Disease relevance of CYLD

• Cylindromas are benign adnexal skin tumors caused by germline mutations in the CYLD gene [1].
• Reduced expression of CYLD in human colon and hepatocellular carcinomas [2].
• Since the Brooke-Spiegler syndrome is characterized by a germline mutation in the CYLD oncosuppressor gene, a biphasic tumor in this setting may represent a true carcinosarcoma [3].
• Spiradenocylindroma of the kidney: clinical and genetic findings suggesting a role of somatic mutation of the CYLD1 gene in the oncogenesis of an unusual renal neoplasm [4].
• We propose that this additional function of CYLD could provide an explanation for the benign nature of most cylindroma lesions [5].

High impact information on CYLD

• Mutations in the CYLD gene cause tumors of hair-follicle keratinocytes [6].
• Cyld-/- tumors and keratinocytes treated with 12-O-tetradecanoylphorbol-13 acetate (TPA) or UV light are hyperproliferative and have elevated cyclin D1 levels [6].
• Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling [6].
• The susceptibility gene (CYLD) has previously been localized to chromosome 16q and has the genetic attributes of a tumour-suppressor gene (recessive oncogene) [7].
• Here we have identified CYLD by detecting germline mutations in 21 cylindromatosis families and somatic mutations in 1 sporadic and 5 familial cylindromas [7].

Biological context of CYLD

• To shed more light on the function of CYLD, we have performed a yeast two hybrid screen using an HaCaT cDNA library that identified the RING finger protein TRIP (TRAF-interacting protein) as interactor with full-length CYLD [1].
• Here we provide evidence that inducible phosphorylation of CYLD is an important mechanism of its regulation [8].
• Interestingly, the CYLD phosphorylation requires IkappaB kinase gamma (IKKgamma) and can be induced by IKK catalytic subunits [8].
• We report here that inhibition of one of these enzymes, the familial cylindromatosis tumour suppressor gene (CYLD), having no known function, enhances activation of the transcription factor NF-kappaB [9].
• Inhibition of CYLD increases resistance to apoptosis, suggesting a mechanism through which loss of CYLD contributes to oncogenesis [9].

Anatomical context of CYLD

• Because TRIP is an inhibitor of nuclear factor (NF)-kappaB activation by tumor necrosis factor (TNF), the effect of CYLD on NF-kappaB activation was investigated in HeLa cells [1].
• CYLD encodes three cytoskeletal-associated-protein-glycine-conserved (CAP-GLY) domains, which are found in proteins that coordinate the attachment of organelles to microtubules [7].
• On the other hand, among the putative suppressor genes demonstrating copy number loss in both cell lines, the 9q region, ATM at 11q22.3, and CYLD at 16q12-13 have not been reported to show loss in conventional cervical cancer cell lines [10].
• Because of a cell-autonomous defect in T cell development, CYLD-deficient mice had substantially fewer mature CD4(+) and CD8(+) single-positive thymocytes and peripheral T cells [11].
• CYLD was downregulated or lost in all tumor cell lines investigated as compared with primary human colonic epithelial cells and hepatocytes, respectively [2].

Associations of CYLD with chemical compounds

• The two proteins bind to a region of CYLD that contains a Cys-box motif and the third cytoskeleton-associated protein-glycine conserved (CAP-Gly) domain [12].
• CYLD knockdown by RNA interference results in hyper-activation of JNK by diverse immune stimuli, including tumor necrosis factor-alpha, interleukin-1, lipopolysaccharide, and an agonistic anti-CD40 antibody [13].
• Phosphate entry into chloride-loaded human erythrocytes is inhibited by treatment of cells with the water-soluble carbodiimide 1-ethyl-3-(4-azonia-4,4-dimethylpentyl)carbodiimide (EAC) in the absence of added nucleophile [14].
• N-(4-Azido-2-nitrophenyl)-2-aminoethylsulfonate, a reversible noncompetitive inhibitor of anion transport did not protect against EAC inhibition of transport but prevented reversal of inhibition in saline medium [14].
• Chiral triazinylammonium chlorides formed in situ from CDMT and chiral tertiary amines are postulated as reactive intermediates involved in the process of enantioselective activation of N-protected amino acids [15].

Physical interactions of CYLD

• Recently, it was reported that CYLD directly interacts with NEMO/IKKgamma and TRAF2 in the NF-kappaB signaling pathway [12].

Enzymatic interactions of CYLD

• TRPA1 is a novel substrate for the de-ubiquitinating activity of CYLD, and this de-ubiquitination has the net effect of increasing the cellular pool of TRPA1 proteins [16].

Regulatory relationships of CYLD

• Under normal conditions, CYLD dominantly suppresses the ubiquitination of TRAF2 [8].
• The results established that CYLD down-regulates NF-kappaB activation by TNF-alpha [1].

Other interactions of CYLD

• Downregulation of CYLD by RNA-mediated interference augments both basal and CD40-mediated activation of NF-kappaB [17].
• In response to cellular stimuli, CYLD undergoes rapid and transient phosphorylation, which is required for signal-induced TRAF2 ubiquitination and activation of downstream signaling events [8].
• Here we report that CYLD, a tumour suppressor that is mutated in familial cylindromatosis, interacts with NEMO, the regulatory subunit of IKK [18].
• CYLD has deubiquitinating activity that is directed towards non-K48-linked polyubiquitin chains, and negatively modulates TRAF-mediated activation of IKK, strengthening the notion that ubiquitination is involved in IKK activation by TRAFs and suggesting that CYLD functions in this process [18].
• Here we show that CYLD is a deubiquitinating enzyme that negatively regulates activation of the transcription factor NF-kappaB by specific tumour-necrosis factor receptors (TNFRs) [17].

Analytical, diagnostic and therapeutic context of CYLD

• Further, quantitative PCR analysis revealed reduced CYLD mRNA expression in most tumor samples compared with non-tumorous tissue [2].
• By sequence analysis, we identified a recurrent mutation 2272C>T (R758X) of the CYLD gene in the affected individuals of this family, which was previously identified in other ethnic families with familial cylindromatosis [19].
• They have now started to investigate the use of CYLD inhibitors in clinical trials [20].
• A surface-marker assay combining immunofluorescence with anti-human immunoglobulin or anti-human brain serum (AHBS) and the formation of rosettes with untreated (E), antibody-sensitized (EA) and complement-coated (EAC) sheep erythrocytes was used to study mononuclear cell suspensions of human lymph nodes [21].

References