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dc.contributor.author
Garcia, Maria Noe
dc.contributor.author
Grasso, Daniel Hector
dc.contributor.author
Lopez Millian, Maria Belen
dc.contributor.author
Hamidi, Tewfik
dc.contributor.author
Loncle, Celine
dc.contributor.author
Tomasini, Richard
dc.contributor.author
Lomberk, Gwen
dc.contributor.author
Porteu, Françoise
dc.contributor.author
Urrutia, Raul
dc.contributor.author
Iovanna, Juan Lucio
dc.date.available
2017-12-15T17:39:01Z
dc.date.issued
2014-09
dc.identifier.citation
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
dc.identifier.issn
0021-9738
dc.identifier.uri
http://hdl.handle.net/11336/30777
dc.description.abstract
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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Society for Clinical Investigation
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by/2.5/ar/
dc.subject
Pancreatic Cancer
dc.subject
Ier3
dc.subject.classification
Patología
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Medicina Básica
dc.subject.classification
CIENCIAS MÉDICAS Y DE LA SALUD
dc.title
IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2017-12-14T13:48:46Z
dc.identifier.eissn
1558-8238
dc.journal.volume
124
dc.journal.number
11
dc.journal.pagination
4709-4722; 76037
dc.journal.pais
Estados Unidos
dc.journal.ciudad
Michigan
dc.description.fil
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
dc.description.fil
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
dc.description.fil
Fil: Lopez Millian, Maria Belen. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. Inserm; Francia
dc.description.fil
Fil: Hamidi, Tewfik. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. Inserm; Francia
dc.description.fil
Fil: Loncle, Celine. Inserm; Francia. Centre National de la Recherche Scientifique; Francia. Aix-Marseille Université; Francia
dc.description.fil
Fil: Tomasini, Richard. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. Inserm; Francia
dc.description.fil
Fil: Lomberk, Gwen. Mayo Clinic. Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine; Estados Unidos
dc.description.fil
Fil: Porteu, Françoise. Inserm; Francia. Université de Paris XI; Francia
dc.description.fil
Fil: Urrutia, Raul. Mayo Clinic. Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine; Estados Unidos
dc.description.fil
Fil: Iovanna, Juan L.. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; Francia. Inserm; Francia
dc.journal.title
Journal of Clinical Investigation
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1172/JCI76037
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.jci.org/articles/view/76037
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