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LKB1 preserves genome integrity by stimulating BRCA1 expression
Serine/threonine kinase 11 (STK11, also known as LKB1) functions as a tumor suppressor in many human cancers. However, paradoxically loss of LKB1 in mouse embryonic fibroblast results in resistance to oncogene-induced transformation. Therefore, it is unclear why loss of LKB1 leads to increased predi...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288185/ https://www.ncbi.nlm.nih.gov/pubmed/25488815 http://dx.doi.org/10.1093/nar/gku1294 |
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author | Gupta, Romi Liu, Alex. Y. Glazer, Peter M. Wajapeyee, Narendra |
author_facet | Gupta, Romi Liu, Alex. Y. Glazer, Peter M. Wajapeyee, Narendra |
author_sort | Gupta, Romi |
collection | PubMed |
description | Serine/threonine kinase 11 (STK11, also known as LKB1) functions as a tumor suppressor in many human cancers. However, paradoxically loss of LKB1 in mouse embryonic fibroblast results in resistance to oncogene-induced transformation. Therefore, it is unclear why loss of LKB1 leads to increased predisposition to develop a wide variety of cancers. Here, we show that LKB1 protects cells from genotoxic stress. Cells lacking LKB1 display increased sensitivity to irradiation, accumulates more DNA double-strand breaks, display defective homology-directed DNA repair (HDR) and exhibit increased mutation rate, compared with that of LKB1-expressing cells. Conversely, the ectopic expression of LKB1 in cells lacking LKB1 protects them against genotoxic stress-induced DNA damage and prevents the accumulation of mutations. We find that LKB1 post-transcriptionally stimulates HDR gene BRCA1 expression by inhibiting the cytoplasmic localization of the RNA-binding protein, HU antigen R, in an AMP kinase-dependent manner and stabilizes BRCA1 mRNA. Cells lacking BRCA1 similar to the cell lacking LKB1 display increased genomic instability and ectopic expression of BRCA1 rescues LKB1 loss-induced sensitivity to genotoxic stress. Collectively, our results demonstrate that LKB1 is a crucial regulator of genome integrity and reveal a novel mechanism for LKB1-mediated tumor suppression with direct therapeutic implications for cancer prevention. |
format | Online Article Text |
id | pubmed-4288185 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-42881852015-02-19 LKB1 preserves genome integrity by stimulating BRCA1 expression Gupta, Romi Liu, Alex. Y. Glazer, Peter M. Wajapeyee, Narendra Nucleic Acids Res Genome Integrity, Repair and Replication Serine/threonine kinase 11 (STK11, also known as LKB1) functions as a tumor suppressor in many human cancers. However, paradoxically loss of LKB1 in mouse embryonic fibroblast results in resistance to oncogene-induced transformation. Therefore, it is unclear why loss of LKB1 leads to increased predisposition to develop a wide variety of cancers. Here, we show that LKB1 protects cells from genotoxic stress. Cells lacking LKB1 display increased sensitivity to irradiation, accumulates more DNA double-strand breaks, display defective homology-directed DNA repair (HDR) and exhibit increased mutation rate, compared with that of LKB1-expressing cells. Conversely, the ectopic expression of LKB1 in cells lacking LKB1 protects them against genotoxic stress-induced DNA damage and prevents the accumulation of mutations. We find that LKB1 post-transcriptionally stimulates HDR gene BRCA1 expression by inhibiting the cytoplasmic localization of the RNA-binding protein, HU antigen R, in an AMP kinase-dependent manner and stabilizes BRCA1 mRNA. Cells lacking BRCA1 similar to the cell lacking LKB1 display increased genomic instability and ectopic expression of BRCA1 rescues LKB1 loss-induced sensitivity to genotoxic stress. Collectively, our results demonstrate that LKB1 is a crucial regulator of genome integrity and reveal a novel mechanism for LKB1-mediated tumor suppression with direct therapeutic implications for cancer prevention. Oxford University Press 2015-01-09 2014-12-08 /pmc/articles/PMC4288185/ /pubmed/25488815 http://dx.doi.org/10.1093/nar/gku1294 Text en © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Genome Integrity, Repair and Replication Gupta, Romi Liu, Alex. Y. Glazer, Peter M. Wajapeyee, Narendra LKB1 preserves genome integrity by stimulating BRCA1 expression |
title | LKB1 preserves genome integrity by stimulating BRCA1 expression |
title_full | LKB1 preserves genome integrity by stimulating BRCA1 expression |
title_fullStr | LKB1 preserves genome integrity by stimulating BRCA1 expression |
title_full_unstemmed | LKB1 preserves genome integrity by stimulating BRCA1 expression |
title_short | LKB1 preserves genome integrity by stimulating BRCA1 expression |
title_sort | lkb1 preserves genome integrity by stimulating brca1 expression |
topic | Genome Integrity, Repair and Replication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288185/ https://www.ncbi.nlm.nih.gov/pubmed/25488815 http://dx.doi.org/10.1093/nar/gku1294 |
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