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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...

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Autores principales: Gupta, Romi, Liu, Alex. Y., Glazer, Peter M., Wajapeyee, Narendra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
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.
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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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