The cylindromatosis gene product, CYLD, interacts with MIB2 to regulate notch signalling.
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Embargo End Date
ICR Authors
Authors
Rajan, N
Elliott, RJR
Smith, A
Sinclair, N
Swift, S
Lord, CJ
Ashworth, A
Elliott, RJR
Smith, A
Sinclair, N
Swift, S
Lord, CJ
Ashworth, A
Document Type
Journal Article
Date
2014-12-15
Date Accepted
2014-10-03
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.
Citation
Oncotarget, 2014, 5 (23), pp. 12126 - 12140
Source Title
Publisher
IMPACT JOURNALS LLC
ISSN
1949-2553
eISSN
1949-2553
Collections
Research Team
Gene Function