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

Authors
Grasso, Daniel Hector; Bintz, Jennifer; Lomberk, Gwen; Molejon, Maria Ines; Loncle, Celine; Garcia, Maria Noé; Lopez Millian, Maria Belen; Urrutia, Raul; Iovanna, Juan
Publication Year
2015
Language
English
Format
article
Status
Published version
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.
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
Subject
PDAC
ONCOGENE-INDUCED SENESCENCE
NUPR1
DNMT1
Inmunología
Medicina Básica
CIENCIAS MÉDICAS Y DE LA SALUD
Access level
Open access
License
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/47430