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USP7 inhibits Ubiquitin. 11 / 11
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"Expert opinionSelective and reversible inhibitors of ubiquitin specific protease 7 : a patent evaluation (WO2013030218) Benedikt M KesslerUniversity of Oxford, Target Discovery Institute, Nuffield Department of Medicine, Oxford, UKThe invention described in this review (WO2013030218) relates to compounds based on the quinazolin-4-one scaffold, their process of preparation and applications to inhibit the ubiquitin specific protease 7 (USP7), a deubiquitinating enzyme (DUB), which is considered a potentially important new drug target for treating cancer and immunological disorders."
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"However, it is still possible that USP7 may antagonize the action of FBXL21 by cleaving the ubiquitin chain (s) formed by FBXL21."
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"As increased TAL1 oncogenic activity was also evident in the accelerated cell growth observed after CRISPR knock-out of half of the USP7 loci in T-ALL cell lines, we hypothesize that USP7 haploinsufficiency in T-ALL down-regulates the ability of this deubiquitylating enzyme to remove ubiquitin from E-proteins, leads to enhanced TAL1 heterodimer formation, which favors TAL1 mediated thymocyte transformation."
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"Ubiquitin ligase activity is therefore required for mRNA degradation and can be prevented either by removal of the RING (RINGless MEX-3C) or by overexpression of the USP7 DUB."
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"In parallel, results from ubiquitination assay indicated that ubiquitin aggregation on TAZ was profoundly induced by β-TRCP or reduced by USP7 (Fig. 5B, lane 2, 3)."
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"Importantly, these effects were independent of p53 status and could be rescued by the MG132 proteasome inhibitor (XREF_FIG), suggesting that USP7 prevents ubiquitin mediated degradation of TRIM27 by the proteasome."
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"Taken together, these data suggest that RNF4 is responsible for sustaining DNA replication and repairing damage that occurs in USP7 mutants.Bortezomib depletes the nuclear pool of ubiquitin and impairs K63-linked polyubiquitination of H2AX, a requirement for the recruitment of BRCA1 and RAD51 to DSBs [74], leading to the accumulation of unrepaired breaks [64]."
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"USP7 or USP11 depletion increased the amount of chromatin-bound Ub–PCNA particularly after UV treatment, but to a lesser extent than USP1 or ATAD5 depletion."
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"This result shows that USP7 reduces proteasome recognition and degradation by removing ubiquitin from HMGB1."
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"This class of allosteric inhibitors has been demonstrated to bind to the ' palm ' region of the USP7 catalytic domain thereby impeding ubiquitin binding (orange, XREF_FIG) [XREF_BIBR, XREF_BIBR]."
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"Although USP7, like all DUBS, deconjugates ubiquitin from several target proteins, inhibition of USP7 promotes the degradation of its primary cellular target, HDM2, resulting in net p53 stabilization and activation [30], [42], [43]."
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