USP46 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 46
HGNC Gene Symbol
USP46
Identifiers
hgnc:20075 NCBIGene:64854 uniprot:P62068
Orthologs
mgi:1916977 rgd:1564808
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP46
Number of Papers
57 retrieved on 2022-05-22

DepMap Analysis

The Dependency Map (DepMap) is a genome-wide pooled CRISPR-Cas9 knockout proliferation screen conducted in more than 700 cancer cell lines spanning many different tumor lineages. Each cell line in the DepMap contains a unique barcode, and each gene knockout is assigned a “dependency score” on a per cell-line basis which quantifies the rate of CRISPR-Cas9 guide drop. It has been found that proteins with similar DepMap scores across cell lines, a phenomenon known as co-dependent genes, have closely related biological functions. This can include activity in the same or parallel pathways or membership in the same protein complex or the same pathway.

We identified the strongest seven co-dependent genes (“Symbol”) for DUBs and ran GO enrichment analysis. We used Biogrid, IntAct, and Pathway Commons PPIDs, and the NURSA protein-protein interaction databases (PPIDs) to determine whether co-dependent genes interact with one another. The “Evidence” column contains the PPIDs in which the interaction appears as well as whether there is support for the association by an INDRA statement. As another approach to identify potential interactors, we looked at proteomics data from the Broad Institute's Cancer Cell Line Encyclopedia (CCLE) for proteins whose expression across ~375 cell lines strongly correlated with the abundance of each DUB; it has previously been observed that proteins in the same complex are frequently significantly co-expressed. The correlations and associated p-values in the CCLE proteomics dataset are provided. And, we determined whether co-dependent genes yield similar transcriptomic signatures in the Broad Institute's Connectivity Map (CMap). A CMap score greater than 90 is considered significantly similar.

DepMap Correlations

Symbol Name DepMap Correlation Evidence CCLE Correlation CCLE Z-score CCLE p-value (adj) CCLE Significant CMAP Score CMAP Type

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP46using the terms from Gene Ontology and gene sets derived from the Gene Ontology Annotations database via MSigDB.

Using the biological processes and other Gene Ontology terms from well characterized DUBs as a positive control, several gene set enrichment analyses were considered. Threshold-less methods like GSEA had relatively poor results. Over-representation analysis with a threshold of of the top 7 highest absolute value Dependency Map correlations yielded the best results and is reported below.

GO Identifier GO Name GO Type p-value p-value (adj.) q-value

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out USP46 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
RPLP1 ribosomal protein lateral stalk subunit P1 9.19e-01 2.36e-10 5.20e-06
PNN pinin, desmosome associated protein 6.43e-01 1.56e-06 1.72e-02
RBM47 RNA binding motif protein 47 9.62e-01 6.78e-06 3.74e-02
RPL7A ribosomal protein L7a 7.06e-01 5.68e-06 3.74e-02
HLTF helicase like transcription factor 6.88e-01 1.02e-05 4.11e-02
RPS4XP11 ribosomal protein S4X pseudogene 11 9.68e-01 1.21e-05 4.11e-02

Gene Set Enrichment Analysis

There were too few differentially expressed genes to run a meaningful GSEA.

Literature Mining

INDRA was used to automatically assemble known mechanisms related to USP46 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
USP46 deubiquitinates GLR1.1. 5 / 5
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These findings suggest that USP-46 functions to deubiquitinate GLR-1 and to protect the receptor from degradation.

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These data support a model in which USP-46 promotes GLR-1 abundance at synapses by deubiquitinating GLR-1 and preventing its degradation in the lysosome.

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The abundance of GLR-1 (4KR), a mutant receptor which can not be ubiquitinated, is unaffected in usp-46 loss-of-function mutants leading to a model where USP-46 deubiquitinates GLR-1 to regulate its abundance.

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Second, we tested whether the amount of ubiquitinated GLR-1 is increased in usp-46 mutant animals, as would be expected if USP-46 deubiquitinates GLR-1.

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These data demonstrate that USP-46 promotes the deubiquitination of GLR-1, which in turn increases the abundance of GLR-1 in the VNC.
USP46 deubiquitinates Histone_H2B. 5 / 5
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Both USP12 and USP46 deubiquitinate histone H2A and H2B, affecting Xenopus development (Joo et al., 2011), and, unlike USP1, these smaller USPs can simultaneously bind WDR20 in addition to WDR48 (Joo [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Usp12 and Usp46 deubiquitinate both H2A and H2B and Uaf-1 is required for this reaction [XREF_BIBR].

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Joo et al. demonstrated that USP46 and USP12 containing fractions from HeLa cells can deubiquitinate histones H2A and H2B to control cell fate and gastrulation during Xenopus development [XREF_BIBR].

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USP12 and USP46 prefer nucleosomal substrates and deubiquitinate both histone H2A and H2B in vitro and in vivo.

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It has also been reported that USP12 and USP46 deubiquitinate histone H2A and H2B thereby playing a role in Xenopus development.
USP46 deubiquitinates GRIA. 5 / 5
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Endogenous USP46 suppresses AMPAR ubiquitination in neurons.

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We found that USP46 suppressed AMPAR ubiquitination leading to an increase in receptor protein amount as well as in receptor synaptic localization.

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Together, these data reveal a conserved mechanism where USP46 deubiquitinates AMPARs at synapses to protect them from degradation and promote their recycling to the cell surface to affect synapse function.

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Given the same type of deubiquitinating enzyme (USP46) is able to deubiquitinate AMPA receptors, and knockdown of USP46 elevated AMPA receptor ubiquitination and reduced AMPA receptor expression in hi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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USP46 over-expression leads to a reduction in AMPAR ubiquitination, whereas knockdown of USP46 by either siRNAs or shRNAs causes a significant increase in AMPAR ubiquitination.
USP46 deubiquitinates GRIA1. 4 / 4
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Mammalian USP46 can deubiquitinate both GluA1 and GluA2 subunits and protect AMPARs from degradation (Huo et al., 2015).

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Mammalian USP46 can deubiquitinate both GluA1 and GluA2 subunits and protect AMPARs from degradation.

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This Editorial Highlight discusses the relevance of a study published in the current issue of Journal of Neurochemistry, in which the authors Huo and collaborators now identified ubiquitin-specific peptidase 46 (USP46) as a specific AMPAR deubiquitinase.

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We observed that USP46 is able to deubiquitinate not only GluA1 but also GluA2, indicating a relative stringency in contrast to the distinct E3 ligases that are employed for GluA1 and GluA2.
USP46 deubiquitinates GRIA2. 3 / 3
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Mammalian USP46 can deubiquitinate both GluA1 and GluA2 subunits and protect AMPARs from degradation.

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Mammalian USP46 can deubiquitinate both GluA1 and GluA2 subunits and protect AMPARs from degradation (Huo et al., 2015).

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We observed that USP46 is able to deubiquitinate not only GluA1 but also GluA2, indicating a relative stringency in contrast to the distinct E3 ligases that are employed for GluA1 and GluA2.
USP46 deubiquitinates AR. 2 / 2
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Here we report that the novel small molecule anti-androgen, galeterone targets USP12 and USP46, two highly homologous deubiquitinating enzymes that control the AR-AKT-MDM2-P53 signalling pathway.

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Furthermore, overexpressed USP46 was able to deubiquitinate AR, similarly to our previous observations for USP12 [XREF_BIBR].
USP46 deubiquitinates Histone-H2A. 2 / 2
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Joo et al. demonstrated that USP46 and USP12 containing fractions from HeLa cells can deubiquitinate histones H2A and H2B to control cell fate and gastrulation during Xenopus development [XREF_BIBR].

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Several DUBs have been implicated in histone deubiquitination, including USP3, USP12, USP22, and USP46, which deubiquitinate both histones H2A and histones H2B [XREF_BIBR].
USP46 deubiquitinates GRIA on K48. 1 / 1
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In contrast, Huo et al. (2015) showed that USP46 preferentially deubiquitinates AMPARs with Lys63- but not Lys48-linked chains in HEK293 cells, suggesting that USP46 chain specificity is controlled by other factors in vivo.
Modified USP46 leads to the deubiquitination of PHLPP1. 1 / 1
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Overexpression of WT USP46 significantly decreased the amount of ubiquitination of PHLPP1 both basally and after MG-132 treatment, while the catalytically inactive mutant USP46 had no effect (XREF_FIG).
USP46 deubiquitinates GAD1. 1 / 1
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No evidence text available
USP46 deubiquitinates H2AC20. 1 / 1
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Regulation of histone H2A and H2B deubiquitination and Xenopus development by USP12 and USP46.

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It will be important in the future to test if USP46 functions in GABA neurons and whether it directly deubiquitinates components of the GABA system.WDR proteins are involved in protein-protein interactions that mediate diverse cellular processes.
USP46 deubiquitinates WDR48. 1 / 1
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Usp12 and Usp46 deubiquitinate both H2A and H2B and Uaf-1 is required for this reaction [XREF_BIBR].
USP46 deubiquitinates H2BC21. 1 / 1
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Regulation of histone H2A and H2B deubiquitination and Xenopus development by USP12 and USP46.
USP46 deubiquitinates USP46. 1 / 1
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Given the same type of deubiquitinating enzyme (USP46) is able to deubiquitinate AMPA receptors, and knockdown of USP46 elevated AMPA receptor ubiquitination and reduced AMPA receptor expression in hi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP46 deubiquitinates PHLPP1. 1 / 1
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ubibrowser
SP1 [137] and USP46 [138] are other DUBs known to deubiquitinate PHLPP1

Other Statements

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
WDR48 affects USP46
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WDR48 activates USP46.
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WDR48 activates USP46. 10 / 21
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WDR48 stimulates the activity of three DUBs, USP12, USP46 and USP1, a DUB which regulates the Fanconi anemia DNA damage pathway.

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Although mammalian USP46 and USP12 DUB activity can be stimulated by two proteins UAF-1 and WDR20, the C. elegans homologs of these genes have not yet been identified.

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The WD-repeat protein WDR48 (USP1 associated factor UAF-1) stimulates activity of ubiquitin specific proteases USP1, USP12, and USP46.

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WDR48 stimulates the activity of three DUBs, USP12, USP46 and USP1, a DUB which regulates the Fanconi anemia DNA damage pathway (Cohn et al., 2007 (Cohn et al., , 2009 Faesen et al., 2011) .

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We found that USP-46 is ubiquitinated and that expression of WDR-48 reduces the levels of ubiquitin-USP-46 conjugates and increases the half-life of USP-46.

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Therefore, this suggests that for some USPs the KG FP reagent may be a better substrate, and provide more relevant kinetic parameters.This study confirmed that the modulator UAF1 activates USP1, USP12[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Interestingly, the Caenorhabditis elegans homologs of WDR20 and WDR48 (also known as UAF1) can bind to and activate USP46.

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For example, USP1, USP12, and USP46 are activated by the WD40-repeat containing UAF1, and USP7 is activated by GMPS (Cohn et al., 2007, 2009; Faesen et al., 2011; van der Knaap et al., 2005).

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Together, UAF1 and WDR20 are able to synergistically stimulate the enzymatic activities of USP12 and USP46 to a peak level.

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However, a structural comparison of the enzyme in these two post-reaction forms revealed few conformational differences, leaving the mechanism of USP46 activation by UAF1 elusive.
WDR48 bound to WDR20 activates USP46. 1 / 1
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We and others previously showed that the WD40-repeat proteins WDR-48 and WDR-20 bind to and stimulate the catalytic activity of USP-46.
WDR48 deubiquitinates USP46.
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WDR48 deubiquitinates USP46. 1 / 1
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The E1 protein from anogenital HPV types interacts with the UAF1 associated deubiquitinating enzymes USP1, USP12, and USP46 to stimulate replication of the viral genome.
USP46 affects GLR1.1
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USP46 activates GLR1.1.
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USP46 activates GLR1.1. 6 / 6
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Furthermore, the co-localization of mCherry : : USP-46 and the endosomal marker Venus : : RAB-5 in the cell body and VNC (XREF_SUPPLEMENTARY) support a model in which USP-46 functions at an endosomal compartment to prevent the targeting of GLR-1 for degradation.

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Taken together with our previous data, these results suggest that USP-46 prevents the degradation of GLR-1 and promotes its surface expression in the VNC.

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Together with data showing that USP-46 partially colocalizes with endosomes, Kowalski et al. (2011) proposed a model where USP-46 acts at endosomes to promote GLR-1 stability and recycling to the cell surface.

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These data suggest a model whereby USP-46 promotes the abundance of GLR-1 at synapses by acting in a pre-MVB compartment (i.e. endosome) to deubiquitinate GLR-1 and thus prevent its lysosomal degradation (XREF_FIG).

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This result suggests that the deubiquitinating activity of USP-46 is required in glr-1-expressing interneurons to promote GLR-1 abundance.

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Several lines of evidence indicate that USP-46 negatively regulates GLR-1 degradation by deubiquitinating the receptor.
Mutated USP46 activates ubiquitinated GLR1.1. 1 / 1
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Conversely, mutant USP46 increases ubiquitinated GLR-1.
USP46 increases the amount of GLR1.1.
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USP46 increases the amount of GLR1.1. 1 / 1
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Usp-46 loss-of-function mutants exhibit increased levels of ubiquitinated GLR-1 and decreased levels of GLR-1 at synapses (Kowalski et al., 2011).
USP46 bound to WDR48 increases the amount of GLR1.1. 1 / 1
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Mechanistically, USP46 can bind with WD40-repeat (WDR) proteins WDR-20 and WDR-48 to stimulate USP46 catalytic activity and increase GLR-1 levels.
USP46 bound to WDR20 increases the amount of GLR1.1. 1 / 1
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Mechanistically, USP46 can bind with WD40-repeat (WDR) proteins WDR-20 and WDR-48 to stimulate USP46 catalytic activity and increase GLR-1 levels.
USP46 decreases the amount of GLR1.1.
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USP46 decreases the amount of GLR1.1. 1 / 1
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Usp-46 loss-of-function mutants exhibit increased levels of ubiquitinated GLR-1 and decreased levels of GLR-1 at synapses (Kowalski et al., 2011) .
USP46 decreases the amount of ubiquitinated GLR1.1. 1 / 1
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Taken together, these data indicate that USP-46 negatively regulates the amount of ubiquitinated GLR-1 in vivo.

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In functional experiments, overexpression of USP46 impaired proliferation and metastasis of HCC cells, whereas knockdown of USP46 enhanced cell proliferation and invasiveness in vitro and in vivo.

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USP46 Inhibits Cell Proliferation in Lung Cancer through PHLPP1/AKT Pathway.

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To determine if PHLPP and USP46 function together to negatively regulate cell proliferation, increasing amount of PHLPP1 plasmids was transfected into HCT116 cells alone or in combination with USP46.

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Furthermore, we found that USP46 suppresses HCC cell proliferation and metastasis by inhibiting YAP1.

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USP46 is downregulated in lung cancer and suppresses the proliferation of lung cancer cells by inhibiting the PHLPP1 and AKT pathway.

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In functional experiments , overexpression of USP46 impaired proliferation and metastasis of HCC cells , whereas knockdown of USP46 enhanced cell proliferation and invasiveness in vitro and in vivo .

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USP46 Inhibits Cell Proliferation in Lung Cancer through PHLPP1 and AKT Pathway.

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Collectively, our results indicated that miR-27a targets USP46 to promote EC cell proliferation and migration, suggesting an oncogene role of miR-27a in EC.

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AKT inhibition slows the proliferation of lung cancer cells that have been downregulated by USP46 and exposed to radiation.

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Ectopic expression of YAP1 rescued the inhibition of cell proliferation and metastasis caused by USP46 overexpression.
WDR20 affects USP46
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WDR20 activates USP46. 7 / 7
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Together, UAF1 and WDR20 are able to synergistically stimulate the enzymatic activities of USP12 and USP46 to a peak level.

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Both WDR48 and WDR20 stimulate USP12 and USP46 catalytic activity (k cat) without increasing substrate binding affinity, suggesting that the WDR proteins may affect DUB activity via a novel structural mechanism.

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Interestingly, the Caenorhabditis elegans homologs of WDR20 and WDR48 (also known as UAF1) can bind to and activate USP46.

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We found that increased expression of WDR-48, but not WDR-20, promotes USP-46 abundance in mammalian cells in culture and in C. elegans neurons in vivo Inhibition of the proteasome increased USP-46 abundance, and this effect was non additive with increased WDR-48 expression.

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USP12 and USP46, but not USP1, can be independently activated by another WD40-repeat-containing protein, WDR20 ().

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Although mammalian USP46 and USP12 DUB activity can be stimulated by two proteins UAF-1 and WDR20, the C. elegans homologs of these genes have not yet been identified.

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USP12 and USP46, but not USP1, can be independently activated by another WD40-repeat-containing protein, WDR20 (Burska et al., 2013; Dahlberg and Juo, 2014; Kee et al., 2010; McClurg et al., 2014) .
WDR20 bound to WDR48 activates USP46. 2 / 2
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Indeed, it has been demonstrated that the binding of WDR20 and WDR48 synergistically activates USP46 39.

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We found that the WD40-repeat proteins WDR-20 and WDR-48 bind and stimulate the catalytic activity of USP-46.
USP46 affects PHLPP1
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USP46 activates PHLPP1.
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USP46 activates PHLPP1. 6 / 6
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USP46 potentiates the tumor suppressor function of PHLPP1 in vivo.

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If USP46 enhances the stability of PHLPP1, then human tumors with downregulation of PHLPP1 protein might also have decreased expression of USP46.

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Functionally, USP46 mediated stabilization of PHLPP and the subsequent inhibition of Akt result in a decrease in cell proliferation and tumorigenesis of colon cancer cells in vivo.

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More importantly, co-expression of USP46 markedly enhanced the ability of PHLPP1 to suppress tumor formation (XREF_FIG).

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USP46 enhances PHLPP mediated negative regulation of Akt in cells.

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Furthermore, knockdown of USP46 attenuated the ability of PHLPP1 to dephosphorylate Akt and to inhibit cell proliferation (XREF_FIG).
USP46 increases the amount of PHLPP1.
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Modified USP46 increases the amount of PHLPP1. 1 / 1
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When a low concentration of PHLPP1 plasmid was transfected into cells alone, the level of PHLPP1 was not sufficient to significantly reduce the rate of cell proliferation, whereas co-expression of USP46 allowed the expression of PHLPP1 to surpass the threshold needed to induce the significant effect (XREF_FIG).
USP46 increases the amount of PHLPP1. 1 / 1
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To determine if the interaction of PHLPP and USP46 is required for USP46 mediated increase of PHLPP expression, the full-length PHLPP1 or the USP46 binding deficient Delta1139 mutant was co-expressed with USP46.
USP46 decreases the amount of PHLPP1.
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USP46 decreases the amount of PHLPP1. 1 / 1
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By stabilizing the expression of PHLPP, USP46 negatively regulates Akt activity in cells and in vivo.
USP46 affects GRIA1
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USP46 decreases the amount of GRIA1.
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USP46 decreases the amount of GRIA1. 2 / 2
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Knock-down of USP46, but not USP12, results in increased levels of ubiquitinated GluA1, decreased surface and total levels of GluA1, and reduced mEPSC amplitudes, consistent with a role for USP46 in deubiquitinating mammalian AMPARs (Huo et al., 2015).

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Knock-down of USP46, but not USP12, results in increased levels of ubiquitinated GluA1, decreased surface and total levels of GluA1, and reduced mEPSC amplitudes, consistent with a role for USP46 in deubiquitinating mammalian AMPARs.
Modified USP46 decreases the amount of GRIA1. 1 / 1
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In infected cortical neurons, over-expression of USP46 significantly reduced the ubiquitination level of GluA1, whereas over-expression of USP12 showed no effect (XREF_FIG), again indicating the specificity of USP46 toward GluA1.
USP46 inhibits GRIA1.
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USP46 inhibits GRIA1. 2 / 2
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We showed that in HEK cells USP46 over-expression negatively regulates the turnover rate of GluA1 and thus stabilizes GluA1 from degradation.

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Internalized GluA1 puncta density was also significantly reduced by USP46 over-expression (XREF_FIG) (Control : 6.42 +/- 0.40 puncta per 10 mum, n = 12 neurons; USP46 : 4.73 +/- 0.61 puncta per 10 mum, n = 12 neurons, p = 0.03).
USP46 activates GRIA1.
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USP46 activates GRIA1. 2 / 2
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We found that the surface GluA1 was significantly enhanced by USP46 over-expression.

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Recently, invivo and invitro studies demonstrated that the DUB USP46 also targets GluA1, regulating AMPAR surface expression, endocytosis, and the strength of synaptic transmission (Huo etal.
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Furthermore, we found that USP46 suppresses HCC cell proliferation and metastasis by inhibiting YAP1.

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Furthermore , we found that USP46 suppresses HCC cell proliferation and metastasis by inhibiting YAP1 .
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Moreover, USP46 enhances the migration and invasion of ESCC cells by mediating the EMT process in vitro, and promotes lymph nodes and lung metastasis of ESCC in vivo.

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Ectopic expression of YAP1 rescued the inhibition of cell proliferation and metastasis caused by USP46 overexpression.
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Valproic acid decreases the amount of USP46. 3 / 3
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ctd
No evidence text available

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No evidence text available

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No evidence text available
USP46 affects AKT
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USP46 inhibits AKT. 3 / 3
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Here, we show that USP46 and PHLPP function together to suppress Akt signaling in a mutually dependent manner.

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Functionally, USP46 mediated stabilization of PHLPP and the subsequent inhibition of Akt result in a decrease in cell proliferation and tumorigenesis of colon cancer cells in vivo.

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USP46 activates the Bcl-2 and caspase-3 apoptotic signaling pathway and inactivates AKT activity.
| 3
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Furthermore, the overexpression of PUM2 in SKOV3 and DDP cells partially recovered the suppressive effect over proliferation and the increased levels of apoptosis induced by the overexpression of USP46.

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In SKOV3 and DDP cells, the upregulation of USP46 expression levels notably suppressed cell viability and increased cell apoptosis.
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The downregulation of USP46 expression levels in SKOV3 cells significantly inhibited cell apoptosis and increased cell viability.
USP46 affects YAP1
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USP46 inhibits YAP1.
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USP46 inhibits YAP1. 2 / 2
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Mechanistically , USP46 promotes the degradation of YAP1 by increasing expression of MST1 , and the increase in MST1 protein antagonizes YAP1 to suppress HCC progression .

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Mechanistically, USP46 promotes the degradation of YAP1 by increasing expression of MST1, and the increase in MST1 protein antagonizes YAP1 to suppress HCC progression.
USP46 activates YAP1.
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USP46 activates YAP1. 1 / 1
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Furthermore, we found that USP46 suppresses HCC cell proliferation and metastasis by inhibiting YAP1.
| 1 1

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In functional experiments, overexpression of USP46 impaired proliferation and metastasis of HCC cells, whereas knockdown of USP46 enhanced cell proliferation and invasiveness in vitro and in vivo.

eidos
In functional experiments , overexpression of USP46 impaired proliferation and metastasis of HCC cells , whereas knockdown of USP46 enhanced cell proliferation and invasiveness in vitro and in vivo .
| 1

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Moreover, USP46 enhances the migration and invasion of ESCC cells by mediating the EMT process in vitro, and promotes lymph nodes and lung metastasis of ESCC in vivo.
| 1 2
USP46 inhibits Cell Survival.
| 1 1
| 1 1

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In SKOV3 / DDP cells , the upregulation of USP46 expression levels notably suppressed cell viability and increased cell apoptosis .

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In SKOV3 and DDP cells, the upregulation of USP46 expression levels notably suppressed cell viability and increased cell apoptosis.
USP46 activates Cell Survival.
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The downregulation of USP46 expression levels in SKOV3 cells significantly inhibited cell apoptosis and increased cell viability.
USP46 affects GRIA
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USP46 inhibits GRIA.
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USP46 inhibits GRIA. 1 / 1
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USP46 over-expression suppresses AMPAR internalization.
USP46 decreases the amount of GRIA.
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USP46 decreases the amount of GRIA. 1 / 1
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Given the same type of deubiquitinating enzyme (USP46) is able to deubiquitinate AMPA receptors, and knockdown of USP46 elevated AMPA receptor ubiquitination and reduced AMPA receptor expression in hi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP46 activates GRIA.
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USP46 activates GRIA. 1 / 1
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These functions of CYLD were implied in a study on another K63-DUB, USP46, which can cleave K63-linked ubiquitination chains from AMPARs and modulate AMPAR internalization and turnover in cultured rat cortical and hippocampal neurons; in this way, USP46 is thought to regulate AMPAR-mediated excitatory synaptic transmission (Huo et al., 2015).
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USP46 affects CASP3
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USP46 increases the amount of CASP3.
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USP46 increases the amount of CASP3. 1 / 1
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The present experimental results demonstrated that the knockdown of USP46 upregulated Bcl-2 expression levels and downregulated the expression levels of Bax, caspase-3 and caspase-9.
USP46 decreases the amount of CASP3.
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USP46 decreases the amount of CASP3. 1 / 1
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The present experimental results demonstrated that the knockdown of USP46 upregulated Bcl-2 expression levels and downregulated the expression levels of Bax, caspase-3 and caspase-9.
USP46 activates CASP3.
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USP46 activates CASP3. 1 / 1
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USP46 activates the Bcl-2 and caspase-3 apoptotic signaling pathway and inactivates AKT activity.
USP12 affects USP46
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USP12 activates USP46.
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USP12 activates USP46. 1 / 1
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Identification of Usp12 as a modifier of HD suggested that Usp12 could rescue neurodegeneration in related disorders, such as amyotrophic lateral sclerosis (ALS) and Parkinson 's disease (PD) that are characterized by proteotoxic stress.
USP12 bound to WDR48 activates USP46. 1 / 1
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In C. elegans, USP46 and USP12 both bind to USP1 associated factor 1 (UAF1 and WDR48) and the binding dramatically enhances the activity of USP12 and USP46.
USP12 inhibits USP46.
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USP12 inhibits USP46. 1 / 1
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We propose a mechanism by which Usp12 suppresses HD related neurodegeneration via induction of autophagy.
Propeller affects USP46
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In this in vitro setting, a construct consisting of only the WDR48 beta propeller (27-359) was able to stimulate USP46 almost as well as the full-length WT WDR48 construct, again corroborating the imp[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Given the distinct binding mode elucidated here, it is less straightforward to reconcile this structure with direct active-site modulation, yet we propose a mechanism centered on WDR48 dependent USP s[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
Muscimol affects USP46
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Muscimol inhibits mutated USP46. 2 / 2
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The muscimol induced current in the hippocampal CA1 pyramidal neurons and hippocampal expression of the 67-kDa isoform of glutamic acid decarboxylase significantly decreased in the Usp46 mutant mice compared to control mice.

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The muscimol induced current in the hippocampal CA1 pyramidal neurons and hippocampal expression of the 67-kDa isoform of glutamic acid decarboxylase were significantly decreased in the Usp46 mutant mice compared to control mice.
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Hsa-miR-873-5p decreases the amount of USP46. 2 / 2
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biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available
2 |
Hsa-miR-6893-3p decreases the amount of USP46. 2 / 2
2 |

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available
2 |
Hsa-miR-6765-3p decreases the amount of USP46. 2 / 2
2 |

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available
2 |
Hsa-miR-5585-5p decreases the amount of USP46. 2 / 2
2 |

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available
2 |
Hsa-miR-548ax decreases the amount of USP46. 2 / 2
2 |

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available
2 |
Hsa-miR-548ao-5p decreases the amount of USP46. 2 / 2
2 |

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available
2 |
Hsa-miR-4797-5p decreases the amount of USP46. 2 / 2
2 |

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available
2 |
Hsa-miR-4722-5p decreases the amount of USP46. 2 / 2
2 |

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available
2 |
Hsa-miR-370-3p decreases the amount of USP46. 2 / 2
2 |

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available
2 |
Hsa-miR-3622b-3p decreases the amount of USP46. 2 / 2
2 |

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available
2 |
Hsa-miR-3622a-3p decreases the amount of USP46. 2 / 2
2 |

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available
2 |
Hsa-miR-1286 decreases the amount of USP46. 2 / 2
2 |

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available
2 |
Hsa-miR-1205 decreases the amount of USP46. 2 / 2
2 |

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available
Bisphenol A affects USP46
2 |
Bisphenol A increases the amount of USP46. 2 / 2
2 |

ctd
No evidence text available

ctd
No evidence text available
USP46 affects Ubiquitin
| 2
| 2

reach
Initially, we hypothesized that mHTT was a substrate of Usp12 deubiquitinating activity, which could be a potential mechanism for regulating stability, localization, or other ubiquitin related signaling activity of ubiquitin conjugated mHTT.

reach
For example, in contrast to the USP46 BL1 residue F258, which supports the tail of Ub, the corresponding USP12 residue F262 is pushed into the catalytic cleft and would collide with the substrate.Using ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) as a substrate, we have previously shown that UAF1 activates USP1 mainly by increasing its catalytic turnover (k cat ), instead of its affinity toward the substrate (K M ) (Cohn et al., 2007) .
TCF3 affects USP46
2 |
TCF3 decreases the amount of USP46. 2 / 2
2 |

biopax:msigdb
No evidence text available

biopax:msigdb
No evidence text available
SPI1 affects USP46
2 |
SPI1 decreases the amount of USP46. 2 / 2
2 |

biopax:msigdb
No evidence text available

biopax:msigdb
No evidence text available
GLR1.1 affects USP46
| 2
GLR1.1 activates USP46. 2 / 2
| 2

reach
To further test whether USP-46 regulation of reversal frequencies is mediated by GLR-1, we examined if usp-46 mutation could suppress the effects of a dominant-active version of GLR-1 (GLR-1 (A/T)), on locomotion behavior.

reach
First, we tested whether USP-46 could interact with GLR-1, as might be expected if GLR-1 were a deubiquitination target of USP-46.

reach
Therefore, in the present study, we examined whether the immobility time is influenced by drugs affecting the action mediated by GABA A receptor using both 3-bp deleted (the Usp46 mutant) and null Usp46 (Usp46 KO) mice.
| 1

reach
Therefore, in the present study, we examined whether the immobility time is influenced by drugs affecting the action mediated by GABA A receptor using both 3-bp deleted (the Usp46 mutant) and null Usp46 (Usp46 KO) mice.
USP46 affects USP46
| 2
USP46 inhibits USP46.
| 1
USP46 inhibits USP46. 1 / 1
| 1

reach
In addition, the expression of USP46 was significantly decreased in 60% of colorectal cancer samples (P < 0.01) indicating a potential tumor suppressor role of USP46.
USP46 activates USP46.
| 1
USP46 bound to WDR48 activates USP46. 1 / 1
| 1

reach
In C. elegans, USP46 and USP12 both bind to USP1 associated factor 1 (UAF1 and WDR48) and the binding dramatically enhances the activity of USP12 and USP46.
USP46 affects CASP9
| 2
USP46 increases the amount of CASP9.
| 1
USP46 increases the amount of CASP9. 1 / 1
| 1

reach
The present experimental results demonstrated that the knockdown of USP46 upregulated Bcl-2 expression levels and downregulated the expression levels of Bax, caspase-3 and caspase-9.
USP46 decreases the amount of CASP9.
| 1
USP46 decreases the amount of CASP9. 1 / 1
| 1

reach
The present experimental results demonstrated that the knockdown of USP46 upregulated Bcl-2 expression levels and downregulated the expression levels of Bax, caspase-3 and caspase-9.
USP46 affects BCL2
| 2
USP46 decreases the amount of BCL2.
| 1
USP46 decreases the amount of BCL2. 1 / 1
| 1

reach
The present experimental results demonstrated that the knockdown of USP46 upregulated Bcl-2 expression levels and downregulated the expression levels of Bax, caspase-3 and caspase-9.
USP46 activates BCL2.
| 1
USP46 activates BCL2. 1 / 1
| 1

reach
USP46 activates the Bcl-2 and caspase-3 apoptotic signaling pathway and inactivates AKT activity.
USP46 affects BAX
| 2
USP46 increases the amount of BAX.
| 1
USP46 increases the amount of BAX. 1 / 1
| 1

reach
The present experimental results demonstrated that the knockdown of USP46 upregulated Bcl-2 expression levels and downregulated the expression levels of Bax, caspase-3 and caspase-9.
USP46 decreases the amount of BAX.
| 1
USP46 decreases the amount of BAX. 1 / 1
| 1

reach
The present experimental results demonstrated that the knockdown of USP46 upregulated Bcl-2 expression levels and downregulated the expression levels of Bax, caspase-3 and caspase-9.
Particulate Matter increases the amount of USP46.
1 |
Particulate Matter increases the amount of USP46. 1 / 1
1 |

ctd
No evidence text available
Particulate Matter decreases the amount of USP46.
1 |
Particulate Matter decreases the amount of USP46. 1 / 1
1 |

ctd
No evidence text available
2 |
Air Pollutants increases the amount of USP46.
1 |
Air Pollutants increases the amount of USP46. 1 / 1
1 |

ctd
No evidence text available
Air Pollutants decreases the amount of USP46.
1 |
Air Pollutants decreases the amount of USP46. 1 / 1
1 |

ctd
No evidence text available
Vinclozolin affects USP46
1 |
Vinclozolin increases the amount of USP46. 1 / 1
1 |

ctd
No evidence text available
| 1

reach
Pimozide, flupenthixol and trifluoperazine did not inhibit USP46 and UAF1 at the highest inhibitor concentrations tested (114 muM), while low level of inhibition by GW7647 was observed (IC 50 = 12 muM, XREF_TABLE).
Topotecan affects USP46
1 |
Topotecan decreases the amount of USP46. 1 / 1
1 |

ctd
No evidence text available
Silver(0) affects USP46
1 |
Silver(0) decreases the amount of USP46. 1 / 1
1 |

ctd
No evidence text available
Quercetin affects USP46
1 |
Quercetin decreases the amount of USP46. 1 / 1
1 |

ctd
No evidence text available
Potassium dichromate increases the amount of USP46. 1 / 1
1 |

ctd
No evidence text available
Piroxicam affects USP46
1 |
Piroxicam decreases the amount of USP46. 1 / 1
1 |

ctd
No evidence text available
Pimozide affects USP46
| 1
| 1

reach
Pimozide, flupenthixol and trifluoperazine did not inhibit USP46 and UAF1 at the highest inhibitor concentrations tested (114 muM), while low level of inhibition by GW7647 was observed (IC 50 = 12 muM, XREF_TABLE).
Phlorizin affects USP46
1 |
Phlorizin decreases the amount of USP46. 1 / 1
1 |

ctd
No evidence text available
Oxaliplatin affects USP46
1 |
Oxaliplatin decreases the amount of USP46. 1 / 1
1 |

ctd
No evidence text available
Nitrazepam affects USP46
| 1
Nitrazepam activates mutated USP46. 1 / 1
| 1

reach
The Usp46 KO mice exhibited short immobility times comparable to the Usp46 mutant mice, which was also increased by nitrazepam administration.
Mono(2-ethylhexyl) phthalate decreases the amount of USP46. 1 / 1
1 |

ctd
No evidence text available
Methylmercury chloride decreases the amount of USP46. 1 / 1
1 |

ctd
No evidence text available
Methyl methanesulfonate increases the amount of USP46. 1 / 1
1 |

ctd
No evidence text available
1 |
Hsa-miR-6815-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-6807-5p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-6751-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-513c-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-513b-5p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-513a-5p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-513a-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-489-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4795-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4766-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4670-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4459 decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4457 decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4433b-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4303 decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4294 decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4282 decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4280 decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-3920 decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
Hsa-miR-375 affects USP46
1 |
Hsa-miR-375 decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-374b-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-3688-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-3681-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-3606-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-338-5p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-3065-5p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-3064-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-27b-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-27a-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-216a-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-195-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-16-2-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-140-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-128-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-125b-2-3p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-1199-5p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-1179 decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-106b-5p decreases the amount of USP46. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
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