dc.contributor.author | Rajan, N | |
dc.contributor.author | Elliott, RJR | |
dc.contributor.author | Smith, A | |
dc.contributor.author | Sinclair, N | |
dc.contributor.author | Swift, S | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Ashworth, A | |
dc.date.accessioned | 2016-09-13T13:19:07Z | |
dc.date.issued | 2014-12-15 | |
dc.identifier.citation | Oncotarget, 2014, 5 (23), pp. 12126 - 12140 | |
dc.identifier.issn | 1949-2553 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/105 | |
dc.identifier.eissn | 1949-2553 | |
dc.identifier.doi | 10.18632/oncotarget.2573 | |
dc.description.abstract | CYLD, an ubiquitin hydrolase, has an expanding repertoire of regulatory roles in cell signalling and is dysregulated in a number of cancers. To dissect CYLD function we used a proteomics approach to identify CYLD interacting proteins and identified MIB2, an ubiquitin ligase enzyme involved in Notch signalling, as a protein which interacts with CYLD. Coexpression of CYLD and MIB2 resulted in stabilisation of MIB2 protein levels and was associated with reduced levels of JAG2, a ligand implicated in Notch signalling. Conversely, gene silencing of CYLD using siRNA, resulted in increased JAG2 expression and upregulation of Notch signalling. We investigated Notch pathway activity in skin tumours from patients with germline mutations in CYLD and found that JAG2 protein levels and Notch target genes were upregulated. In particular, RUNX1 was overexpressed in CYLD defective tumour cells. Finally, primary cell cultures of CYLD defective tumours demonstrated reduced viability when exposed to γ-secretase inhibitors that pharmacologically target Notch signalling. Taken together these data indicate an oncogenic dependency on Notch signalling and suggest potential novel therapeutic approaches for patients with CYLD defective tumours. | |
dc.format | Print | |
dc.format.extent | 12126 - 12140 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | IMPACT JOURNALS LLC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Neoplasms | |
dc.subject | Skin Neoplasms | |
dc.subject | Ubiquitin-Protein Ligases | |
dc.subject | Tumor Suppressor Proteins | |
dc.subject | Oligonucleotide Array Sequence Analysis | |
dc.subject | Tissue Array Analysis | |
dc.subject | Immunohistochemistry | |
dc.subject | Immunoprecipitation | |
dc.subject | Signal Transduction | |
dc.subject | Receptors, Notch | |
dc.subject | HEK293 Cells | |
dc.subject | Real-Time Polymerase Chain Reaction | |
dc.subject | Deubiquitinating Enzyme CYLD | |
dc.title | The cylindromatosis gene product, CYLD, interacts with MIB2 to regulate notch signalling. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2014-10-03 | |
rioxxterms.versionofrecord | 10.18632/oncotarget.2573 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2014-12 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Oncotarget | |
pubs.issue | 23 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.publication-status | Published | |
pubs.volume | 5 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Lord, Christopher | |