IndraLab

Statements


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"However, the insufficient resolution and the absence of polyubiquitylated substrates in these studies preclude understanding of USP14-mediated proteasome regulation at the atomic level."

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"In a more targeted approach, an active-site ubiquitin probe (HA-Ub-VMS) has been used to demonstrate that USP14/UCHL5 inhibition by a small molecule (b-AP15) inhibits the 19S proteasome in a reconstituted biochemical assay."

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"The deubiquitinating enzyme ubiquitin specific peptidase 14 (USP14) has been shown to modulate both proteasome activity and autophagy."

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"Thus, USP14 creates a second kinetic checkpoint and drives the proteasome to choose between two alternative pathways of USP14-regulated conformational transitions—one that sterically impedes substrate commitment and the other that kinetically antagonizes RPN11 by outpacing the coupling of RPN11-directed deubiquitylation and substrate translocation, rather than directly inhibiting the DUB activity of RPN11."

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"This multi-checkpoint mechanism integrates catalytic and non-catalytic effects of USP14-mediated proteasome regulation into a comprehensively coordinated, elegantly timed process of substrate degradation."

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"In contrast, siRNA of either UCHL5 or USP14 alone did not affect proteasome composition but did increase the rate of proteasome activity, supporting previous studies."

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"Recently, a small chemical compound (IU1) capable of inhibiting USP14 deubiquitination was shown to enhance proteasome mediated degradation of some substrates, including several proteins associated with neural degenerative diseases [XREF_BIBR]."

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"The inhibition of USP14 and UCHL5 by WP1130 is expected to induce a functional block of proteasome function in cells, but this has not been tested.Eeyarestatin-1 (Eer1) ( Fig. 9 ) was identified in a [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"These data suggested that huaier extract induces proteasome mediated degradation of AR-FL and AR-V7 by downregulation USP14."

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"These results strongly suggest that the USP14 mediated proteasome activity regulation may be directly related to various human diseases including cancer."

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"Depletion of USP14 alone enhances proteasome activity, whereas co-depletion with UCHL5 inhibits the proteasome, indicating some cross-dependence for these DUBs during protein degradation."

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"UBL domain of Usp14 and other proteins stimulates proteasome activities and protein degradation in cells."

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"Hence, we speculated that Aur inhibited androgen receptor signaling by PKC pathway and promoted the degradation of androgen receptor result from USP14 and UCHL5 inhibition.Interestingly, inhibition of[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Usp14 and Ubp6 can enhance the ATPase activity of the proteasome and partially open the CP gate [52,56-58]."

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"Remarkably, Akt dependent phosphorylation of USP14 elevates the catalytic activity of proteasome associated USP14 beyond this level."

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"Most of ubiquitinated proteins were accumulated after proteasome inhibition caused by USP14 and UCHL5 inhibition."

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"The result showed that USP14 overexpression increasingly reduced IκBα protein level, however, this effect vanished in the presence of MG132 treatment ( Fig. 3 D), illustrating that USP14 accelerates p[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"A series of studies have demonstrated that Ubp6 and USP14 enhances the ATPase activity of proteasome and opens the 20S gate upon treatment with ubiquitin, ubiquitin protein conjugate or active site directed probes, such as ubiquitin aldehyde (Ubal) or ubiquitin vinyl sulfone (UbVS) (XREF_FIG A, right bottom panel) [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR]."

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"Structural dynamics insights from this study pinpoint the important local conformational landscape of USP14 by the phosphorylation event, which would be critical for understanding USP14-mediated proteasome regulation and designing future therapeutics."

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"Accordingly , the inhibition of USP14 could improve the proteasome degradation activity [ 14 ] ."

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"These USP14 specific aptamers effectively inhibited deubiquitinating activity and enhanced proteasome activity in vitro."

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"Hence, inhibition of Usp14 stimulates proteasome-dependent degradation of its substrates, and it can overall enhance protein degradation (Lee et al., 2010)."

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"Conversely, USP14 might also activate proteolysis by degrading ubiquitin chains on target proteins and thereby enhance gate opening of the 20S proteasome."

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"In addition to this, other strategies under investigation for enhancing the activity of proteasome functioning include inhibition of USP14 that inhibits processing of proteasome employing pyrazolone and inhibition of the deubiquitinating enzyme that causes proteolysis of the proteasome [249, 250]."

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"Loss of Ubp6 function, for example, increases aneuploidy tolerance in yeast, presumably due to an elevated proteasome capacity for turning over higher protein levels, and pharmacological inhibition of Usp14 in human cells has been shown to stimulate proteasome activity XREF_BIBR - XREF_BIBR."

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"The inhibition of UCHL5 and USP14 deubiquitinase activity by WP1130 is expected to block the function of the proteasome in tumor tissue cells, but this still needs to be tested (D'Arcy et al., 2015)."