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dc.contributor.authorLopez-Mateo, Irene
dc.contributor.authorArruabarrena-Aristorena, Amaia
dc.contributor.authorArtaza-Irigaray, Cristina
dc.contributor.authorLopez, Juan Antonio 
dc.contributor.authorCalvo, Enrique 
dc.contributor.authorBelandia, Borja
dc.date.accessioned2017-10-30T13:15:43Z
dc.date.available2017-10-30T13:15:43Z
dc.date.issued2016
dc.identifierISI:000377686500017
dc.identifier.citationBiosci Rep. 2016; 36(3):e00343
dc.identifier.issn0144-8463
dc.identifier.urihttp://hdl.handle.net/20.500.12105/5217
dc.description.abstractHEY1 (hairy/enhancer-of-split related with YRPW motif 1) is a member of the basic helix-loop-helix-orange (bHLH-O) family of transcription repressors that mediate Notch signalling. HEY1 acts as a positive regulator of the tumour suppressor p53 via still unknown mechanisms. A MALDI-TOF/TOF MS analysis has uncovered a novel HEY1 regulatory phosphorylation event at Ser-68. Strikingly, this single phosphorylation event controls HEY1 stability and function: simulation of HEY1 Ser-68 phosphorylation increases HEY1 protein stability but inhibits its ability to enhance p53 transcriptional activity. Unlike wild-type HEY1, expression of the phosphomimetic mutant HEY1-S68D failed to induce p53-dependent cell cycle arrest and it did not sensitize U2OS cells to p53-activating chemotherapeutic drugs. We have identified two related kinases, STK38 (serine/threonine kinase 38) and STK38L (serine/threonine kinase 38 like), which interact with and phosphorylate HEY1 at Ser-68. HEY1 is phosphorylated at Ser-68 during mitosis and it accumulates in the centrosomes of mitotic cells, suggesting a possible integration of HEY1-dependent signalling in centrosome function. Moreover, HEY1 interacts with a subset of p53-activating ribosomal proteins. Ribosomal stress causes HEY1 relocalization from the nucleoplasm to perinucleolar structures termed nucleolar caps. HEY1 interacts physically with at least one of the ribosomal proteins, RPL11, and both proteins cooperate in the inhibition of MDM2-mediated p53 degradation resulting in a synergistic positive effect on p53 transcriptional activity. HEY1 itself also interacts directly with MDM2 and it is subjected to MDM2-mediated degradation. Simulation of HEY1 Ser-68 phosphorylation prevents its interaction with p53, RPL11 and MDM2 and abolishes HEY1 migration to nucleolar caps upon ribosomal stress. Our findings uncover a novel mechanism for cross-talk between Notch signalling and nucleolar stress.
dc.description.sponsorshipThis work was supported by the Spanish Ministerio de Ciencia e Innovacion [grant number SAF2010-21013]; the Fondo Europeo de Desarrollo Regional (FEDER); the program JAE-PREDOC from the CSIC [grant number JAEPre\_2011\_00874]; the Spanish Ministerio de Economia y Competitividad; and the Pro-CNIC Foundation.
dc.language.isoeng
dc.publisherPORTLAND PRESS LTD
dc.relation.isversionofPublisher's version
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectcentrosome
dc.subjectHEY1
dc.subjectp53
dc.subjectphosphorylation
dc.subjectribosomal stress
dc.subjectSTK38
dc.subjectCYCLIN-DEPENDENT KINASE
dc.subjectMITOTIC SPINDLE
dc.subjectNUCLEOLAR CAPS
dc.subjectP53
dc.subjectPROTEIN
dc.subjectNOTCH
dc.subjectPATHWAY
dc.subjectCENTROSOMES
dc.subjectCANCER
dc.subjectHERP
dc.titleHEY1 functions are regulated by its phosphorylation at Ser-68
dc.typeArtículo
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID27129302
dc.format.volume36
dc.identifier.doi10.1042/BSR20160123
dc.contributor.funderMinisterio de Ciencia e Innovación (España)
dc.contributor.funderEuropean Regional Development Fund (ERDF/FEDER)
dc.contributor.funderMinisterio de Economía y Competitividad (España)
dc.contributor.funderFundación ProCNIC
dc.description.peerreviewed
dc.identifier.e-issn1573-4935
dc.relation.publisherversionhttps://doi.org/10.1042/BSR20160123
dc.identifier.journalBioscience reports
dc.repisalud.orgCNICCNIC::Unidades técnicas::Proteómica / Metabolómica
dc.repisalud.institucionCNIC
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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