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...
Autores principales: | , , , , , , , , |
---|---|
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 |