Cargando…

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

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 effec...

Descripción completa

Detalles Bibliográficos
Autores principales: Grasso, Daniel, Bintz, Jennifer, Lomberk, Gwen, Molejon, Maria Ines, Loncle, Celine, Garcia, Maria Noé, Lopez, Maria Belen, Urrutia, Raul, Iovanna, Juan L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663475/
https://www.ncbi.nlm.nih.gov/pubmed/26617245
http://dx.doi.org/10.1038/srep17549
_version_ 1782403303375634432
author Grasso, Daniel
Bintz, Jennifer
Lomberk, Gwen
Molejon, Maria Ines
Loncle, Celine
Garcia, Maria Noé
Lopez, Maria Belen
Urrutia, Raul
Iovanna, Juan L.
author_facet Grasso, Daniel
Bintz, Jennifer
Lomberk, Gwen
Molejon, Maria Ines
Loncle, Celine
Garcia, Maria Noé
Lopez, Maria Belen
Urrutia, Raul
Iovanna, Juan L.
author_sort Grasso, Daniel
collection PubMed
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.
format Online
Article
Text
id pubmed-4663475
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-46634752015-12-03 Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation Grasso, Daniel Bintz, Jennifer Lomberk, Gwen Molejon, Maria Ines Loncle, Celine Garcia, Maria Noé Lopez, Maria Belen Urrutia, Raul Iovanna, Juan L. Sci Rep Article 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. Nature Publishing Group 2015-11-30 /pmc/articles/PMC4663475/ /pubmed/26617245 http://dx.doi.org/10.1038/srep17549 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Grasso, Daniel
Bintz, Jennifer
Lomberk, Gwen
Molejon, Maria Ines
Loncle, Celine
Garcia, Maria Noé
Lopez, Maria Belen
Urrutia, Raul
Iovanna, Juan L.
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
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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663475/
https://www.ncbi.nlm.nih.gov/pubmed/26617245
http://dx.doi.org/10.1038/srep17549
work_keys_str_mv AT grassodaniel pivotalroleofthechromatinproteinnupr1inkrasinducedsenescenceandtransformation
AT bintzjennifer pivotalroleofthechromatinproteinnupr1inkrasinducedsenescenceandtransformation
AT lomberkgwen pivotalroleofthechromatinproteinnupr1inkrasinducedsenescenceandtransformation
AT molejonmariaines pivotalroleofthechromatinproteinnupr1inkrasinducedsenescenceandtransformation
AT loncleceline pivotalroleofthechromatinproteinnupr1inkrasinducedsenescenceandtransformation
AT garciamarianoe pivotalroleofthechromatinproteinnupr1inkrasinducedsenescenceandtransformation
AT lopezmariabelen pivotalroleofthechromatinproteinnupr1inkrasinducedsenescenceandtransformation
AT urrutiaraul pivotalroleofthechromatinproteinnupr1inkrasinducedsenescenceandtransformation
AT iovannajuanl pivotalroleofthechromatinproteinnupr1inkrasinducedsenescenceandtransformation