Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2

The p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally re...

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Autores: García Cano, Jesús, Sánchez Tena, Susana, Sala Gastón, Joan, Figueras i Amat, Agnès, Viñals Canals, Francesc, Bartrons Bach, Ramon, Ventura Pujol, Francesc, Rosa López, José Luis
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
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:2445/152990
Acceso en línea:https://hdl.handle.net/2445/152990
Access Level:acceso abierto
Palabra clave:Proteïnes supressores de tumors
Ubiqüitina
Tumor suppressor protein
Ubiquitin
id ES_d219e1b0842e45f10c44f91674c93fdb
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spelling Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2García Cano, JesúsSánchez Tena, SusanaSala Gastón, JoanFigueras i Amat, AgnèsViñals Canals, FrancescBartrons Bach, RamonVentura Pujol, FrancescRosa López, José LuisProteïnes supressores de tumorsUbiqüitinaTumor suppressor proteinUbiquitinThe p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally regulated by p53 in a negative feedback loop. The p53 protein is transcriptionally active as a tetramer, and this oligomerization state is modulated by a complex formed by NEURL4 and the ubiquitin E3 ligase HERC2. Here, we report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its protein stability, as it reduces its mRNA expression by inhibition of its promoter activation. DNA damage induced by bleomycin dissociates MDM2 from the p53/HERC2/NEURL4 complex and increases the phosphorylation and acetylation of oligomeric p53 bound to HERC2 and NEURL4. Moreover, the MDM2 promoter, which contains p53‐response elements, competes with HERC2 for binding of oligomeric, phosphorylated and acetylated p53. We integrate these findings in a model showing the pivotal role of HERC2 in p53‐MDM2 loop regulation. Altogether, these new insights in p53 pathway regulation are of great interest in cancer and may provide new therapeutic targets.FEBS Press2020202020202020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion18 p.application/pdfhttps://hdl.handle.net/2445/152990Articles 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/10.1002/1878-0261.12592Molecular Oncology, 2020, vol. 14, num. 1, p. 69-86https://doi.org/10.1002/1878-0261.12592cc-by (c) García Cano, Jesús et al., 2020http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1529902026-05-29T05:05:01Z
dc.title.none.fl_str_mv Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2
title Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2
spellingShingle Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2
García Cano, Jesús
Proteïnes supressores de tumors
Ubiqüitina
Tumor suppressor protein
Ubiquitin
title_short Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2
title_full Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2
title_fullStr Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2
title_full_unstemmed Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2
title_sort Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2
dc.creator.none.fl_str_mv García Cano, Jesús
Sánchez Tena, Susana
Sala Gastón, Joan
Figueras i Amat, Agnès
Viñals Canals, Francesc
Bartrons Bach, Ramon
Ventura Pujol, Francesc
Rosa López, José Luis
author García Cano, Jesús
author_facet García Cano, Jesús
Sánchez Tena, Susana
Sala Gastón, Joan
Figueras i Amat, Agnès
Viñals Canals, Francesc
Bartrons Bach, Ramon
Ventura Pujol, Francesc
Rosa López, José Luis
author_role author
author2 Sánchez Tena, Susana
Sala Gastón, Joan
Figueras i Amat, Agnès
Viñals Canals, Francesc
Bartrons Bach, Ramon
Ventura Pujol, Francesc
Rosa López, José Luis
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Proteïnes supressores de tumors
Ubiqüitina
Tumor suppressor protein
Ubiquitin
topic Proteïnes supressores de tumors
Ubiqüitina
Tumor suppressor protein
Ubiquitin
description The p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally regulated by p53 in a negative feedback loop. The p53 protein is transcriptionally active as a tetramer, and this oligomerization state is modulated by a complex formed by NEURL4 and the ubiquitin E3 ligase HERC2. Here, we report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its protein stability, as it reduces its mRNA expression by inhibition of its promoter activation. DNA damage induced by bleomycin dissociates MDM2 from the p53/HERC2/NEURL4 complex and increases the phosphorylation and acetylation of oligomeric p53 bound to HERC2 and NEURL4. Moreover, the MDM2 promoter, which contains p53‐response elements, competes with HERC2 for binding of oligomeric, phosphorylated and acetylated p53. We integrate these findings in a model showing the pivotal role of HERC2 in p53‐MDM2 loop regulation. Altogether, these new insights in p53 pathway regulation are of great interest in cancer and may provide new therapeutic targets.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020
2020
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/2445/152990
url https://hdl.handle.net/2445/152990
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/10.1002/1878-0261.12592
Molecular Oncology, 2020, vol. 14, num. 1, p. 69-86
https://doi.org/10.1002/1878-0261.12592
dc.rights.none.fl_str_mv cc-by (c) García Cano, Jesús et al., 2020
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) García Cano, Jesús et al., 2020
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 18 p.
application/pdf
dc.publisher.none.fl_str_mv FEBS Press
publisher.none.fl_str_mv FEBS Press
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 15,811543

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