IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation

Autores
Garcia, Maria Noe; Grasso, Daniel Hector; Lopez Millian, Maria Belen; Hamidi, Tewfik; Loncle, Celine; Tomasini, Richard; Lomberk, Gwen; Porteu, Françoise; Urrutia, Raul; Iovanna, Juan Lucio
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Activating mutations in the KRAS oncogene are prevalent in pancreatic ductal adenocarcinoma (PDAC). We previously demonstrated that pancreatic intraepithelial neoplasia (PanIN) formation, which precedes malignant transformation, associates with the expression of immediate early response 3 (Ier3) as part of a prooncogenic transcriptional pathway. Here, we evaluated the role of IER3 in PanIN formation and PDAC development. In human pancreatic cancer cells, IER3 expression efficiently sustained ERK1/2 phosphorylation by inhibiting phosphatase PP2A activity. Moreover, IER3 enhanced KrasG12D-dependent oncogenesis in the pancreas, as both PanIN and PDAC development were delayed in IER3-deficient KrasG12D mice. IER3 expression was discrete in healthy acinar cells, becoming highly prominent in peritumoral acini, and particularly high in acinar ductal metaplasia (ADM) and PanIN lesions, where IER3 colocalized with phosphorylated ERK1/2. However, IER3 was absent in undifferentiated PDAC, which suggests that the IER3-dependent pathway is an early event in pancreatic tumorigenesis. IER3 expression was induced by both mild and severe pancreatitis, which promoted PanIN formation and progression to PDAC in KrasG12D mice. In IER3-deficient mice, pancreatitis abolished KrasG12D-induced proliferation, which suggests that pancreatitis enhances the oncogenic effect of KRAS through induction of IER3 expression. Together, our data indicate that IER3 supports KRASG12D-associated oncogenesis in the pancreas by sustaining ERK1/2 phosphorylation via phosphatase PP2A inhibition.
Fil: Garcia, Maria Noe. Inserm; Francia. Centre National de la Recherche Scientifique; Francia. Aix-Marseille Université; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina
Fil: Grasso, Daniel Hector. Aix-Marseille Université; Francia. Inserm; Francia. Centre National de la Recherche Scientifique; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina
Fil: Lopez Millian, Maria Belen. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. Inserm; Francia
Fil: Hamidi, Tewfik. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. Inserm; Francia
Fil: Loncle, Celine. Inserm; Francia. Centre National de la Recherche Scientifique; Francia. Aix-Marseille Université; Francia
Fil: Tomasini, Richard. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. Inserm; Francia
Fil: Lomberk, Gwen. Mayo Clinic. Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine; Estados Unidos
Fil: Porteu, Françoise. Inserm; Francia. Université de Paris XI; Francia
Fil: Urrutia, Raul. Mayo Clinic. Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine; Estados Unidos
Fil: Iovanna, Juan L.. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. Inserm; Francia
Materia
Pancreatic Cancer
Ier3
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:11336/30777
Acceder
id CONICETDig_80942fd497bbce5e80cbcfa7ba4c9929
oai_identifier_str oai:ri.conicet.gov.ar:11336/30777
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylationGarcia, Maria NoeGrasso, Daniel HectorLopez Millian, Maria BelenHamidi, TewfikLoncle, CelineTomasini, RichardLomberk, GwenPorteu, FrançoiseUrrutia, RaulIovanna, Juan LucioPancreatic CancerIer3https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Activating mutations in the KRAS oncogene are prevalent in pancreatic ductal adenocarcinoma (PDAC). We previously demonstrated that pancreatic intraepithelial neoplasia (PanIN) formation, which precedes malignant transformation, associates with the expression of immediate early response 3 (Ier3) as part of a prooncogenic transcriptional pathway. Here, we evaluated the role of IER3 in PanIN formation and PDAC development. In human pancreatic cancer cells, IER3 expression efficiently sustained ERK1/2 phosphorylation by inhibiting phosphatase PP2A activity. Moreover, IER3 enhanced KrasG12D-dependent oncogenesis in the pancreas, as both PanIN and PDAC development were delayed in IER3-deficient KrasG12D mice. IER3 expression was discrete in healthy acinar cells, becoming highly prominent in peritumoral acini, and particularly high in acinar ductal metaplasia (ADM) and PanIN lesions, where IER3 colocalized with phosphorylated ERK1/2. However, IER3 was absent in undifferentiated PDAC, which suggests that the IER3-dependent pathway is an early event in pancreatic tumorigenesis. IER3 expression was induced by both mild and severe pancreatitis, which promoted PanIN formation and progression to PDAC in KrasG12D mice. In IER3-deficient mice, pancreatitis abolished KrasG12D-induced proliferation, which suggests that pancreatitis enhances the oncogenic effect of KRAS through induction of IER3 expression. Together, our data indicate that IER3 supports KRASG12D-associated oncogenesis in the pancreas by sustaining ERK1/2 phosphorylation via phosphatase PP2A inhibition.Fil: Garcia, Maria Noe. Inserm; Francia. Centre National de la Recherche Scientifique; Francia. Aix-Marseille Université; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Grasso, Daniel Hector. Aix-Marseille Université; Francia. Inserm; Francia. Centre National de la Recherche Scientifique; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Lopez Millian, Maria Belen. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. Inserm; FranciaFil: Hamidi, Tewfik. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. Inserm; FranciaFil: Loncle, Celine. Inserm; Francia. Centre National de la Recherche Scientifique; Francia. Aix-Marseille Université; FranciaFil: Tomasini, Richard. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. Inserm; FranciaFil: Lomberk, Gwen. Mayo Clinic. Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine; Estados UnidosFil: Porteu, Françoise. Inserm; Francia. Université de Paris XI; FranciaFil: Urrutia, Raul. Mayo Clinic. Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine; Estados UnidosFil: Iovanna, Juan L.. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. Inserm; FranciaAmerican Society for Clinical Investigation2014-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/30777Garcia, Maria Noe; Grasso, Daniel Hector; Lopez Millian, Maria Belen; Hamidi, Tewfik; Loncle, Celine; et al.; IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation; American Society for Clinical Investigation; Journal of Clinical Investigation; 124; 11; 9-2014; 4709-4722; 760370021-97381558-8238CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1172/JCI76037info:eu-repo/semantics/altIdentifier/url/https://www.jci.org/articles/view/76037info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:10:30Zoai:ri.conicet.gov.ar:11336/30777instacron: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:34982025-09-03 10:10:30.873CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation
title IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation
spellingShingle IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation
Garcia, Maria Noe
Pancreatic Cancer
Ier3
title_short IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation
title_full IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation
title_fullStr IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation
title_full_unstemmed IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation
title_sort IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation
dc.creator.none.fl_str_mv Garcia, Maria Noe
Grasso, Daniel Hector
Lopez Millian, Maria Belen
Hamidi, Tewfik
Loncle, Celine
Tomasini, Richard
Lomberk, Gwen
Porteu, Françoise
Urrutia, Raul
Iovanna, Juan Lucio
author Garcia, Maria Noe
author_facet Garcia, Maria Noe
Grasso, Daniel Hector
Lopez Millian, Maria Belen
Hamidi, Tewfik
Loncle, Celine
Tomasini, Richard
Lomberk, Gwen
Porteu, Françoise
Urrutia, Raul
Iovanna, Juan Lucio
author_role author
author2 Grasso, Daniel Hector
Lopez Millian, Maria Belen
Hamidi, Tewfik
Loncle, Celine
Tomasini, Richard
Lomberk, Gwen
Porteu, Françoise
Urrutia, Raul
Iovanna, Juan Lucio
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Pancreatic Cancer
Ier3
topic Pancreatic Cancer
Ier3
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Activating mutations in the KRAS oncogene are prevalent in pancreatic ductal adenocarcinoma (PDAC). We previously demonstrated that pancreatic intraepithelial neoplasia (PanIN) formation, which precedes malignant transformation, associates with the expression of immediate early response 3 (Ier3) as part of a prooncogenic transcriptional pathway. Here, we evaluated the role of IER3 in PanIN formation and PDAC development. In human pancreatic cancer cells, IER3 expression efficiently sustained ERK1/2 phosphorylation by inhibiting phosphatase PP2A activity. Moreover, IER3 enhanced KrasG12D-dependent oncogenesis in the pancreas, as both PanIN and PDAC development were delayed in IER3-deficient KrasG12D mice. IER3 expression was discrete in healthy acinar cells, becoming highly prominent in peritumoral acini, and particularly high in acinar ductal metaplasia (ADM) and PanIN lesions, where IER3 colocalized with phosphorylated ERK1/2. However, IER3 was absent in undifferentiated PDAC, which suggests that the IER3-dependent pathway is an early event in pancreatic tumorigenesis. IER3 expression was induced by both mild and severe pancreatitis, which promoted PanIN formation and progression to PDAC in KrasG12D mice. In IER3-deficient mice, pancreatitis abolished KrasG12D-induced proliferation, which suggests that pancreatitis enhances the oncogenic effect of KRAS through induction of IER3 expression. Together, our data indicate that IER3 supports KRASG12D-associated oncogenesis in the pancreas by sustaining ERK1/2 phosphorylation via phosphatase PP2A inhibition.
Fil: Garcia, Maria Noe. Inserm; Francia. Centre National de la Recherche Scientifique; Francia. Aix-Marseille Université; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina
Fil: Grasso, Daniel Hector. Aix-Marseille Université; Francia. Inserm; Francia. Centre National de la Recherche Scientifique; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina
Fil: Lopez Millian, Maria Belen. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. Inserm; Francia
Fil: Hamidi, Tewfik. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. Inserm; Francia
Fil: Loncle, Celine. Inserm; Francia. Centre National de la Recherche Scientifique; Francia. Aix-Marseille Université; Francia
Fil: Tomasini, Richard. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. Inserm; Francia
Fil: Lomberk, Gwen. Mayo Clinic. Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine; Estados Unidos
Fil: Porteu, Françoise. Inserm; Francia. Université de Paris XI; Francia
Fil: Urrutia, Raul. Mayo Clinic. Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine; Estados Unidos
Fil: Iovanna, Juan L.. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. Inserm; Francia
description Activating mutations in the KRAS oncogene are prevalent in pancreatic ductal adenocarcinoma (PDAC). We previously demonstrated that pancreatic intraepithelial neoplasia (PanIN) formation, which precedes malignant transformation, associates with the expression of immediate early response 3 (Ier3) as part of a prooncogenic transcriptional pathway. Here, we evaluated the role of IER3 in PanIN formation and PDAC development. In human pancreatic cancer cells, IER3 expression efficiently sustained ERK1/2 phosphorylation by inhibiting phosphatase PP2A activity. Moreover, IER3 enhanced KrasG12D-dependent oncogenesis in the pancreas, as both PanIN and PDAC development were delayed in IER3-deficient KrasG12D mice. IER3 expression was discrete in healthy acinar cells, becoming highly prominent in peritumoral acini, and particularly high in acinar ductal metaplasia (ADM) and PanIN lesions, where IER3 colocalized with phosphorylated ERK1/2. However, IER3 was absent in undifferentiated PDAC, which suggests that the IER3-dependent pathway is an early event in pancreatic tumorigenesis. IER3 expression was induced by both mild and severe pancreatitis, which promoted PanIN formation and progression to PDAC in KrasG12D mice. In IER3-deficient mice, pancreatitis abolished KrasG12D-induced proliferation, which suggests that pancreatitis enhances the oncogenic effect of KRAS through induction of IER3 expression. Together, our data indicate that IER3 supports KRASG12D-associated oncogenesis in the pancreas by sustaining ERK1/2 phosphorylation via phosphatase PP2A inhibition.
publishDate 2014
dc.date.none.fl_str_mv 2014-09
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/11336/30777
Garcia, Maria Noe; Grasso, Daniel Hector; Lopez Millian, Maria Belen; Hamidi, Tewfik; Loncle, Celine; et al.; IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation; American Society for Clinical Investigation; Journal of Clinical Investigation; 124; 11; 9-2014; 4709-4722; 76037
0021-9738
1558-8238
CONICET Digital
CONICET
url http://hdl.handle.net/11336/30777
identifier_str_mv Garcia, Maria Noe; Grasso, Daniel Hector; Lopez Millian, Maria Belen; Hamidi, Tewfik; Loncle, Celine; et al.; IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation; American Society for Clinical Investigation; Journal of Clinical Investigation; 124; 11; 9-2014; 4709-4722; 76037
0021-9738
1558-8238
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1172/JCI76037
info:eu-repo/semantics/altIdentifier/url/https://www.jci.org/articles/view/76037
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
application/pdf
dc.publisher.none.fl_str_mv American Society for Clinical Investigation
publisher.none.fl_str_mv American Society for Clinical Investigation
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 13.13397

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