title: 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.
authors.affiliation: The CRUK Gene Function Laboratory and Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK. Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Rajan
authors.affiliation: The CRUK Gene Function Laboratory and Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Richard J R
authors.initials: RJ
authors.lastname: Elliott
authors.affiliation: The CRUK Gene Function Laboratory and Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Alice
authors.initials: A
authors.lastname: Smith
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Naomi
authors.initials: N
authors.lastname: Sinclair
authors.affiliation: The CRUK Gene Function Laboratory and Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Swift
authors.affiliation: The CRUK Gene Function Laboratory and Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.affiliation: The CRUK Gene Function Laboratory and Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
mesh_terms: D000074749:Deubiquitinating Enzyme CYLD; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D051880:Receptors, Notch; D025521:Tumor Suppressor Proteins; C478156:MIB2 protein, human; D044767:Ubiquitin-Protein Ligases; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD