A bacterial cytotoxin identifies the RhoA exchange factor Net1 as a key effector in the response to DNA damage.

<h4>Background</h4>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 intermedia...

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Autores principales:	Lina Guerra, Heather S Carr, Agneta Richter-Dahlfors, Maria G Masucci, Monica Thelestam, Jeffrey A Frost, Teresa Frisan
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/13685e220b60404b877b4cb86ec0367a
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spelling	oai:doaj.org-article:13685e220b60404b877b4cb86ec0367a2021-11-25T06:12:17ZA bacterial cytotoxin identifies the RhoA exchange factor Net1 as a key effector in the response to DNA damage.1932-620310.1371/journal.pone.0002254https://doaj.org/article/13685e220b60404b877b4cb86ec0367a2008-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18509476/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Principal findings</h4>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.<h4>Significance</h4>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.Lina GuerraHeather S CarrAgneta Richter-DahlforsMaria G MasucciMonica ThelestamJeffrey A FrostTeresa FrisanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 5, p e2254 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lina Guerra Heather S Carr Agneta Richter-Dahlfors Maria G Masucci Monica Thelestam Jeffrey A Frost Teresa Frisan A bacterial cytotoxin identifies the RhoA exchange factor Net1 as a key effector in the response to DNA damage.
description	<h4>Background</h4>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.<h4>Principal findings</h4>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.<h4>Significance</h4>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.
format	article
author	Lina Guerra Heather S Carr Agneta Richter-Dahlfors Maria G Masucci Monica Thelestam Jeffrey A Frost Teresa Frisan
author_facet	Lina Guerra Heather S Carr Agneta Richter-Dahlfors Maria G Masucci Monica Thelestam Jeffrey A Frost Teresa Frisan
author_sort	Lina Guerra
title	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_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_sort	bacterial cytotoxin identifies the rhoa exchange factor net1 as a key effector in the response to dna damage.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/13685e220b60404b877b4cb86ec0367a
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A bacterial cytotoxin identifies the RhoA exchange factor Net1 as a key effector in the response to DNA damage.

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