The E3 ubiquitin protein ligase HERC2 modulates the activity of tumor protein p53 by regulating its oligomerization

The tumor suppressor p53 is a transcription factor that coordinates the cellular response to several kinds of stress. p53 inactivation is an important step in tumor progression. Oligomerization of p53 is critical for its post-translational modification and its ability to regulate the transcription o...

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Autores: Cubillos Rojas, Mónica, Amair-Pinedo, Fabiola, Peiró-Jordán, Roser, Bartrons Bach, Ramon, Ventura Pujol, Francesc, Rosa López, José Luis
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2014
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/181296
Acceso en línea:https://hdl.handle.net/2445/181296
Access Level:acceso abierto
Palabra clave:Ubiqüitina
Proteïnes supressores de tumors
Metabolisme
Ubiquitin
Tumor suppressor protein
Metabolism
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spelling The E3 ubiquitin protein ligase HERC2 modulates the activity of tumor protein p53 by regulating its oligomerizationCubillos Rojas, MónicaAmair-Pinedo, FabiolaPeiró-Jordán, RoserBartrons Bach, RamonVentura Pujol, FrancescRosa López, José LuisUbiqüitinaProteïnes supressores de tumorsMetabolismeUbiquitinTumor suppressor proteinMetabolismThe tumor suppressor p53 is a transcription factor that coordinates the cellular response to several kinds of stress. p53 inactivation is an important step in tumor progression. Oligomerization of p53 is critical for its post-translational modification and its ability to regulate the transcription of target genes necessary to inhibit tumor growth. Here, we report that the HECT E3 ubiquitin ligase HERC2 interacts with p53. This interaction involves the CPH domain of HERC2 and the last 43 amino acid residues of p53. Through this interaction, HERC2 regulates p53 activity. RNA interference experiments showed how HERC2 depletion reduces the transcriptional activity of p53 without affecting its stability. This regulation of p53 activity by HERC2 is independent of proteasome or MDM2 activity. Under these conditions, upregulation of cell growth and increased focus formation were observed, showing the functional relevance of the HERC2/p53 interaction. This interaction was maintained after DNA damage caused by the chemotherapeutic drug bleomycin. In these stressed cells, p53 phosphorylation was not impaired by HERC2 knockdown. Interestingly, p53 mutations that affect its tetramerization domain disrupted the HERC2/p53 interaction suggesting a role for HERC2 in p53 oligomerization. This regulatory role was shown using cross-linking assays. Thus, the inhibition of p53 activity after HERC2 depletion can be attributed to a reduction in p53 oligomerization. Ectopic expression of HERC2 (residues 2292 to 2923) confirmed these observations. Altogether, these results identify HERC2 as a novel regulator of p53 signaling.American Society for Biochemistry and Molecular Biology2021202120142021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion14 p.application/pdfhttps://hdl.handle.net/2445/181296Articles publicats en revistes (Ciències Fisiològiques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1074/jbc.M113.527978Journal of Biological Chemistry, 2014, vol. 289, num. 21, p. 14782-14795https://doi.org/10.1074/jbc.M113.527978(c) American Society for Biochemistry and Molecular Biology, 2014info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1812962026-05-29T05:05:01Z
dc.title.none.fl_str_mv The E3 ubiquitin protein ligase HERC2 modulates the activity of tumor protein p53 by regulating its oligomerization
title The E3 ubiquitin protein ligase HERC2 modulates the activity of tumor protein p53 by regulating its oligomerization
spellingShingle The E3 ubiquitin protein ligase HERC2 modulates the activity of tumor protein p53 by regulating its oligomerization
Cubillos Rojas, Mónica
Ubiqüitina
Proteïnes supressores de tumors
Metabolisme
Ubiquitin
Tumor suppressor protein
Metabolism
title_short The E3 ubiquitin protein ligase HERC2 modulates the activity of tumor protein p53 by regulating its oligomerization
title_full The E3 ubiquitin protein ligase HERC2 modulates the activity of tumor protein p53 by regulating its oligomerization
title_fullStr The E3 ubiquitin protein ligase HERC2 modulates the activity of tumor protein p53 by regulating its oligomerization
title_full_unstemmed The E3 ubiquitin protein ligase HERC2 modulates the activity of tumor protein p53 by regulating its oligomerization
title_sort The E3 ubiquitin protein ligase HERC2 modulates the activity of tumor protein p53 by regulating its oligomerization
dc.creator.none.fl_str_mv Cubillos Rojas, Mónica
Amair-Pinedo, Fabiola
Peiró-Jordán, Roser
Bartrons Bach, Ramon
Ventura Pujol, Francesc
Rosa López, José Luis
author Cubillos Rojas, Mónica
author_facet Cubillos Rojas, Mónica
Amair-Pinedo, Fabiola
Peiró-Jordán, Roser
Bartrons Bach, Ramon
Ventura Pujol, Francesc
Rosa López, José Luis
author_role author
author2 Amair-Pinedo, Fabiola
Peiró-Jordán, Roser
Bartrons Bach, Ramon
Ventura Pujol, Francesc
Rosa López, José Luis
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Ubiqüitina
Proteïnes supressores de tumors
Metabolisme
Ubiquitin
Tumor suppressor protein
Metabolism
topic Ubiqüitina
Proteïnes supressores de tumors
Metabolisme
Ubiquitin
Tumor suppressor protein
Metabolism
description The tumor suppressor p53 is a transcription factor that coordinates the cellular response to several kinds of stress. p53 inactivation is an important step in tumor progression. Oligomerization of p53 is critical for its post-translational modification and its ability to regulate the transcription of target genes necessary to inhibit tumor growth. Here, we report that the HECT E3 ubiquitin ligase HERC2 interacts with p53. This interaction involves the CPH domain of HERC2 and the last 43 amino acid residues of p53. Through this interaction, HERC2 regulates p53 activity. RNA interference experiments showed how HERC2 depletion reduces the transcriptional activity of p53 without affecting its stability. This regulation of p53 activity by HERC2 is independent of proteasome or MDM2 activity. Under these conditions, upregulation of cell growth and increased focus formation were observed, showing the functional relevance of the HERC2/p53 interaction. This interaction was maintained after DNA damage caused by the chemotherapeutic drug bleomycin. In these stressed cells, p53 phosphorylation was not impaired by HERC2 knockdown. Interestingly, p53 mutations that affect its tetramerization domain disrupted the HERC2/p53 interaction suggesting a role for HERC2 in p53 oligomerization. This regulatory role was shown using cross-linking assays. Thus, the inhibition of p53 activity after HERC2 depletion can be attributed to a reduction in p53 oligomerization. Ectopic expression of HERC2 (residues 2292 to 2923) confirmed these observations. Altogether, these results identify HERC2 as a novel regulator of p53 signaling.
publishDate 2014
dc.date.none.fl_str_mv 2014
2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/181296
url https://hdl.handle.net/2445/181296
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1074/jbc.M113.527978
Journal of Biological Chemistry, 2014, vol. 289, num. 21, p. 14782-14795
https://doi.org/10.1074/jbc.M113.527978
dc.rights.none.fl_str_mv (c) American Society for Biochemistry and Molecular Biology, 2014
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) American Society for Biochemistry and Molecular Biology, 2014
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 14 p.
application/pdf
dc.publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,198674

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