Epstein-Barr virus down-regulates tumor suppressor DOK1 expression

Autores
Siouda, Maha; Frecha, Cecilia Ariana; Accardi, Rosita; Yue, Jiping; Cuenin, Cyrille; Grufat, Henri; Manet, Evelyne; Herceg, Zdenko; Sylla, Bakary S.; Tommasino, Massimo
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The DOK1 tumor suppressor gene encodes an adapter protein that acts as a negative regulator of several signaling pathways. We have previously reported that DOK1 expression is up-regulated upon cellular stress, via the transcription factor E2F1, and down-regulated in a variety of human malignancies due to aberrant hypermethylation of its promoter. Here we show that Epstein Barr virus (EBV) infection of primary human B-cells leads to the down-regulation of DOK1 gene expression via the viral oncoprotein LMP1. LMP1 alone induces recruitment to the DOK1 promoter of at least two independent inhibitory complexes, one containing E2F1/pRB/DNMT1 and another containing at least EZH2. These events result in tri-methylation of histone H3 at lysine 27 (H3K27me3) of the DOK1 promoter and gene expression silencing. We also present evidence that the presence of additional EBV proteins leads to further repression of DOK1 expression with an additional mechanism. Indeed, EBV infection of B-cells induces DNA methylation at the DOK1 promoter region including the E2F1 responsive elements that, in turn, lose the ability to interact with E2F complexes. Treatment of EBV-infected B-cell-lines with the methyl-transferase inhibitor 5-aza-2′-deoxycytidine rescues DOK1 expression. In summary, our data show the deregulation of DOK1 gene expression by EBV and provide novel insights into the regulation of the DOK1 tumor suppressor in viral-related carcinogenesis.
Fil: Siouda, Maha. World Health Organization; Francia
Fil: Frecha, Cecilia Ariana. World Health Organization; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Accardi, Rosita. World Health Organization; Francia
Fil: Yue, Jiping. World Health Organization; Francia
Fil: Cuenin, Cyrille. World Health Organization; Francia
Fil: Grufat, Henri. Inserm; Francia. Université Claude Bernard Lyon 1; Francia. Centre National de la Recherche Scientifique; Francia. Ecole Normale Supérieure; Francia
Fil: Manet, Evelyne. Inserm; Francia. Université Claude Bernard Lyon 1; Francia. Centre National de la Recherche Scientifique; Francia. Ecole Normale Supérieure; Francia
Fil: Herceg, Zdenko. World Health Organization; Francia
Fil: Sylla, Bakary S.. World Health Organization; Francia
Fil: Tommasino, Massimo. World Health Organization; Francia
Materia
Epstein Barr Virus
Dok1
E2f1
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/17390
Acceder
id CONICETDig_aea4bdd810f3a231da894afa3f3f4839
oai_identifier_str oai:ri.conicet.gov.ar:11336/17390
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Epstein-Barr virus down-regulates tumor suppressor DOK1 expressionSiouda, MahaFrecha, Cecilia ArianaAccardi, RositaYue, JipingCuenin, CyrilleGrufat, HenriManet, EvelyneHerceg, ZdenkoSylla, Bakary S.Tommasino, MassimoEpstein Barr VirusDok1E2f1https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The DOK1 tumor suppressor gene encodes an adapter protein that acts as a negative regulator of several signaling pathways. We have previously reported that DOK1 expression is up-regulated upon cellular stress, via the transcription factor E2F1, and down-regulated in a variety of human malignancies due to aberrant hypermethylation of its promoter. Here we show that Epstein Barr virus (EBV) infection of primary human B-cells leads to the down-regulation of DOK1 gene expression via the viral oncoprotein LMP1. LMP1 alone induces recruitment to the DOK1 promoter of at least two independent inhibitory complexes, one containing E2F1/pRB/DNMT1 and another containing at least EZH2. These events result in tri-methylation of histone H3 at lysine 27 (H3K27me3) of the DOK1 promoter and gene expression silencing. We also present evidence that the presence of additional EBV proteins leads to further repression of DOK1 expression with an additional mechanism. Indeed, EBV infection of B-cells induces DNA methylation at the DOK1 promoter region including the E2F1 responsive elements that, in turn, lose the ability to interact with E2F complexes. Treatment of EBV-infected B-cell-lines with the methyl-transferase inhibitor 5-aza-2′-deoxycytidine rescues DOK1 expression. In summary, our data show the deregulation of DOK1 gene expression by EBV and provide novel insights into the regulation of the DOK1 tumor suppressor in viral-related carcinogenesis.Fil: Siouda, Maha. World Health Organization; FranciaFil: Frecha, Cecilia Ariana. World Health Organization; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Accardi, Rosita. World Health Organization; FranciaFil: Yue, Jiping. World Health Organization; FranciaFil: Cuenin, Cyrille. World Health Organization; FranciaFil: Grufat, Henri. Inserm; Francia. Université Claude Bernard Lyon 1; Francia. Centre National de la Recherche Scientifique; Francia. Ecole Normale Supérieure; FranciaFil: Manet, Evelyne. Inserm; Francia. Université Claude Bernard Lyon 1; Francia. Centre National de la Recherche Scientifique; Francia. Ecole Normale Supérieure; FranciaFil: Herceg, Zdenko. World Health Organization; FranciaFil: Sylla, Bakary S.. World Health Organization; FranciaFil: Tommasino, Massimo. World Health Organization; FranciaPublic Library of Science2014-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/17390Siouda, Maha; Frecha, Cecilia Ariana; Accardi, Rosita; Yue, Jiping; Cuenin, Cyrille; et al.; Epstein-Barr virus down-regulates tumor suppressor DOK1 expression; Public Library of Science; Plos Pathogens; 10; 5; 5-2014; 1-14, e10041251553-7366enginfo:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004125info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.ppat.1004125info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:37:18Zoai:ri.conicet.gov.ar:11336/17390instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 15:37:18.378CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Epstein-Barr virus down-regulates tumor suppressor DOK1 expression
title Epstein-Barr virus down-regulates tumor suppressor DOK1 expression
spellingShingle Epstein-Barr virus down-regulates tumor suppressor DOK1 expression
Siouda, Maha
Epstein Barr Virus
Dok1
E2f1
title_short Epstein-Barr virus down-regulates tumor suppressor DOK1 expression
title_full Epstein-Barr virus down-regulates tumor suppressor DOK1 expression
title_fullStr Epstein-Barr virus down-regulates tumor suppressor DOK1 expression
title_full_unstemmed Epstein-Barr virus down-regulates tumor suppressor DOK1 expression
title_sort Epstein-Barr virus down-regulates tumor suppressor DOK1 expression
dc.creator.none.fl_str_mv Siouda, Maha
Frecha, Cecilia Ariana
Accardi, Rosita
Yue, Jiping
Cuenin, Cyrille
Grufat, Henri
Manet, Evelyne
Herceg, Zdenko
Sylla, Bakary S.
Tommasino, Massimo
author Siouda, Maha
author_facet Siouda, Maha
Frecha, Cecilia Ariana
Accardi, Rosita
Yue, Jiping
Cuenin, Cyrille
Grufat, Henri
Manet, Evelyne
Herceg, Zdenko
Sylla, Bakary S.
Tommasino, Massimo
author_role author
author2 Frecha, Cecilia Ariana
Accardi, Rosita
Yue, Jiping
Cuenin, Cyrille
Grufat, Henri
Manet, Evelyne
Herceg, Zdenko
Sylla, Bakary S.
Tommasino, Massimo
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Epstein Barr Virus
Dok1
E2f1
topic Epstein Barr Virus
Dok1
E2f1
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The DOK1 tumor suppressor gene encodes an adapter protein that acts as a negative regulator of several signaling pathways. We have previously reported that DOK1 expression is up-regulated upon cellular stress, via the transcription factor E2F1, and down-regulated in a variety of human malignancies due to aberrant hypermethylation of its promoter. Here we show that Epstein Barr virus (EBV) infection of primary human B-cells leads to the down-regulation of DOK1 gene expression via the viral oncoprotein LMP1. LMP1 alone induces recruitment to the DOK1 promoter of at least two independent inhibitory complexes, one containing E2F1/pRB/DNMT1 and another containing at least EZH2. These events result in tri-methylation of histone H3 at lysine 27 (H3K27me3) of the DOK1 promoter and gene expression silencing. We also present evidence that the presence of additional EBV proteins leads to further repression of DOK1 expression with an additional mechanism. Indeed, EBV infection of B-cells induces DNA methylation at the DOK1 promoter region including the E2F1 responsive elements that, in turn, lose the ability to interact with E2F complexes. Treatment of EBV-infected B-cell-lines with the methyl-transferase inhibitor 5-aza-2′-deoxycytidine rescues DOK1 expression. In summary, our data show the deregulation of DOK1 gene expression by EBV and provide novel insights into the regulation of the DOK1 tumor suppressor in viral-related carcinogenesis.
Fil: Siouda, Maha. World Health Organization; Francia
Fil: Frecha, Cecilia Ariana. World Health Organization; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Accardi, Rosita. World Health Organization; Francia
Fil: Yue, Jiping. World Health Organization; Francia
Fil: Cuenin, Cyrille. World Health Organization; Francia
Fil: Grufat, Henri. Inserm; Francia. Université Claude Bernard Lyon 1; Francia. Centre National de la Recherche Scientifique; Francia. Ecole Normale Supérieure; Francia
Fil: Manet, Evelyne. Inserm; Francia. Université Claude Bernard Lyon 1; Francia. Centre National de la Recherche Scientifique; Francia. Ecole Normale Supérieure; Francia
Fil: Herceg, Zdenko. World Health Organization; Francia
Fil: Sylla, Bakary S.. World Health Organization; Francia
Fil: Tommasino, Massimo. World Health Organization; Francia
description The DOK1 tumor suppressor gene encodes an adapter protein that acts as a negative regulator of several signaling pathways. We have previously reported that DOK1 expression is up-regulated upon cellular stress, via the transcription factor E2F1, and down-regulated in a variety of human malignancies due to aberrant hypermethylation of its promoter. Here we show that Epstein Barr virus (EBV) infection of primary human B-cells leads to the down-regulation of DOK1 gene expression via the viral oncoprotein LMP1. LMP1 alone induces recruitment to the DOK1 promoter of at least two independent inhibitory complexes, one containing E2F1/pRB/DNMT1 and another containing at least EZH2. These events result in tri-methylation of histone H3 at lysine 27 (H3K27me3) of the DOK1 promoter and gene expression silencing. We also present evidence that the presence of additional EBV proteins leads to further repression of DOK1 expression with an additional mechanism. Indeed, EBV infection of B-cells induces DNA methylation at the DOK1 promoter region including the E2F1 responsive elements that, in turn, lose the ability to interact with E2F complexes. Treatment of EBV-infected B-cell-lines with the methyl-transferase inhibitor 5-aza-2′-deoxycytidine rescues DOK1 expression. In summary, our data show the deregulation of DOK1 gene expression by EBV and provide novel insights into the regulation of the DOK1 tumor suppressor in viral-related carcinogenesis.
publishDate 2014
dc.date.none.fl_str_mv 2014-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/17390
Siouda, Maha; Frecha, Cecilia Ariana; Accardi, Rosita; Yue, Jiping; Cuenin, Cyrille; et al.; Epstein-Barr virus down-regulates tumor suppressor DOK1 expression; Public Library of Science; Plos Pathogens; 10; 5; 5-2014; 1-14, e1004125
1553-7366
url http://hdl.handle.net/11336/17390
identifier_str_mv Siouda, Maha; Frecha, Cecilia Ariana; Accardi, Rosita; Yue, Jiping; Cuenin, Cyrille; et al.; Epstein-Barr virus down-regulates tumor suppressor DOK1 expression; Public Library of Science; Plos Pathogens; 10; 5; 5-2014; 1-14, e1004125
1553-7366
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004125
info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.ppat.1004125
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.22299

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