Research Papers:

The cylindromatosis gene product, CYLD, interacts with MIB2 to regulate notch signalling

Neil Rajan _, Richard J.R. Elliott, Alice Smith, Naomi Sinclair, Sally Swift, Christopher J. Lord and Alan Ashworth

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Oncotarget. 2014; 5:12126-12140. https://doi.org/10.18632/oncotarget.2573

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Neil Rajan1,2,*, Richard J.R. Elliott1,*, Alice Smith1, Naomi Sinclair2, Sally Swift1, Christopher J. Lord1, Alan Ashworth1

1The CRUK Gene Function Laboratory and Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK

2Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK

*These authors contributed equally to this work

Correspondence to:

Neil Rajan, e-mail: [email protected]

Keywords: CYLD, Notch, JAG2, MIB2, RUNX1, cylindroma, spiradenoma

Received: August 15, 2014     Accepted: October 03, 2014     Published: November 03, 2014


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.

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