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CYLD  -  cylindromatosis (turban tumor syndrome)

Homo sapiens

 
 
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Disease relevance of CYLD

 

High impact information on CYLD

 

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

  1. The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor. Regamey, A., Hohl, D., Liu, J.W., Roger, T., Kogerman, P., Toftgard, R., Huber, M. J. Exp. Med. (2003) [Pubmed]
  2. Reduced expression of CYLD in human colon and hepatocellular carcinomas. Hellerbrand, C., Bumes, E., Bataille, F., Dietmaier, W., Massoumi, R., Bosserhoff, A.K. Carcinogenesis (2007) [Pubmed]
  3. Carcinosarcoma arising in a patient with multiple cylindromas. De Francesco, V., Frattasio, A., Pillon, B., Stinco, G., Scott, C.A., Trotter, D., Patrone, P. The American Journal of dermatopathology. (2005) [Pubmed]
  4. 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. Ströbel, P., Zettl, A., Ren, Z., Starostik, P., Riedmiller, H., Störkel, S., Müller-Hermelink, H.K., Marx, A. Am. J. Surg. Pathol. (2002) [Pubmed]
  5. The tumor suppressor CYLD regulates entry into mitosis. Stegmeier, F., Sowa, M.E., Nalepa, G., Gygi, S.P., Harper, J.W., Elledge, S.J. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  6. Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. Massoumi, R., Chmielarska, K., Hennecke, K., Pfeifer, A., Fässler, R. Cell (2006) [Pubmed]
  7. Identification of the familial cylindromatosis tumour-suppressor gene. Bignell, G.R., Warren, W., Seal, S., Takahashi, M., Rapley, E., Barfoot, R., Green, H., Brown, C., Biggs, P.J., Lakhani, S.R., Jones, C., Hansen, J., Blair, E., Hofmann, B., Siebert, R., Turner, G., Evans, D.G., Schrander-Stumpel, C., Beemer, F.A., van Den Ouweland, A., Halley, D., Delpech, B., Cleveland, M.G., Leigh, I., Leisti, J., Rasmussen, S. Nat. Genet. (2000) [Pubmed]
  8. Regulation of the deubiquitinating enzyme CYLD by IkappaB kinase gamma-dependent phosphorylation. Reiley, W., Zhang, M., Wu, X., Granger, E., Sun, S.C. Mol. Cell. Biol. (2005) [Pubmed]
  9. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Brummelkamp, T.R., Nijman, S.M., Dirac, A.M., Bernards, R. Nature (2003) [Pubmed]
  10. Conventional and array-based comparative genomic hybridization analyses of novel cell lines harboring HPV18 from glassy cell carcinoma of the uterine cervix. Hirai, Y., Kawamata, Y., Takeshima, N., Furuta, R., Kitagawa, T., Kawaguchi, T., Hasumi, K., Sugai, S., Noda, T. Int. J. Oncol. (2004) [Pubmed]
  11. Regulation of T cell development by the deubiquitinating enzyme CYLD. Reiley, W.W., Zhang, M., Jin, W., Losiewicz, M., Donohue, K.B., Norbury, C.C., Sun, S.C. Nat. Immunol. (2006) [Pubmed]
  12. The CAP-Gly domain of CYLD associates with the proline-rich sequence in NEMO/IKKgamma. Saito, K., Kigawa, T., Koshiba, S., Sato, K., Matsuo, Y., Sakamoto, A., Takagi, T., Shirouzu, M., Yabuki, T., Nunokawa, E., Seki, E., Matsuda, T., Aoki, M., Miyata, Y., Hirakawa, N., Inoue, M., Terada, T., Nagase, T., Kikuno, R., Nakayama, M., Ohara, O., Tanaka, A., Yokoyama, S. Structure (Camb.) (2004) [Pubmed]
  13. Negative regulation of JNK signaling by the tumor suppressor CYLD. Reiley, W., Zhang, M., Sun, S.C. J. Biol. Chem. (2004) [Pubmed]
  14. Reversible and irreversible inhibition of phosphate transport in human erythrocytes by a membrane impermeant carbodiimide. Craik, J.D., Reithmeier, R.A. J. Biol. Chem. (1985) [Pubmed]
  15. A novel generation of coupling reagents. Enantiodifferentiating coupling reagents prepared in situ from 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and chiral tertiary amines. Kamiński, Z.J., Kolesińska, B., Kamińska, J.E., Góra, J. J. Org. Chem. (2001) [Pubmed]
  16. TRPA1 is a substrate for de-ubiquitination by the tumor suppressor CYLD. Stokes, A., Wakano, C., Koblan-Huberson, M., Adra, C.N., Fleig, A., Turner, H. Cell. Signal. (2006) [Pubmed]
  17. CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Trompouki, E., Hatzivassiliou, E., Tsichritzis, T., Farmer, H., Ashworth, A., Mosialos, G. Nature (2003) [Pubmed]
  18. The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Kovalenko, A., Chable-Bessia, C., Cantarella, G., Israël, A., Wallach, D., Courtois, G. Nature (2003) [Pubmed]
  19. Diverse phenotype of Brooke-Spiegler syndrome associated with a nonsense mutation in the CYLD tumor suppressor gene. Zhang, G., Huang, Y., Yan, K., Li, W., Fan, X., Liang, Y., Sun, L., Li, H., Zhang, S., Gao, M., Du, W., Yang, S., Liu, J., Zhang, X. Exp. Dermatol. (2006) [Pubmed]
  20. Small RNA: can RNA interference be exploited for therapy? Wall, N.R., Shi, Y. Lancet (2003) [Pubmed]
  21. Differentiation between benign and malignant human lymph nodes by means of immunologic markers. Brubaker, D.B., Whiteside, T.L. Cancer (1979) [Pubmed]
 
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