Show simple item record

dc.contributor.authorMason, Bethanyen
dc.contributor.authorFlach, Susanneen
dc.contributor.authorTeixeira, Felipe Ren
dc.contributor.authorManzano Garcia, Raquelen
dc.contributor.authorRueda, Oscar Men
dc.contributor.authorAbraham, Jeanen
dc.contributor.authorCaldas, Carlosen
dc.contributor.authorEdwards, Paulen
dc.contributor.authorLaman, Heikeen
dc.date.accessioned2019-09-18T23:30:10Z
dc.date.available2019-09-18T23:30:10Z
dc.date.issued2020-07en
dc.identifier.issn1420-682X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/296924
dc.description.abstractIn cancer, many genes are mutated by genome rearrangement, but our understanding of the functional consequences of this remains rudimentary. Here we report the F-box protein encoded by FBXL17 is disrupted in the region of the gene that encodes its substrate-binding leucine rich repeat (LRR) domain. Truncating Fbxl17 LRRs impaired its association with the other SCF holoenzyme subunits Skp1, Cul1 and Rbx1, and decreased ubiquitination activity. Loss of the LRRs also differentially affected Fbxl17 binding to its targets. Thus, genomic rearrangements in FBXL17 are likely to disrupt SCFFbxl17-regulated networks in cancer cells. To investigate the functional effect of these rearrangements, we performed a yeast two-hybrid screen to identify Fbxl17-interacting proteins. Among the 37 binding partners Uap1, an enzyme involved in O-GlcNAcylation of proteins, was identified most frequently. We demonstrate that Fbxl17 binds to UAP1 directly and inhibits its phosphorylation, which we propose regulates UAP1 activity. Knockdown of Fbxl17 expression elevated O-GlcNAcylation in breast cancer cells, arguing for a functional role for Fbxl17 in this metabolic pathway.
dc.description.sponsorshipFunding was provided by Breast Cancer Now (2013NovPhD172) to BM and HL and PAWE, and Cancer Research UK (C1023/A14545 and C1023/A9140) to PAWE; SF was supported by a Wildy Studentship from Gonville & Caius College, and the Department of Pathology, University of Cambridge. FRT was funded by a BEPE-FAPESP fellowship (2012/09241-8). The Personalised Breast Cancer Program is funded by Addenbrookes Charitable Trust, the Mark Foundation and Cancer Research UK grants to CC and JEA.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherSpringer Nature
dc.rightsAll rights reserved
dc.rights.uri
dc.subjectCell Line, Tumoren
dc.subjectHumansen
dc.subjectBreast Neoplasmsen
dc.subjectUbiquitin-Protein Ligasesen
dc.subjectAcetylglucosamineen
dc.subjectF-Box Proteinsen
dc.subjectProtein Processing, Post-Translationalen
dc.subjectSequence Deletionen
dc.subjectPhosphorylationen
dc.subjectFemaleen
dc.subjectDNA Breaksen
dc.subjectUbiquitinationen
dc.subjectHEK293 Cellsen
dc.titleFbxl17 is rearranged in breast cancer and loss of its activity leads to increased global O-GlcNAcylation.en
dc.typeArticle
prism.endingPage2620
prism.issueIdentifier13en
prism.publicationDate2020en
prism.publicationNameCellular and molecular life sciences : CMLSen
prism.startingPage2605
prism.volume77en
dc.identifier.doi10.17863/CAM.43965
dcterms.dateAccepted2019-09-16en
rioxxterms.versionofrecord10.1007/s00018-019-03306-yen
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2020-07en
dc.contributor.orcidMason, Bethany [0000-0002-1157-0469]
dc.contributor.orcidTeixeira, Felipe R [0000-0003-0251-2686]
dc.contributor.orcidAbraham, Jean [0000-0003-0688-4807]
dc.contributor.orcidCaldas, Carlos [0000-0003-3547-1489]
dc.contributor.orcidEdwards, Paul [0000-0002-4789-3374]
dc.contributor.orcidLaman, Heike [0000-0002-6089-171X]
dc.identifier.eissn1420-9071
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idBreast Cancer Campaign (2013NovPhD172)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (60098573)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (CB4140)
pubs.funder-project-idCancer Research UK (A7199)
pubs.funder-project-idCancer Research UK (A15580)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NF-SI-0515-10090)
pubs.funder-project-idCancer Research UK (A27657)
pubs.funder-project-idCancer Research UK (A9140)
pubs.funder-project-idBreast Cancer Now (2013NovPhD172)
pubs.funder-project-idBreast Cancer Campaign (2008NovPR21)
pubs.funder-project-idCancer Research UK (14545)
pubs.funder-project-idBreast Cancer Campaign (2014MaySP294)
cam.orpheus.successThu Jan 30 10:40:04 GMT 2020 - Embargo updated*
rioxxterms.freetoread.startdate2020-09-27


Files in this item

Thumbnail
Thumbnail
Thumbnail
Thumbnail

This item appears in the following Collection(s)

Show simple item record