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CYLD activates NFkappaB. 74 / 81
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"Although comparable CYLD mRNA levels were present in both tumor and normal tissue, direct binding of miR-182 to 3′UTR of CYLD activated NF-κB in tumor cells."
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"However, subsequent studies have indicated that although CYLD targets NF-kappaB signaling factors, its function may depend on the cell type and stimulating receptor [XREF_BIBR]."
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"These miR then directly target the tumor suppressor genes, phosphatase and tensin homolog (PTEN) and cylindomatosis (CYLD), thereby promote NF-kappaB activity which is required to maintain the transformed state [XREF_BIBR]."
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"Across all solid tumor types, frequent inactivating TRAF3 and CYLD alterations that are predicted to constitutively activate NF-kappaB pathways, while inhibiting innate immunity, occur only in HPV+ HNSCC."
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"Deubiquitinases A20 and Cezanne, but not CYLD, are induced by NF-kappaB to negatively regulate TAK1 and NF-kappaB activity by removing K63 polyubiquitin chains [XREF_BIBR]."
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"In addition, NF-kappaB deubiquitinases CYLD and A20, which negatively regulate canonical NF-kappaB signaling, can induce NF-kappaB downstream of the BCR in miR-17 ~ 92 overexpressing B cells, and thus, have also been proposed as targets of oncomiR-1, [XREF_BIBR]."
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"The inhibition of NF-kB activation by CYLD is mediated, at least in part, by the deubiquitination and inactivation of TRAF2 and, to a lesser extent, TRAF6 [ xref ]."
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"However, Treg development is not rescued in CARMA1/CYLD-double deficient mice, where the lack of the deubiquitinase CYLD activates NF-κB through TAK1/IKK."
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"Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling."
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"The inhibition of NF-kB activation by CYLD is mediated, at least in part, by the deubiquitination and inactivation of TRAF2 and, to a lesser extent, TRAF6 [XREF_BIBR]."
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"Conversely, Tax inactivates multiple DUBs that oppose NF-kappaB activation including A20 and CYLD [XREF_BIBR]."
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"Our study supported the involvement of six candidate genes in susceptibility to psoriasis : SCL12A8, which belongs to the solute carrier gene family; FLG and TGM5, which are involved in epidermal differentiation; CARD15 and CYLD, which modulate the transcription factor NF-kB; and IL1RN, which encodes an IL receptor antagonist."
19554025
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"These assumptions are strengthened by our observations which show that both inhibition of NF-kappaB activation by CYLD and association of CYLD with RIP are dependent on optineurin."
21408173
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"However, constitutive phosphorylation of CYLD by IKK inactivates CYLD in HTLV-1-induced leukemia to promote heightened NF-kappaB activation."
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"In support of this view, MALT1 proteolysis of the inhibitory deubiquitinases A20 and CYLD potentiates NF-kappaB and JNK, respectively [XREF_BIBR, XREF_BIBR], while cleavage of the RNase Regnase-1 prolongs mRNA stability of T cell effector genes [XREF_BIBR]."
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"71 The gene CYLD is mutated in familial cylindromatosis, an autosomal dominant disease characterized by benign tumors derived from cells of skin appendages 72 and thus it can be considered as a TS, CYLD inhibits tumor cell proliferation by blocking BCL-3-dependent NF-kappaB signaling."
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"XREF_BIBR, XREF_BIBR Activated IKEKE also regulates CYLD, 8 which is a deubiquitinase of several nuclear factor (NF)-kappaB regulators, including tumor necrosis factor receptor associated factor 2, 6 (TRAF2, TRAF6) and NEMO (IKK-gamma), to activate the canonical NF-kappaB pathway."
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"Both A20 and CYLD are direct transcriptional targets of NF-kappaB and, as such, are rapidly induced upon NF-kappaB activation, thereby providing essential feedback mechanisms promoting the cessation of the NF-kappaB response."
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"CYLD restricts inflammation by inhibiting NFkappaB activation [XREF_BIBR], yet it can induce innate immune responses by stabilizing STING, a cytosolic DNA sensor and a major regulator of type I interferon signaling, via its deubiquitination on K48 linked chains [XREF_BIBR]."
| PMC
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"Because the genes encoding these two proteins are regulated by NF-kappaB, this result further supported the conclusion that CYLD deficiency causes the constitutive activation of NF-kappaB."
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"If NEMO ubiquitinylation negatively regulates NF-kB signaling, then CYLD expression should enhance RIP2 's activation of NF-kB."
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"CYLD deficiency promotes the activation of NF-kappaB and induction of anti-apoptotic genes in germ cells."
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"Lack of CYLD in cells would elevate NF-kappaB activation, which likely contributes to tumor development."
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"The CYLD deficiency causes marked activation of NF-kappaB in germ cells, which is associated with heightened expression of anti-apoptotic genes, such as Bcl-2."
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"A recent study demonstrated that IKBKE but not IKKalpha and beta phosphorylates CYLD XREF_BIBR, which is a deubiquitinase of several NF-kappaB regulators, including TRAF2, TRAF6, and NEMO, to activate the NF-kappaB pathway XREF_BIBR - XREF_BIBR."
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"However, in other studies, CYLD deficiency did not affect peripheral B cell numbers, but increased NF-kappaB activation upon stimulation."
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"Mutations in TRAF3 or CYLD Activate NF-kappaB Signaling in HPV Positive HNSCC."
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"Optineurin is essential both for inhibition of TNFα-induced NF-κB activation by CYLD and its association with RIP."
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"On the other hand, mice that express overactive NF-kappaB or lack the negative regulator of NF-kappaB signaling CYLD, develop NKT cells but fail to mature and populate the lymphoid organs and peripheral tissues."
29312339
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"Numerous studies in vitro and in vivo have validated that CYLD mediates NF-kappaB activation by deubiquitinating TRAF2 , TRAF6 , and NEMO , making it an important regulator in the adaptive immune response ."
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"Of the 128 screened siRNA pools, 15 matched these criteria including those targeting the known negative regulators of NF-kappaB signalling CYLD and A20."
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"That is, inhibition of endogenous CYLD expression by CYLD siRNA in C33A cells (XREF_FIG) abrogated the hypoxia induced NF-kappaB activation associated with ectopic E6 expression (XREF_FIG)."
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"These assumptions are strengthened by our observations which show that both inhibition of NF-κB activation by CYLD and association of CYLD with RIP are dependent on optineurin."
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"Ablation of CYLD, NFKBIA, TRAF2, or TRAF3 induces hyperactivation of the canonical and/or noncanonical NF-kappaB pathways and subsequently diminishes CC-122-induced apoptosis in 5 of 6 DLBCL cell lines."
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"The inhibition of NF-kappaB activation by CYLD is mediated, at least in part, by the deubiquitination and inactivation of TRAF2 and, to a lesser extent, TRAF6."
18245814
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"However, Treg development is not rescued in CARMA1 and CYLD-double deficient mice, where the lack of the deubiquitinase CYLD activates NF-kappaB through TAK1 and IKK."
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"Because CYLD modulates the NF-kappaB pathway, a crucial mediator of inflammation, 15-18 these data suggest that CYLD may regulate vascular remodeling.Previous studies have suggested that the DUB activ[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Although CYLD suppression was shown to decrease the induction of NF-kappaB, its role in activating cell death with K. pneumoniae infection was not established."
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"Although comparable CYLD mRNA levels were present in both tumor and normal tissue, direct binding of miR-182 to 3 ' UTR of CYLD activated NF-kappaB in tumor cells."
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"Importantly, this effect is blocked by concurrent inhibition of CYLD, suggesting that miR-181b-1 regulates NF-kappaB through CYLD."
20797623
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"We show that CYLD deficiency causes constitutive NF-kappaB activation in thymocytes, which is associated with enhanced frequency of Treg cells."
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"The inhibition of NF-kappaB activation by CYLD is mediated, at least in part, by the deubiquitination and inactivation of TNFR associated factor 2 (TRAF2) and, to a lesser extent, TRAF6."
12917689
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"miR-181b (activated by STAT3), has recently been identified as involved in a positive feedback loop by inhibiting CYLD (negative regulator of NF-kappaB), which in turn causes increased NF-kappaB, that completes the loop by leading to STAT3 activation."
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"Further examination showed that phosphorylation of CYLD at S418 decreases its deubiquitinase activity and increases NF-kappaB activation."
19481526
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"Because gammaTE inhibits TAK1 phosphorylation (XREF_FIG) and overexpression of CYLD or A20 blocks NF-kappaB activation in cells and animals, we investigated whether gammaTE has any impact on these NF-kappaB negative regulators."
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"Since optineurin knockdown cells accumulate higher levels of ubiquitinated RIP and CYLD fails to abolish NF-kappaB activation, it is plausible that optineurin is required for deubiquitination of RIP by CYLD."
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"Both CYLD and TRAF2 phosphorylation thus increase ubiquitin-dependent NF-kB signaling."
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"Intriguingly, LEF1 depletion mediated CYLD upregulation was sufficient to negatively modulate NF-kappaB signaling pathway in MM cells."
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"In addition to activation via PI3K-Akt (described above), it has been proposed in T-ALL that the Notch gene Hes1 suppresses the expression of the tumor suppressor Cyld, an inhibitor of NF-kB, leading to NF-kB activation and enhanced T-ALL cell survival."
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"In the GCB subtype, CYLD and UBD which activate NF-kappaB were downregulated in CXCR4 + compared to CXCR4 - DLBCL patients."
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"Other transcripts that are up-regulated in the dorsal group have a role during signal transduction : APC negatively regulates Wnt signaling XREF_BIBR, MACF1 positively regulates Wnt signaling XREF_BIBR, CYLD and MAST2 positively regulates NF-kappaB pathway XREF_BIBR."
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"Although A20 and CYLD target the same set of NF-kappaB signaling factors, knockout mouse studies indicate nonredundant roles."
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"The tumor suppressor, CYLD, inhibits NF-kappaB activation in a deubiquitinase dependent manner, by removing K63 linked ubiquitin chains from a variety of signaling proteins, including TRAF2, TRAF6, and RIP1 in T cells and other immune cells XREF_BIBR."
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"It plays a role in numerous signalling pathways, for example it has been shown to phosphorylate CYLD, which in turn activates the NF-kappaB pathway via deubiquitination of several NF-kappaB regulator proteins."
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"Previous reports have demonstrated that Notch signal represses the expression of CYLD that negatively regulates NF-kappaB activation in macrophages XREF_BIBR."
27680285
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"In conclusion , the present study suggests that colon cancer may be inhibited through miR-181b downregulation to promote CYLD expression , which in turn attenuates NF-kappaB activity ."
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"CYLD deficiency promotes constitutive NF-kappaB activity in thymocytes and peripheral T cells, and is associated with enhanced T reg cell frequencies."
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"In line with this, it was also reported that hypoxia could promote an E6-dependent ubiquitylation and degradation of CYLD in HPV-infected cells, activating in turn the proinflammatory transcription factor NF-κB [ xref ]."
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"In contrast, when the NF-kappaB pathway is overactive, as in mice expressing the constitutively activated IkappaB kinase in hematopoietic cells or mice deficient in the negative regulator of NF-kappaB signalling CYLD, NKT cellsdevelop but these cells fail to mature and to populate the periphery 61."
29142275
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"These researchers found that the familial cylindromatosis tumour suppressor gene (CYLD), previously of unknown function, could enhance the activation of the transcription factor NF-kappaB, leading to increased resistance to apoptosis."
14585643
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"Inactivation of the CYLD deubiquitinase by HPV E6 mediates hypoxia induced NF-kappaB activation."
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"XREF_BIBR, XREF_BIBR Similarly, in a hepatocytespecific cylindromatosis deficient (CYLD Deltahep) mouse model, which typically has increased hepatocyte TAK1 and NF-kappaB activation, TAK1 deletion decreased HCC development."
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"Wild-type but not the mutant CYLD strongly inhibited NF-kappaB activation by CC2D1A, whereas RNA interference of CYLD enhanced NF-kappaB activation by CC2D1A (XREF_FIG C)."
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"As displayed in Figure xref F, Cyld −/− BMDM showed enhanced activation of NF-κB as indicated by increased phosporylation of p65 and IκB-α."
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"Importantly, the inhibition of NF-kappaB activity by an IKK inhibitor decreased p-STAT1 to equally low levels in both Lm infected WT and Cyld -/- BMDM indicating that the activation of STAT1 was dependent on the augmented Listeria induced NF-kappaB activation."
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"CYLD deficiency causes spontaneous IKK and NF-kappaB activation, associated with aberrant T cell activation and development of intestinal inflammation."
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"CYLD reduced IL-6, ROS production and killing of Lm in Listeria infected macrophages by impairing NF-kappaB activation."
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"As further validation, we assessed whether CYLD phosphorylation modulates NF-kappaB activity in the context of transformation."
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"63 Although how CYLD regulates Bcl3 expression is unclear, one possibility is suggested by the finding that the CYLD ex7/8 B cells display constitutive NF-kappaB activity and overexpress several NF-kappaB target genes, including RelB, NF-kappaB2, and TRAF2."
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"One study demonstrated that Cyld is targeted for degradation by HPV (human papillomavirus) E6 virus, to prolong NF-kappaB activation following hypoxia [XREF_BIBR]."
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"Biochemical studies of CYLD -/- peripheral T cells and B cells showed constitutively phosphorylated IKKbeta and activated NF-kappaB [XREF_BIBR, XREF_BIBR]."
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"As expected, CYLD knockdown by the two CYLD specific siRNAs significantly increased NF-kappaB reporter luciferase activity and the expression levels of the eight NF-kappaB target genes."
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"It is possible that the negative regulation of NF-kappaB mediated by CYLD contributes to its tumour suppression function given the increasingly recognized role for NF-kappaB in cancer advancement."
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"A major challenge in future studies is to show how ubiquitination of the CYLD targets regulates the NF-kappaB signaling."
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