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CYLD inhibits IKK_complex. 30 / 31
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"CYLD and A20 function as deubiquitination enzymes to inhibit IKK by targeting RIP1 upstream of IKK, while CUEDC2 acts as an adaptor protein to keep IKK in an inactivated status by recruiting a phospha[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"These observations suggest that suppression of CYLD enhances the activity of the IKK kinase and the nuclear localization of NF-kappaB transcription factors."
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"Notch is capable of enhancing NF-kappaB activity by a Hes1 dependent mechanism (Hes1 mediated suppression of Cyld, a deubiquitinase that negatively regulates the IKK complex) 53 and Hes1 independent mechanisms (NICD induced expression of NF-kappaB, NICD enhanced IKKalpha activity, or NICD mediated NF-kappaB nuclear retention) XREF_BIBR - XREF_BIBR."
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"These include the deubiquitination enzymes CYLD and A20 that inhibit IKK, and the ubiquitin binding proteins NEMO and TAB2 which are the regulatory subunits of IKK and TAK1 kinase complexes, respectively."
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"Conversely, loss of the K63 specific deubiquitinase CYLD causes spontaneous activation of IKK and JNK as well as their upstream kinase Tak1."
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"However, despite its essential role in spontaneous activation of TAK1 in T cells, the loss of CYLD in Jurkat T cells did not appreciably prolong the IKK activation induced by TNFalpha."
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"In doing so, CYLD inhibits IKK activation by agents such as TNFalpha, IL-1beta and phorbol ester (PMA)."
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"In T cell acute lymphoblastic leukemia (T-ALL), CYLD expression is repressed by the Notch and Hes1 pathway to promote persistent IKK activation and cell survival [XREF_BIBR]."
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"Despite its essential role in suppressing the constitutive activity of IKKbeta in T cells, the loss of CYLD in Jurkat T cells did not appreciably prolong the IKK activation induced by TNF-alpha or mitogens."
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"Overexpression of CYLD inhibits IKK activation, whereas reducing CYLD expression has the opposite effect XREF_BIBR, XREF_BIBR, XREF_BIBR."
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"Further support to this model came from the discoveries by other laboratories that CYLD and A20 function as deubiquitination enzymes to inhibit IKK (reviewed by V. Dixit)."
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"CYLD inhibits IKK by cleaving K63 linked polyubiquitin chains on TRAF2, TRAF6 and NEMO XREF_BIBR, XREF_BIBR Interestingly, in patients with the cylindromas (a type of tumor), a mutation in the DUB domains of CYLD has been reported, suggesting its role of tumorgenesis 19."
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"Importantly, expression of wildtype CYLD, but not its catalytically inactive mutant, strongly inhibited Tax stimulated activation of IKK, supporting a role for Tax ubiquitination in the activation of IKK signaling."
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"CYLD deletion causes accumulation of constitutively active TAK1, and its downstream kinases JNK and IKK, which results in T cells that become hyper-responsive to TCR stimulation."
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"The loss of CYLD in both primary T cells and the Jurkat T cell line causes the constitutive activation of Tak1 as well as its downstream targets JNK and IKK."
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"Cyld -deficient mice have been generated by different groups, and these mice display a myriad of phenotypes that overall support the conclusion that CYLD inhibits IKK and NF-kappaB and contributes, at[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"The effect of CYLD was not specific to RIG-I, as CYLD also deubiquitinated and inhibited the signaling activities of TBK1 and IKKɛ."
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"CYLD inhibits IKK by cleaving K63-linked polyubiquitin chains on TRAF2, TRAF6 and NEMO xref , xref Interestingly, in patients with the cylindromas (a type of tumor), a mutation in the DUB domains of CYLD has been reported, suggesting its role of tumorgenesis xref ."
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"We further demonstrate that CYLD also negatively regulates IkappaB kinase, although this function of CYLD is seen in a receptor dependent manner."
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"CYLD inhibits Tax stimulated activation of IKK but not that of Tak1."
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"One of these DUBs is the cylindromatosis tumor suppressor protein, CYLD, which inhibits IKK activation by cleaving K63-linked poly-ubiquitin chains on several proteins, including TRAF2, TRAF6 and NEMO."
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"Hes1, which is downstream of Notch signalling, can inhibit the transcription of the deubiquitinase CYLD, which negatively regulates IKK [44]."
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"We also overexpressed in HEK293 cells the deubiquitinase CYLD, which can remove ubiquitin chains with linear as well as KLys-63 linkages (XREF_FIG D) and which inhibited full IKK activation by TNF-alpha (XREF_FIG E)."
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"CYLD negatively regulates the activation of IKK and JNK, and its expression is markedly upregulated under conditions of RANKL induced osteoclastogenesis [XREF_BIBR]."
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"In mature T cells, CYLD targets TAK1 for inactivation to downregulate IKK and NF-kappaB activation [XREF_BIBR]."
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"CYLD also negatively regulates the IKK related kinases, IKKepsilon and TBK1, by the same mechanisms."
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"The NF-kappaB signaling pathway is a key regulator of inflammatory responses and CYLD may negatively regulate IKK complex activation to inhibit the NF-kappaB signaling pathway via deubiquitinating IKKgamma."
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"These include IkappaBalpha re-synthesis with consequent export of RelA containing dimers to the nucleus, ubiquitin mediated RelA proteasomal degradation triggered by its phosphorylation by IKKalpha and implemented by SOCS1 and COMMD1 or PDLIM2 proteins, RelA displacement from DNA by PIAS proteins, and inactivation of the IKK complex or its upstream regulators by the A20 and CYLD deubiquitinating enzymes."
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"161 Cylindromatosis (CYLD) has been shown to inhibit NFkappaB activation 160 and more recent results indicate that this inhibition might be mediated via the ability of CYLD to hydrolyze unanchored polyubiquitin chains and thus inhibit TAK1 and IKK activation."
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"Furthermore, addition of viral OTU (vOTU) WT but not the mutant C40A, or CYLD WT but not the mutant C601A, also blocked IKK activation by Tax (XREF_FIG)."
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