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Neat1 is a p53-inducible lincRNA essential for transformation suppression

Authors :
Daniela Kenzelmann Broz
Stephano S. Mello
Pawel K. Mazur
Laura D. Attardi
John L. Rinn
Carolyn Sinow
Hannes Vogel
Julien Sage
Laura D. Wood
Tetsuro Hirose
Jamie F. Conklin Imam
Shinichi Nakagawa
Kathryn T. Bieging-Rolett
Nitin Raj
Source :
Genes & Development. 31:1095-1108
Publication Year :
2017
Publisher :
Cold Spring Harbor Laboratory, 2017.

Abstract

The p53 gene is mutated in over half of all cancers, reflecting its critical role as a tumor suppressor. Although p53 is a transcriptional activator that induces myriad target genes, those p53-inducible genes most critical for tumor suppression remain elusive. Here, we leveraged p53 ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) and RNA-seq (RNA sequencing) data sets to identify new p53 target genes, focusing on the noncoding genome. We identify Neat1, a noncoding RNA (ncRNA) constituent of paraspeckles, as a p53 target gene broadly induced by mouse and human p53 in different cell types and by diverse stress signals. Using fibroblasts derived from Neat1−/− mice, we examined the functional role of Neat1 in the p53 pathway. We found that Neat1 is dispensable for cell cycle arrest and apoptosis in response to genotoxic stress. In sharp contrast, Neat1 plays a crucial role in suppressing transformation in response to oncogenic signals. Neat1 deficiency enhances transformation in oncogene-expressing fibroblasts and promotes the development of premalignant pancreatic intraepithelial neoplasias (PanINs) and cystic lesions in KrasG12D-expressing mice. Neat1 loss provokes global changes in gene expression, suggesting a mechanism by which its deficiency promotes neoplasia. Collectively, these findings identify Neat1 as a p53-regulated large intergenic ncRNA (lincRNA) with a key role in suppressing transformation and cancer initiation, providing fundamental new insight into p53-mediated tumor suppression.

Details

ISSN :
15495477 and 08909369
Volume :
31
Database :
OpenAIRE
Journal :
Genes & Development
Accession number :
edsair.doi...........7c35d149ea942e063e1614a2871281b4
Full Text :
https://doi.org/10.1101/gad.284661.116