The cylindromatosis gene product, CYLD, interacts with MIB2 to regulate notch signalling.
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.
Collections
Subject
Humans
Neoplasms
Skin Neoplasms
Ubiquitin-Protein Ligases
Tumor Suppressor Proteins
Oligonucleotide Array Sequence Analysis
Tissue Array Analysis
Immunohistochemistry
Immunoprecipitation
Signal Transduction
Receptors, Notch
HEK293 Cells
Real-Time Polymerase Chain Reaction
Deubiquitinating Enzyme CYLD
Research team
Gene Function
Language
eng
Date accepted
2014-10-03
License start date
2014-12
Citation
Oncotarget, 2014, 5 (23), pp. 12126 - 12140
Publisher
IMPACT JOURNALS LLC