maria Noé
Lopez Millian, Maria Belen
Urrutia, Raul
Iovanna, Juan
author Grasso, Daniel Hector
author_facet Grasso, Daniel Hector
Bintz, Jennifer
Lomberk, Gwen
Molejon, Maria Ines
Loncle, Celine
Garcia, Maria Noé
Lopez Millian, Maria Belen
Urrutia, Raul
Iovanna, Juan
author_role author
author2 Bintz, Jennifer
Lomberk, Gwen
Molejon, Maria Ines
Loncle, Celine
Garcia, Maria Noé
Lopez Millian, Maria Belen
Urrutia, Raul
Iovanna, Juan
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv PDAC
ONCOGENE-INDUCED SENESCENCE
NUPR1
DNMT1
topic PDAC
ONCOGENE-INDUCED SENESCENCE
NUPR1
DNMT1
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Nupr1 is a chromatin protein, which cooperates with Kras(G12D) to induce PanIN formation and pancreatic cancer development in mice, though the molecular mechanisms underlying this effect remain to be fully characterized. In the current study, we report that Nupr1 acts as a gene modifier of the effect of Kras(G12D)-induced senescence by regulating Dnmt1 expression and consequently genome-wide levels of DNA methylation. Congruently, 5-aza-2'-deoxycytydine, a general inhibitor of DNA methylation, reverses the Kras(G12D)-induced PanIN development by promoting senescence. This requirement of Nupr1 expression, however, is not restricted to the pancreas since in lung of Nupr1(-/-) mice the expression of Kras(G12D) induces senescence instead of transformation. Therefore, mechanistically this data reveals that epigenetic events, at least at the level of DNA methylation, modulate the functional outcome of common genetic mutations, such as Kras(G12D), during carcinogenesis. The biomedical relevance of these findings lies in that they support the rational for developing similar therapeutic interventions in human aimed at controlling either the initiation or progression of cancer.
Fil: Grasso, Daniel Hector. Centre de Recherche en Cancérologie de Marseille; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina
Fil: Bintz, Jennifer. Centre de Recherche en Cancérologie de Marseille; Francia
Fil: Lomberk, Gwen. Mayo Clinic; Estados Unidos
Fil: Molejon, Maria Ines. Centre de Recherche en Cancérologie de Marseille; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina
Fil: Loncle, Celine. Centre de Recherche en Cancérologie de Marseille; Francia
Fil: Garcia, Maria Noé. Centre de Recherche en Cancérologie de Marseille; Francia
Fil: Lopez Millian, Maria Belen. Centre de Recherche en Cancérologie de Marseille; Francia
Fil: Urrutia, Raul. Mayo Clinic; Estados Unidos
Fil: Iovanna, Juan. Centre de Recherche en Cancérologie de Marseille; Francia
description Nupr1 is a chromatin protein, which cooperates with Kras(G12D) to induce PanIN formation and pancreatic cancer development in mice, though the molecular mechanisms underlying this effect remain to be fully characterized. In the current study, we report that Nupr1 acts as a gene modifier of the effect of Kras(G12D)-induced senescence by regulating Dnmt1 expression and consequently genome-wide levels of DNA methylation. Congruently, 5-aza-2'-deoxycytydine, a general inhibitor of DNA methylation, reverses the Kras(G12D)-induced PanIN development by promoting senescence. This requirement of Nupr1 expression, however, is not restricted to the pancreas since in lung of Nupr1(-/-) mice the expression of Kras(G12D) induces senescence instead of transformation. Therefore, mechanistically this data reveals that epigenetic events, at least at the level of DNA methylation, modulate the functional outcome of common genetic mutations, such as Kras(G12D), during carcinogenesis. The biomedical relevance of these findings lies in that they support the rational for developing similar therapeutic interventions in human aimed at controlling either the initiation or progression of cancer.
publishDate 2015
dc.date.none.fl_str_mv 2015-11
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/11336/47430
Grasso, Daniel Hector; Bintz, Jennifer; Lomberk, Gwen; Molejon, Maria Ines; Loncle, Celine; et al.; Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation; Nature Publishing Group; Scientific Reports; 5; 1754; 11-2015; 1-11
2045-2322
CONICET Digital
CONICET
url http://hdl.handle.net/11336/47430
identifier_str_mv Grasso, Daniel Hector; Bintz, Jennifer; Lomberk, Gwen; Molejon, Maria Ines; Loncle, Celine; et al.; Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation; Nature Publishing Group; Scientific Reports; 5; 1754; 11-2015; 1-11
2045-2322
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/srep17549
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/srep17549
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/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 13.24909

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