IBIMOL   23987
INSTITUTO DE BIOQUIMICA Y MEDICINA MOLECULAR PROFESOR ALBERTO BOVERIS
Unidad Ejecutora - UE
artículos
Título:
Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation
Autor/es:
DANIEL GRASSO; JENNIFER BINTZ; GWEN LOMBERK; MARÍA INÉS MOLEJÓN; CELINE LONCLE; MARIA NOÉ GARCIA; MARIA BELEN LOPEZ-MILLIAN; RAUL URRUTIA; JUAN IOVANNA
Revista:
Scientific Reports
Editorial:
Nature Publishing Group
Referencias:
Lugar: Londres; Año: 2015 vol. 5 p. 1 - 11
Resumen:
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.