USP24 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 24
HGNC Gene Symbol
USP24
Identifiers
hgnc:12623 NCBIGene:23358 uniprot:Q9UPU5
Orthologs
mgi:1919936 rgd:1306799
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP24
Number of Papers
32 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
RPA4 replication protein A4 0.191
EPS8L2 EPS8 like 2 -0.19 0.01 -0.04 9.13e-01
BRI3 brain protein I3 0.188 0.05 0.19 5.63e-01
LEXM lymphocyte expansion molecule 0.185
PDCD6 programmed cell death 6 -0.182 0.16 0.80 5.86e-03
LRIG2 leucine rich repeats and immunoglobulin like domains 2 0.179 -0.12 -0.77 7.26e-02
C1orf87 chromosome 1 open reading frame 87 0.178

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP24using 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 USP24 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
S100A6 S100 calcium binding protein A6 6.02e-01 3.15e-12 3.05e-08
RPLP1 ribosomal protein lateral stalk subunit P1 7.96e-01 2.75e-08 1.33e-04
RPS9 ribosomal protein S9 1.30e+00 5.51e-08 1.77e-04
RPS12 ribosomal protein S12 1.05e+00 2.54e-07 6.14e-04
RPLP2 ribosomal protein lateral stalk subunit P2 6.46e-01 6.77e-07 1.31e-03
RPS28 ribosomal protein S28 1.02e+00 1.48e-06 2.39e-03
RPL11 ribosomal protein L11 -3.75e-01 7.83e-06 8.41e-03
RPL7A ribosomal protein L7a 7.11e-01 7.55e-06 8.41e-03
MT-CO3 mitochondrially encoded cytochrome c oxidase III 2.31e-01 3.73e-05 3.28e-02
STX17 syntaxin 17 8.45e-01 5.96e-05 4.80e-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 USP24 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
USP24 deubiquitinates TP53. 7 / 7
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Under both normal and stressed conditions p53 is also deubiquitinated by USP24 and thus stabilizing its level.

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These findings show that USP24 can deubiquitinate p53 in vitro.

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They found also that USP24 deubiquitylates p53, activating the PUMA pathway, a regulator of DNA-damage-induced apoptosis.

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Review

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USP24 deubiquitinates p53 in vivo and in vitro.

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Our data show that USP24 deubiquitinates p53 in vivo and in vitro, leading to p53 stabilization and activation.

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In this study, we demonstrate that USP24 deubiquitinates p53 in human cells.
USP24 leads to the deubiquitination of ULK1. 3 / 3
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We detected increased levels of ULK1 ubiquitination following USP24 knockdown as compared to nt controls).

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Our data indicate that USP24 knockdown leads to increase in ULK1 ubiquitination, increased ULK1 protein stability and kinase activity.

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These data suggest that USP24 normally negatively regulates ubiquitination and stability of ULK1, therefore interrupting the positive feed-back amplifying induction of autophagy.
USP24 deubiquitinates EP300. 3 / 3
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Indeed, we observed that USP24 interacts with p300, and knockdown of USP24 increased p300 ubiquitination, and this effect of USP24 knockdown was abolished after treatment with the proteasome inhibitor MG132.

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USP24 deubiquitinates and stabilizes the histone acetyltransferase p300, thereby facilitating histone H3 acetylation of the IL-6 promoter and thus IL-6 transcription.

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The in vitro enzymatic assay using the purified USP24 protein demonstrated that USP24 decreased the p300 ubiquitination signal (XREF_FIG).
USP24 deubiquitinates DDB2. 3 / 3
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USP24 targeting DDB2 and p53

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DDB2 is deubiquitinated by USP24, stabilizing the entire UV-DDB-CUL4 E3 ligase from proteasomal degradation [XREF_BIBR].

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Usp24-mediated ddb2 deubiquitination prevents ddb2 degradation
USP24 deubiquitinates BTRC. 2 / 2
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These results provide evidence that USP24 directly deubiquitinates and stabilizes beta-TrCP.

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To further clarify whether USP24 directly targets beta-TrCP for deubiquitination, an in vitro deubiquitination assay was performed, and purified human USP24 significantly decreased the beta-TrCP ubiquitination signal.
USP24 leads to the deubiquitination of E2F4. 1 / 1
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Conversely, knockdown of USP24 in A549 cells increased the E2F4 ubiquitination signal (XREF_FIG).
USP24 deubiquitinates BH3. 1 / 1
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In agreement with previous reports indicating that USP24 may de-ubiquitinate the pro apoptotic BH3 protein BAX [31], we also observed a decrease in BAX protein levels in USP24 knockdown cells).
USP24 leads to the deubiquitination of PTTG1. 1 / 1
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Knockdown of USP24 decreased securin expression and increased the securin ubiquitination signal, whereas USP24 overexpression increased securin expression (XREF_FIG; XREF_SUPPLEMENTARY).
USP24 deubiquitinates BAX. 1 / 1
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In agreement with previous reports indicating that USP24 may de-ubiquitinate the pro apoptotic BH3 protein BAX [31], we also observed a decrease in BAX protein levels in USP24 knockdown cells).

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
USP24 affects IL6
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USP24 increases the amount of IL6.
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USP24 increases the amount of IL6. 10 / 10
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These results indicate that USP24 may upregulate IL-6 expression through directly stabilizing p300 and indirectly induce NF-kappaB expression through p300 in M2 macrophages.

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Here, we provide direct evidence to support that USP24 promotes IL-6 expression, which might be beneficial for cancer therapy.

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In this study, another interesting point is the discovery of distinct molecular mechanisms regulating IL-6 expression in M2 macrophages and lung cancer cells in response to USP24.

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In this study, we found that USP24 increased IL-6 expression by decreasing the stability of DNMT1 by stabilizing beta-TrCP in lung cancer cells and increasing the stability of p300 in both lung cancer cells and M2 macrophages, thereby resulting in the acetylation of histone H3 and demethylation of the IL-6 promoter, respectively.

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Finally, we found that knockdown of DNMT1 in USP24-knockdown A549 cells can rescue IL-6 level, suggesting that USP24 mediated DNMT1 degradation is really involved in IL-6 expression.

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USP24 increases IL-6 expression by epigenetic regulation.

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In addition to the p300 stabilization induced by USP24 in cancer cells to regulate IL-6 expression through increased histone H3 acetylation, USP24 also reduces DNA methylation in the promoter region of IL-6 in lung cancer cells, but not in M2 macrophages, to increase IL-6 transcription by decreasing DNMT1 protein stability.

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In M2 macrophages, USP24 increased p300 levels, subsequently enhancing the levels of NF-kappaB and IL-6.

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The IL-6 levels secreted from M2 macrophages and A549 cells decreased after USP24 knockdown, suggesting that USP24 upregulation in the tumor associated microenvironment and cancer cells during tumorigenesis increased IL-6 expression.

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Here, we also observed that USP24 in lung cancer cells increased IL-6 expression.
Modified USP24 increases the amount of IL6. 1 / 1
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While studying the role of USP24 upregulation in M2 macrophages, we found that USP24 expression in M2 macrophages enhanced cancer metastasis by inducing IL-6 expression.
USP24 activates IL6.
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USP24 activates IL6. 6 / 6
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USP24 induces IL-6 in TME through deubiquitinating p300 and beta-TrCP, and whether WP1130 inhibiting USP24 affects IL-6 in TME needs more investigation [XREF_BIBR].

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USP24 induces IL-6 in tumor associated microenvironment by stabilizing p300 and beta-TrCP and promotes cancer malignancy.

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Adding the physiological dose of IL-6 to the media of USP24-knockdown cells can rescue the effect of USP24 knockdown, suggesting that the USP24 mediated IL-6 in M2 macrophages and in lung cancer is an important factor that affects USP24 induced lung cancer malignancy.

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To examine whether USP24 mediated IL-6 was indeed functioning in lung cancer metastasis and angiogenesis, IL-6 was added to conditioned medium derived from USP24-knockdown M2 macrophages to address malignant lung cancer cell activity.

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IL-6 upregulation by USP24 increases cancer malignancy.

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USP24 induces IL-6 in TME through deubiquitinating p300 and beta-TrCP , and whether WP1130 inhibiting USP24 affects IL-6 in TME needs more investigation [ 100 ] .
USP24 decreases the amount of IL6.
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USP24 decreases the amount of IL6. 1 / 1
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After analyzing the five CpG sites upstream of the transcription start site, we found that the methylation status of a CpG site located at -123 was increased in A549 cells but not in M2 macrophages after USP24 knockdown, indicating that a decrease in IL-6 methylation induced by USP24 in A549 cells, but not in M2 macrophages, increases IL-6 mRNA levels.
USP24 affects EP300
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USP24 decreases the amount of EP300.
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USP24 decreases the amount of EP300. 2 / 6
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Knockdown of USP24 decreases Bax and p300 levels, and reduces Ku70 acetylation, thereby preventing cancer cell apoptosis.

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14 In this study, we found that USP24 downregulation decreased the p300 level, thereby decreasing Ku70 acetylation.
USP24 activates EP300.
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USP24 activates EP300. 5 / 5
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USP24 induces apoptosis by stabilizing p300 and Bax.

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In cancer cells, USP24 increased p300 and beta-TrCP, thus increasing the acetylation of histone H3 and the degradation of DNMT1 and IkappaB, resulting in the recruitment of histone H3 acetylation to the promoter region of IL-6, the reduction of DNA methylation, and the promotion of NF-kappaB nuclear translocation, thereby facilitating IL-6 expression.

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This study shows that USP24 mediates p300, NF-kappaB, DNMT1, and beta-TrCP to regulate IL-6 expression, thus affecting cancer metastasis.

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Thus, GFP-USP24 increased p300 protein stability, whereas knockdown USP24 decreased its stability (XREF_FIG; XREF_SUPPLEMENTARY) and USP24 interacted with p300 (XREF_FIG).

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Because our previous study confirmed that p300 is a USP24 substrate in lung cancer cells 31, we wanted to confirm whether p300 is also directly regulated by USP24 in M2 macrophages.
USP24 increases the amount of EP300.
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USP24 increases the amount of EP300. 2 / 2
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In M2 macrophages, USP24 increased p300 levels, subsequently enhancing the levels of NF-kappaB and IL-6.

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Similarly, knockdown of USP24 decreased the p300 level but did not affect its mRNA level (XREF_FIG).
Modified USP24 increases the amount of EP300. 1 / 1
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Overexpression of GFP-USP24 increased the p300 level but did not affect its mRNA level.
USP24 inhibits EP300.
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USP24 inhibits EP300. 1 / 1
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Knockdown of USP24 also decreased the protein stability of p300 in M2 macrophages and A549 cancer cells.
USP24 affects BAX
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USP24 decreases the amount of BAX.
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USP24 decreases the amount of BAX. 2 / 6
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Knockdown of USP24 decreases Bax and p300 levels, and reduces Ku70 acetylation, thereby preventing cancer cell apoptosis.

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Knockdown of USP24 decreased the Bax and caspase-3 levels; conversely, these protein levels were increased in GFP-USP24-expressing cells, although no alterations were observed in the Bax mRNA level (XREF_FIG; XREF_SUPPLEMENTARY).
USP24 activates BAX.
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USP24 activates BAX. 4 / 5
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USP24 induces apoptosis by stabilizing p300 and Bax.

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In addition, USP24 also directed Bax protein stability to result in cell apoptosis.

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USP24 knockdown decreases Bax protein stability in A549 and U2OS cells (XREF_FIG; XREF_SUPPLEMENTARY).

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The localization of Bax in cells expressing GFP-USP24 indicated that USP24 expression increased Bax 's mitochondrial localization, implying that USP24 induced cell apoptosis (XREF_FIG).
USP24 inhibits BAX.
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USP24 inhibits ubiquitinated BAX. 1 / 1
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GFP-USP24 overexpression decreased the ubiquitinated Bax signal, and this effect was reversed by USP24 knockdown (XREF_FIG).
USP24 increases the amount of BAX.
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USP24 increases the amount of BAX. 1 / 1
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MG132 treatment rescued the Bax level, indicating that USP24 increased the Bax level by enhancing protein stability, thereby contributing to cell apoptosis (XREF_SUPPLEMENTARY).
USP24 affects DDB2
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USP24 activates DDB2.
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USP24 activates DDB2. 3 / 4
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USP24 targeting DDB2 and p53.

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Knockdown of USP24 resulted in a decreased level of DDB2, suggesting that USP24 stabilizes DDB2 by removing the ubiquitin moiety from modified DDB2, thereby preventing DDB2 degradation.

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Usp24-mediated ddb2 deubiquitination prevents ddb2 degradation
USP24 activates ubiquitinated DDB2. 2 / 2
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To examine if USP24 can target ubiquitinated DDB2 in vitro, we treated HeLa cells expressing Hig tagged DDB2 with MG132, a proteosome inhibitor, XREF_BIBR for 1 h and exposed HeLa cells to UVC (10 J/m 2) to stimulate DDB2 uniquitination for another hour, Ni-NTA beads were then used to pulldown modified His DDB2.

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Our group previously reported that ubiquitinated DDB2 can be targeted by USP24, and in this study, we demonstrate that USP24 is a p53 deubiquitinase, required for p53 stabilization in unstressed cells, as well as for p53 stabilization and PUMA activation after DNA damage.
USP24 increases the amount of DDB2.
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USP24 increases the amount of DDB2. 3 / 3
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Importantly, knockdown of USP24 in two human cell lines decreased the steady-state levels of DDB2, indicating that USP24 mediated DDB2 deubiquitination prevents DDB2 degradation.

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Importantly, knockdown of USP24 in two human cell lines decreased the steady-state levels of DDB2, indicating that USP24 mediated DDB2 deubiquitination prevents DDB2 degradation.
| PMC

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As indicated in XREF_FIG, knockdown of USP24 decreased the steady-state levels of DDB2 in both HeLa and 293T cells.
USP24 decreases the amount of DDB2.
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USP24 decreases the amount of DDB2. 1 / 1
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Knockdown of USP24 decreases steady-state level of DDB2.
USP24 affects autophagy
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USP24 inhibits autophagy.
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Furthermore, we observed elevated levels of USP24 in the substantia nigra of a subpopulation of idiopathic PD patients, suggesting that USP24 may negatively regulate autophagy in PD.

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Furthermore, our data demonstrate elevated levels of USP24 in some cases of idiopathic PD, suggesting that USP24 may negatively regulate autophagy in PD.

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Our data indicate that USP24 mRNA and protein levels are also elevated in the substantia nigra of a subset of idiopathic PD patients, suggesting that suppression of autophagy by USP24 could also occur in at least some cases of non familial PD.

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Therefore, USP24 negatively regulates autophagy flux in human iPSC derived dopaminergic neurons, similarly to what we observed in cell lines.

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Consistently, in the original screen [25] USP24 knockdown failed to upregulate autophagy in cells overexpressing BCL-2, which binds and inhibits activity of the class III PtdIns3K subunit BECN1 [34]).
USP24 activates autophagy.
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USP24 is another modulator of autophagy which may also influence PD progression as it can regulate dopaminergic neurite outgrowth, but the potential as a disease modulator is not evaluated yet.

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Blocking lysosomal function with bafilomycin led to significant increase in accumulation of GFP-LC3 positive autophagosomes in USP24 knockdown cells, indicating that USP24 is negatively regulating autophagy flux without affecting lysosomal degradation).

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Knockdown of USP24 in cell lines and in human induced-pluripotent stem cells (iPSC) differentiated into dopaminergic neurons resulted in elevated ULK1 protein levels and increased autophagy flux in a manner independent of MTORC1 but dependent on the class III phosphatidylinositol 3-kinase (PtdIns3K) activity.

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Knockdown of USP24 also led to increase in levels of the autophagosome associated lipidated form of LC3 (LC3-II) [30]), confirming increase in autophagy.
USP24 affects TP53
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USP24 activates TP53.
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USP24 activates TP53. 4 / 4
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It has been shown that USP24 targets p53 to regulate UV induced apoptosis.

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This third, independent assay format thus supports a direct interaction between USP24, p53 and orf10.Novel modulators of p53 signaling encoded by unknown genes of emerging viruses Next, we deleted USP24 gene in U2OS cells using CRISPR and Cas9, which generated three independent US2OS-DeltaUSP24 cell populations upon long-term selection.

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Evidence that USP24 targets p53 to protect genome stability.

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USP24 targeting DDB2 and p53.
USP24 activates ubiquitinated TP53. 1 / 1
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These findings strongly suggest that USP24 directly targets ubiquitinated p53 and removes the ubiquitin moiety, thereby preventing p53 degradation.
USP24 inhibits TP53.
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USP24 inhibits TP53. 2 / 3
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Depletion of USP24 significantly attenuates p53 dependent apoptosis induced by DNA damage.

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Knockdown of USP24 failed to prevent stabilization of p53 following etoposide treatment of H4 cells), suggesting that in this cell type USP24 may be dispensable for DNA damage responses or that the very low residual USP24 protein may be sufficient.
USP24 decreases the amount of TP53.
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USP24 decreases the amount of TP53. 1 / 1
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In the absence of MG132 treatment, USP24 depletion reduced the steady state levels of p53 (XREF_FIG, lane 1 vs 2).
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Furthermore, we demonstrated that knockdown of USP24 but not USP9X could significantly induce growth inhibition and apoptosis of T-ALL cells.

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USP24 depletion inhibits apoptosis in response to UV damage.

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Silencing USP24 increases the cancer formation by inhibiting cellular apoptosis and increasing cellular proliferation.

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Depletion of USP24 significantly attenuates p53 dependent apoptosis induced by DNA damage.
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USP24 induces apoptosis by stabilizing p300 and Bax.

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Using this deactivated CRISP-Cas9-SAM system we successfully reactivated USP24 and demonstrate that endogenously induced USP24 could partially rescue the apoptosis induced by WP1130 in Jurkat cells.

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Down-regulation of USP24 but not USP9X induces growth inhibition and apoptosis of T-ALL cells.

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These results indicate that USP24 promotes UV induced apoptosis in HCT116 cells, consistent with the notion that p53 directed apoptosis is attenuated in USP24 depleted cells which lack robust p53 stabilization after UV treatment.
USP24 affects E2F4
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USP24 decreases the amount of E2F4.
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USP24 decreases the amount of E2F4. 2 / 3
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USP24 inhibits the G1-S transition by increasing the E2F4 level.

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Knockdown of USP24 decreased the E2F4, p130 and TFDP1 levels, which form a complex to regulate the G1-S transition, but did not alter the E2F4 and TDFP1 mRNA levels (XREF_FIG; XREF_SUPPLEMENTARY).
Modified USP24 decreases the amount of E2F4. 1 / 1
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The molecular mechanism involves a decrease in the USP24 level, which reduces the expression of E2F4 and its partner TFDP1, and thus increases the G1/S transition.
USP24 inhibits E2F4.
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USP24 inhibits E2F4. 1 / 1
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Knockdown of USP24 decreased E2F4 protein stability (XREF_FIG; XREF_SUPPLEMENTARY).
USP24 activates E2F4.
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USP24 activates E2F4. 1 / 1
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Taken together, our results demonstrated that USP24 knockdown decreased E2F4, p130 and TFDP1, resulting in an increase in the E2F1 levels and a subsequent increase in the G1-S transition, leading to tumorigenesis.
USP24 affects PTTG1
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USP24 decreases the amount of PTTG1.
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USP24 decreases the amount of PTTG1. 1 / 3
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Knockdown of USP24 decreased securin expression and increased the securin ubiquitination signal, whereas USP24 overexpression increased securin expression (XREF_FIG; XREF_SUPPLEMENTARY).
USP24 increases the amount of PTTG1.
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USP24 increases the amount of PTTG1. 1 / 1
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Taken together, our results suggested that USP24 was decreased by APC/C cdc20 to decrease the securin level, which was beneficial for the metaphase-anaphase transition and enhanced cell cycle progression.
Modified USP24 increases the amount of PTTG1. 1 / 1
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Knockdown of USP24 decreased securin expression and increased the securin ubiquitination signal, whereas USP24 overexpression increased securin expression (XREF_FIG; XREF_SUPPLEMENTARY).
USP24 affects DNMT1
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USP24 inhibits DNMT1.
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USP24 inhibits DNMT1. 3 / 3
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Finally, we found that knockdown of DNMT1 in USP24-knockdown A549 cells can rescue IL-6 level, suggesting that USP24 mediated DNMT1 degradation is really involved in IL-6 expression.

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USP24 decreases DNMT1 and IkappaB through stabilizing beta-TrCP.

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In this study, we observed that USP24 increased DNMT1 degradation in cancer cells, but not in M2 macrophages, leading to decreased DNA methylation.
USP24 decreases the amount of DNMT1.
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USP24 decreases the amount of DNMT1. 1 / 1
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beta-TrCP overexpression in USP24-knockdown cells prevented the upregulation of DNMT1and IkappaB induced by USP24 knockdown and demonstrated that beta-TrCP is critical in the USP24 induced increase of DNMT1 and IkappaB expression.
USP24 activates DNMT1.
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USP24 activates DNMT1. 1 / 1
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This study shows that USP24 mediates p300, NF-kappaB, DNMT1, and beta-TrCP to regulate IL-6 expression, thus affecting cancer metastasis.
USP24 affects NFkappaB
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USP24 activates NFkappaB.
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However, in this study, USP24-activated NF-κB did not increase CCL2, implying that other factors regulated by USP24 might negatively regulate CCL2 expression.

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This study shows that USP24 mediates p300, NF-kappaB, DNMT1, and beta-TrCP to regulate IL-6 expression, thus affecting cancer metastasis.

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In this study, we discovered the underlying mechanisms by which USP24 not only promotes IkappaB degradation by stabilizing beta-transduction repeat containing E3 ubiquitin protein ligase (beta-TrCP) in lung cancer cells but also induces the upregulation of NF-kappaB in M2 macrophages, resulting in an increase in IL-6 expression.
USP24 increases the amount of NFkappaB.
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USP24 increases the amount of NFkappaB. 1 / 1
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In M2 macrophages, USP24 increased p300 levels, subsequently enhancing the levels of NF-kappaB and IL-6.
USP24 affects IKB
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USP24 inhibits IKB.
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USP24 inhibits IKB. 3 / 3
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beta-TrCP overexpression in USP24-knockdown cells prevented the upregulation of DNMT1and IkappaB induced by USP24 knockdown and demonstrated that beta-TrCP is critical in the USP24 induced increase of DNMT1 and IkappaB expression.

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USP24 decreases DNMT1 and IkappaB through stabilizing beta-TrCP.

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In this study, we discovered the underlying mechanisms by which USP24 not only promotes IkappaB degradation by stabilizing beta-transduction repeat containing E3 ubiquitin protein ligase (beta-TrCP) in lung cancer cells but also induces the upregulation of NF-kappaB in M2 macrophages, resulting in an increase in IL-6 expression.
USP24 increases the amount of IKB.
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USP24 increases the amount of IKB. 1 / 1
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beta-TrCP overexpression in USP24-knockdown cells prevented the upregulation of DNMT1and IkappaB induced by USP24 knockdown and demonstrated that beta-TrCP is critical in the USP24 induced increase of DNMT1 and IkappaB expression.
KRAS affects USP24
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KRAS-G12D decreases the amount of USP24. 3 / 3
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Taken together, these data revealed that Kras G12D - or EGFR L858R -mediated pathways negatively regulated USP24 expression, which might trigger lung cancer formation.

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XREF_BIBR, XREF_BIBR Although their levels were increased in some specimens from late-stage lung cancer patients, inhibition of Kras G12D - or EGFR L858R -mediated activities in all cell lines at different stages increased the USP24 level.

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Based on the data in this study and our previous study, we propose that EGFR L858R - and Kras G12D -mediated signaling pathways inhibit USP24 expression, which is beneficial for cancer formation during the early stage.
KRAS decreases the amount of USP24. 1 / 1
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Furthermore, the data in XREF_FIG indicated that USP24 expression was also negatively regulated by EGFR- and Kras activated signaling pathways.
USP24 affects USP24
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USP24 increases the amount of USP24.
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USP24 increases the amount of USP24. 1 / 2
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XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Our recent study showed that USP24 variants from SNPs and RNA editing products increased the levels of USP24 and MDM2, which regulates Suv39h1 in lung cancer cells, subsequently resulting in an increase in metastatic activities during lung cancer progression.
USP24 inhibits USP24.
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USP24 inhibits USP24. 1 / 1
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Here we found that the phosphorylation of several USP24 residues was regulated by EGF treatment and mitotic CDK1 to enhance USP24 degradation in a polyubiquitination dependent manner.
USP24 decreases the amount of USP24.
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Phosphorylated USP24 decreases the amount of USP24. 1 / 1
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Mutations at these residues increased the USP24 half-life during mitosis, suggesting that USP24 phosphorylation during mitosis decreased USP24 expression (XREF_FIG).
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Interestingly, it has been reported that some polymorphisms of USP24 and USP40 significantly decrease the risk of developing PD [22,23].

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Our results demonstrated that USP24 rs487230 T allele and CT/TT genotype notably decreased the risk of developing PD in the AAO> = 60 year subgroup of patients.

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The USP24 T allele also seemed to reduce PD risk independently in the group> = 60 years (OR = 0.64, 95% CI 0.44-0.91, P = 0.023).
USP24 affects BTRC
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USP24 activates BTRC. 3 / 3
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This study shows that USP24 mediates p300, NF-kappaB, DNMT1, and beta-TrCP to regulate IL-6 expression, thus affecting cancer metastasis.

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In cancer cells, USP24 increased p300 and beta-TrCP, thus increasing the acetylation of histone H3 and the degradation of DNMT1 and IkappaB, resulting in the recruitment of histone H3 acetylation to the promoter region of IL-6, the reduction of DNA methylation, and the promotion of NF-kappaB nuclear translocation, thereby facilitating IL-6 expression.

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To further clarify whether USP24 directly targets beta-TrCP for deubiquitination, an in vitro deubiquitination assay was performed, and purified human USP24 significantly decreased the beta-TrCP ubiquitination signal.
ATM affects USP24
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ATM activates USP24. 2 / 3
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Moreover, UV induced USP24 accumulation appears to be ATM dependent; inhibition of ATM by either KU-55933 or a specific siRNA prevented USP24 accumulation after UV (XREF_FIG).

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Taken together, these data suggest that the ATM kinase mediated phosphorylation of USP24 is involved in USP24 stabilization/up regulation following UV irradiation.
Bisphenol A affects USP24
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Bisphenol A decreases the amount of USP24.
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Bisphenol A decreases the amount of USP24. 2 / 2
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Bisphenol A increases the amount of USP24.
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Bisphenol A increases the amount of USP24. 1 / 1
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USP24 affects cell death
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USP24 activates cell death.
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GFP-USP24 expression, but not GFP, led to rounded cells and, finally, cell death.

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Direct Usp24 KD resulted in marked induction of myeloma cell death that was associated with a reduction of Mcl-1.
USP24 inhibits cell death.
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Knockdown of USP24 suppressed the cell death during pUL38 deficient HCMV infection, suggesting that pUL38 achieved its function by antagonizing the function of USP24.
USP24 affects ULK1
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USP24 decreases the amount of ULK1.
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USP24 decreases the amount of ULK1. 2 / 2
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Real time qPCR data revealed no significant change in ULK1 mRNA levels following knockdown of USP24.

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These data indicate that the observed increase in ULK1 protein levels following USP24 knockdown is not due to transcriptional upregulation.
USP24 inhibits ULK1.
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USP24 inhibits ULK1. 1 / 1
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USP24 knockdown decreased degradation of the ULK1 protein in the presence of protein synthesis inhibitor, cycloheximide).
USP24 affects SQSTM1
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USP24 activates SQSTM1.
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USP24 activates SQSTM1. 2 / 2
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Knockdown of USP24 increased the rate of degradation of the autophagy adaptor protein SQSTM1 and p62).

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Knockdown of USP24 increased the rate of degradation of the autophagy adaptor protein SQSTM1 and p62).
USP24 increases the amount of SQSTM1.
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USP24 increases the amount of SQSTM1. 1 / 1
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Decrease in SQSTM1 levels following USP24 knockdown was attenuated in the presence of bafilomycin, confirming dependence on lysosomal degradation).
USP24 affects PARP1
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USP24 inhibits PARP1.
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USP24 inhibits PARP1. 2 / 2
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In p53 +/+ cells, cleaved PARP started to appear as early as three hours after UV irradiation and depletion of USP24 resulted in slow and reduced PARP cleavage (XREF_FIG, right panel).

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USP24 depletion inhibits PUMA activation and PARP cleavage in response to UV damage.
USP24 activates PARP1.
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USP24 activates PARP1. 1 / 1
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To examine whether USP24 regulates the apoptotic response to UV through the p53 pathway, we compared the effects of USP24 depletion on UV induced PARP cleavage in two isogenic cell lines : HCT116 p53 +/+ and HCT116 p53-/-.
USP24 bound to GSDMB activates cell population proliferation. 1 / 1
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USP24 and GSDMB complex promotes bladder cancer proliferation via activation of the STAT3 pathway.

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Furthermore, knockdown of USP24 markedly inhibits the proliferation of Jurkat cells.

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Silencing USP24 increases the cancer formation by inhibiting cellular apoptosis and increasing cellular proliferation.
USP24 affects TFDP1
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USP24 increases the amount of TFDP1.
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Modified USP24 increases the amount of TFDP1. 1 / 1
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The molecular mechanism involves a decrease in the USP24 level, which reduces the expression of E2F4 and its partner TFDP1, and thus increases the G1/S transition.
USP24 decreases the amount of TFDP1.
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USP24 decreases the amount of TFDP1. 1 / 1
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Knockdown of USP24 decreased the E2F4, p130 and TFDP1 levels, which form a complex to regulate the G1-S transition, but did not alter the E2F4 and TDFP1 mRNA levels (XREF_FIG; XREF_SUPPLEMENTARY).
USP24 activates TFDP1.
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USP24 activates TFDP1. 1 / 1
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Taken together, our results demonstrated that USP24 knockdown decreased E2F4, p130 and TFDP1, resulting in an increase in the E2F1 levels and a subsequent increase in the G1-S transition, leading to tumorigenesis.
EGFR affects USP24
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EGFR decreases the amount of USP24.
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EGFR-L858R decreases the amount of USP24. 1 / 1
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Taken together, these data revealed that Kras G12D - or EGFR L858R -mediated pathways negatively regulated USP24 expression, which might trigger lung cancer formation.
EGFR decreases the amount of USP24. 1 / 1
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Furthermore, the data in XREF_FIG indicated that USP24 expression was also negatively regulated by EGFR- and Kras activated signaling pathways.
EGFR inhibits USP24.
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Mutated EGFR inhibits USP24. 1 / 1
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Therefore, during the initiation of tumor formation, EGFR mutations decrease USP24 to increase the degradation of p300 and Bax, and thus repress cell apoptosis.
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Valproic acid decreases the amount of USP24. 2 / 2
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Cisplatin affects USP24
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Cisplatin decreases the amount of USP24. 2 / 2
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USP9X affects USP24
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USP9X inhibits USP24. 2 / 2
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In order to determine whether USP9X promote the degradation of USP24, we over-expressed USP9X in 293T cells and examined the protein level of USP24.

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Moreover, the decreasing of USP24 could be rescued by MG132, indicating that USP9X can promote the degradation of USP24.

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After IL-6 was added to the M2 macrophages conditioned medium, this effect was rescued, indicating that the USP24 induced metastasis activity is due to upregulated IL-6, which can be expressed by M2 macrophages or cancer cells.

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These findings further implied that NF-kappaB is indeed involved in USP24 promoted metastasis.
USP24 affects cell cycle
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USP24 inhibits cell cycle.
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In addition, knockdown of USP24 increases cell cycle progression by enhancing the G1-S transition and metaphase-anaphase transition.
USP24 activates cell cycle.
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Overexpression of E2F4 in USP24 silenced cells rescued only the E2F1 mRNA level and partially abolished the effect of the USP24 knockdown on the G1-S transition and colony formation (XREF_FIG; XREF_SUPPLEMENTARY), implying that E2F4 might be involved in USP24 mediated cell cycle progression.
USP24 affects GSDMB
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USP24 bound to GSDMB inhibits GSDMB. 1 / 1
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Furthermore, we also demonstrated that USP24 interacted with GSDMB and prevented GSDMB from degradation in bladder cancer cells.
USP24 inhibits GSDMB. 1 / 1
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Furthermore , we also demonstrated that USP24 interacted with GSDMB and prevented GSDMB from degradation in bladder cancer cells .
USP24 affects Cyclin
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Modified USP24 increases the amount of Cyclin. 1 / 1
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Overexpression of GFP-USP24 increased the cyclin B1 level, suggesting that USP24 was beneficial for cells that remained in mitosis (XREF_SUPPLEMENTARY).
USP24 increases the amount of Cyclin. 1 / 1
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Knockdown of USP24 increased the CDK1 and cyclin B1 levels, and increased the ratio of cells in the G2/M stage, indicating that USP24 reduction was beneficial for cell cycle progression (XREF_SUPPLEMENTARY).
USP24 affects CCNB1
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Modified USP24 increases the amount of CCNB1. 1 / 1
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Overexpression of GFP-USP24 increased the cyclin B1 level, suggesting that USP24 was beneficial for cells that remained in mitosis (XREF_SUPPLEMENTARY).
USP24 increases the amount of CCNB1. 1 / 1
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Knockdown of USP24 increased the CDK1 and cyclin B1 levels, and increased the ratio of cells in the G2/M stage, indicating that USP24 reduction was beneficial for cell cycle progression (XREF_SUPPLEMENTARY).
USP24 affects BCAR1
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USP24 decreases the amount of BCAR1.
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USP24 decreases the amount of BCAR1. 1 / 1
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Knockdown of USP24 decreased the E2F4, p130 and TFDP1 levels, which form a complex to regulate the G1-S transition, but did not alter the E2F4 and TDFP1 mRNA levels (XREF_FIG; XREF_SUPPLEMENTARY).
USP24 activates BCAR1.
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USP24 activates BCAR1. 1 / 1
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Taken together, our results demonstrated that USP24 knockdown decreased E2F4, p130 and TFDP1, resulting in an increase in the E2F1 levels and a subsequent increase in the G1-S transition, leading to tumorigenesis.
TP53 affects USP24
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TP53 inhibits USP24.
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TP53 inhibits USP24. 1 / 1
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These results indicate that USP24 promotes UV induced apoptosis in HCT116 cells, consistent with the notion that p53 directed apoptosis is attenuated in USP24 depleted cells which lack robust p53 stabilization after UV treatment.
TP53 activates USP24.
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TP53 activates USP24. 1 / 1
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It has been shown that USP24 targets p53 to regulate UV induced apoptosis.
Tungsten affects USP24
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Tungsten decreases the amount of USP24. 1 / 1
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Troglitazone decreases the amount of USP24. 1 / 1
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Trichostatin A increases the amount of USP24. 1 / 1
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Topotecan affects USP24
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Topotecan decreases the amount of USP24. 1 / 1
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Sunitinib affects USP24
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Sunitinib increases the amount of USP24. 1 / 1
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Sodium fluoride increases the amount of USP24. 1 / 1
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Potassium chromate decreases the amount of USP24. 1 / 1
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Phlorizin affects USP24
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Phlorizin decreases the amount of USP24. 1 / 1
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Paracetamol affects USP24
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Paracetamol decreases the amount of USP24. 1 / 1
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Oxaliplatin affects USP24
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Oxaliplatin decreases the amount of USP24. 1 / 1
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Nickel atom affects USP24
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Nickel atom increases the amount of USP24. 1 / 1
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Mono(2-ethylhexyl) phthalate decreases the amount of USP24. 1 / 1
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Methylmercury chloride decreases the amount of USP24. 1 / 1
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Methapyrilene decreases the amount of USP24. 1 / 1
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Jinfukang affects USP24
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Jinfukang decreases the amount of USP24. 1 / 1
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Irinotecan affects USP24
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Irinotecan decreases the amount of USP24. 1 / 1
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Indometacin affects USP24
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Indometacin decreases the amount of USP24. 1 / 1
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Hsa-miR-935 affects USP24
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Hsa-miR-935 decreases the amount of USP24. 1 / 1
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Hsa-miR-196a-5p decreases the amount of USP24. 1 / 1
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Hsa-miR-193b-3p decreases the amount of USP24. 1 / 1
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Hsa-miR-181b-5p decreases the amount of USP24. 1 / 1
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Hsa-miR-1226-3p decreases the amount of USP24. 1 / 1
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Hsa-let-7d-5p decreases the amount of USP24. 1 / 1
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Gentamycin affects USP24
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Gentamycin increases the amount of USP24. 1 / 1
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Gefitinib affects USP24
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Gefitinib increases the amount of USP24. 1 / 1
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Gefitinib and FTI-276, which inhibited the EGFR and Kras activities 21 in the A431 and A549 cell lines, respectively, increased USP24 expression (XREF_FIG).
Ethyl methanesulfonate decreases the amount of USP24. 1 / 1
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Ethanol affects USP24
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Ethanol decreases the amount of USP24. 1 / 1
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Dexamethasone decreases the amount of USP24. 1 / 1
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Cyclosporin A increases the amount of USP24. 1 / 1
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Cefaloridine decreases the amount of USP24. 1 / 1
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Butanal affects USP24
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Butanal decreases the amount of USP24. 1 / 1
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Bisphenol F affects USP24
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Bisphenol F decreases the amount of USP24. 1 / 1
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Auramine O affects USP24
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Auramine O increases the amount of USP24. 1 / 1
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Atrazine affects USP24
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Atrazine decreases the amount of USP24. 1 / 1
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Aldosterone affects USP24
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Given that USP2-4 is strikingly induced by aldosterone [ 17 ] , the induction of USP2-4 may therefore function as a node of the negative feedback loop for MR signaling .
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Aflatoxin B1 increases the amount of USP24. 1 / 1
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Acetamide affects USP24
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Acetamide decreases the amount of USP24. 1 / 1
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Zoledronic Acid decreases the amount of USP24. 1 / 1
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The localization of Bax in cells expressing GFP-USP24 indicated that USP24 expression increased Bax 's mitochondrial localization, implying that USP24 induced cell apoptosis (XREF_FIG).
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In the liver , USP2-4 promotes gluconeogenesis and increases low density lipoprotein ( LDL ) uptake by upregulating the LDL receptor .
USP24 affects ferritin
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pUL38 blocked USP24 mediated ferritin degradation in lysosomes, which could otherwise be detrimental to the lysosome and initiate cell death.
USP24 affects VEGF
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USP24 increases the amount of VEGF. 1 / 1
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The data indicated that the knockdown of USP24 in M2 macrophages decreased Angiopoirtin-2, CD40L, IL-6, tumor necrosis factor alpha (TNF-alpha), Thrombospondin-1 and vascular endothelial growth factor (VEGF) levels, indicating that USP24 is involved in angiogenesis.
USP24 affects USP9X
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USP24 increases the amount of USP9X. 1 / 1
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Interestingly, knockdown of USP24 in Jurkat cells significantly induced cell death and reduced Mcl-1 but not USP9X protein level.
USP24 affects SUV39H1
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USP24 increases the amount of SUV39H1. 1 / 1
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USP24 was also found to target histones by controlling the levels of the histone-lysine N-methyltransferase Suv39h1, resulting in a modulation of the H3K9me levels.
USP24 affects STAT3
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USP24 activates STAT3. 1 / 1
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Besides, we also showed that USP24 stabilized GSDMB to activate STAT3 signaling, which was blocked by the USP24 inhibitor.
USP24 affects RUNX2
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USP24 decreases the amount of RUNX2. 1 / 1
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However, unlike HAUSP, USP24 was unable to interact with RUNX2 and reduce ubiquitination levels of RUNX2, suggesting that HAUSP, not USP24, functions as a bona-fide RUNX2-DUB.
USP24 affects PI3K
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USP24 activates PI3K. 1 / 1
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In addition, we found that USP24 phosphorylation at Ser2604 was declined by U0126, which inhibited the Erk1/2 activities in A549 cells (XREF_FIG); however, USP24 phosphorylation was not decreased by LY294002, which inhibited the PI3K activities (XREF_SUPPLEMENTARY).
USP24 affects NCOA4
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USP24 inhibits NCOA4. 1 / 1
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