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A Bacterial Cytotoxin Identifies the RhoA Exchange Factor Net1 as a Key Effector in the Response to DNA Damage

BACKGROUND: Exposure of adherent cells to DNA damaging agents, such as the bacterial cytolethal distending toxin (CDT) or ionizing radiations (IR), activates the small GTPase RhoA, which promotes the formation of actin stress fibers and delays cell death. The signalling intermediates that regulate R...

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Autores principales: Guerra, Lina, Carr, Heather S., Richter-Dahlfors, Agneta, Masucci, Maria G., Thelestam, Monica, Frost, Jeffrey A., Frisan, Teresa
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386254/
https://www.ncbi.nlm.nih.gov/pubmed/18509476
http://dx.doi.org/10.1371/journal.pone.0002254
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author Guerra, Lina
Carr, Heather S.
Richter-Dahlfors, Agneta
Masucci, Maria G.
Thelestam, Monica
Frost, Jeffrey A.
Frisan, Teresa
author_facet Guerra, Lina
Carr, Heather S.
Richter-Dahlfors, Agneta
Masucci, Maria G.
Thelestam, Monica
Frost, Jeffrey A.
Frisan, Teresa
author_sort Guerra, Lina
collection PubMed
description BACKGROUND: Exposure of adherent cells to DNA damaging agents, such as the bacterial cytolethal distending toxin (CDT) or ionizing radiations (IR), activates the small GTPase RhoA, which promotes the formation of actin stress fibers and delays cell death. The signalling intermediates that regulate RhoA activation and promote cell survival are unknown. PRINCIPAL FINDINGS: We demonstrate that the nuclear RhoA-specific Guanine nucleotide Exchange Factor (GEF) Net1 becomes dephosphorylated at a critical inhibitory site in cells exposed to CDT or IR. Expression of a dominant negative Net1 or Net1 knock down by iRNA prevented RhoA activation, inhibited the formation of stress fibers, and enhanced cell death, indicating that Net1 activation is required for this RhoA-mediated responses to genotoxic stress. The Net1 and RhoA-dependent signals involved activation of the Mitogen-Activated Protein Kinase p38 and its downstream target MAPK-activated protein kinase 2. SIGNIFICANCE: Our data highlight the importance of Net1 in controlling RhoA and p38 MAPK mediated cell survival in cells exposed to DNA damaging agents and illustrate a molecular pathway whereby chronic exposure to a bacterial toxin may promote genomic instability.
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spelling pubmed-23862542008-05-28 A Bacterial Cytotoxin Identifies the RhoA Exchange Factor Net1 as a Key Effector in the Response to DNA Damage Guerra, Lina Carr, Heather S. Richter-Dahlfors, Agneta Masucci, Maria G. Thelestam, Monica Frost, Jeffrey A. Frisan, Teresa PLoS One Research Article BACKGROUND: Exposure of adherent cells to DNA damaging agents, such as the bacterial cytolethal distending toxin (CDT) or ionizing radiations (IR), activates the small GTPase RhoA, which promotes the formation of actin stress fibers and delays cell death. The signalling intermediates that regulate RhoA activation and promote cell survival are unknown. PRINCIPAL FINDINGS: We demonstrate that the nuclear RhoA-specific Guanine nucleotide Exchange Factor (GEF) Net1 becomes dephosphorylated at a critical inhibitory site in cells exposed to CDT or IR. Expression of a dominant negative Net1 or Net1 knock down by iRNA prevented RhoA activation, inhibited the formation of stress fibers, and enhanced cell death, indicating that Net1 activation is required for this RhoA-mediated responses to genotoxic stress. The Net1 and RhoA-dependent signals involved activation of the Mitogen-Activated Protein Kinase p38 and its downstream target MAPK-activated protein kinase 2. SIGNIFICANCE: Our data highlight the importance of Net1 in controlling RhoA and p38 MAPK mediated cell survival in cells exposed to DNA damaging agents and illustrate a molecular pathway whereby chronic exposure to a bacterial toxin may promote genomic instability. Public Library of Science 2008-05-28 /pmc/articles/PMC2386254/ /pubmed/18509476 http://dx.doi.org/10.1371/journal.pone.0002254 Text en Guerra et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Guerra, Lina
Carr, Heather S.
Richter-Dahlfors, Agneta
Masucci, Maria G.
Thelestam, Monica
Frost, Jeffrey A.
Frisan, Teresa
A Bacterial Cytotoxin Identifies the RhoA Exchange Factor Net1 as a Key Effector in the Response to DNA Damage
title A Bacterial Cytotoxin Identifies the RhoA Exchange Factor Net1 as a Key Effector in the Response to DNA Damage
title_full A Bacterial Cytotoxin Identifies the RhoA Exchange Factor Net1 as a Key Effector in the Response to DNA Damage
title_fullStr A Bacterial Cytotoxin Identifies the RhoA Exchange Factor Net1 as a Key Effector in the Response to DNA Damage
title_full_unstemmed A Bacterial Cytotoxin Identifies the RhoA Exchange Factor Net1 as a Key Effector in the Response to DNA Damage
title_short A Bacterial Cytotoxin Identifies the RhoA Exchange Factor Net1 as a Key Effector in the Response to DNA Damage
title_sort bacterial cytotoxin identifies the rhoa exchange factor net1 as a key effector in the response to dna damage
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386254/
https://www.ncbi.nlm.nih.gov/pubmed/18509476
http://dx.doi.org/10.1371/journal.pone.0002254
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