USP38 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 38
HGNC Gene Symbol
USP38
Identifiers
hgnc:20067 NCBIGene:84640 uniprot:Q8NB14
Orthologs
mgi:1922091 rgd:1311974
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP38
Number of Papers
21 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
CDKN1A cyclin dependent kinase inhibitor 1A -0.323 -0.10 -0.63 3.49e-01
TP53 tumor protein p53 -0.318 -0.10 -0.62 2.94e-01
ADRM1 ADRM1 26S proteasome ubiquitin receptor 0.288 0.16 0.78 6.82e-02
CHEK2 checkpoint kinase 2 -0.251 0.21 1.08 1.08e-02
TP53BP1 tumor protein p53 binding protein 1 -0.248 -0.30 -1.76 1.24e-04
MDM2 MDM2 proto-oncogene 0.244 -0.11 -0.67 4.03e-01
IPO9 importin 9 0.223 0.32 1.68 4.33e-05

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP38using 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
GO:0071479 cellular response to ionizing radiation Biological Process 1.33e-11 7.07e-09 1.93e-09
GO:0010212 response to ionizing radiation Biological Process 5.60e-10 2.98e-07 3.77e-08
GO:0031570 DNA integrity checkpoint Biological Process 7.79e-10 4.15e-07 3.77e-08
GO:0071478 cellular response to radiation Biological Process 1.97e-09 1.05e-06 7.17e-08
GO:0000075 cell cycle checkpoint Biological Process 3.76e-09 2.01e-06 9.90e-08
GO:0072395 signal transduction involved in cell cycle checkpoint Biological Process 7.39e-09 3.94e-06 1.53e-07
GO:0090399 replicative senescence Biological Process 1.12e-08 5.96e-06 1.81e-07
GO:0071158 positive regulation of cell cycle arrest Biological Process 1.12e-08 5.98e-06 1.81e-07
GO:0044774 mitotic DNA integrity checkpoint Biological Process 3.30e-08 1.76e-05 3.83e-07
GO:0071156 regulation of cell cycle arrest Biological Process 3.43e-08 1.83e-05 3.83e-07
GO:0071214 cellular response to abiotic stimulus Biological Process 2.79e-08 1.49e-05 3.83e-07
GO:0030330 DNA damage response, signal transduction by p53 class mediator Biological Process 3.18e-08 1.69e-05 3.83e-07
GO:1902807 negative regulation of cell cycle G1/S phase transition Biological Process 7.25e-08 3.86e-05 7.46e-07
GO:0042770 signal transduction in response to DNA damage Biological Process 7.71e-08 4.11e-05 7.46e-07
GO:0071480 cellular response to gamma radiation Biological Process 1.12e-07 5.96e-05 1.02e-06
GO:0009314 response to radiation Biological Process 1.45e-07 7.73e-05 1.24e-06
GO:0007093 mitotic cell cycle checkpoint Biological Process 1.89e-07 1.01e-04 1.53e-06
GO:1902806 regulation of cell cycle G1/S phase transition Biological Process 4.09e-07 2.18e-04 3.13e-06
GO:0010332 response to gamma radiation Biological Process 8.00e-07 4.26e-04 5.81e-06
GO:0007050 cell cycle arrest Biological Process 9.06e-07 4.83e-04 6.27e-06
GO:0072331 signal transduction by p53 class mediator Biological Process 1.28e-06 6.82e-04 8.05e-06
GO:1901988 negative regulation of cell cycle phase transition Biological Process 1.26e-06 6.71e-04 8.05e-06
GO:0002039 p53 binding Molecular Function 1.33e-06 7.09e-04 8.05e-06
GO:0097193 intrinsic apoptotic signaling pathway Biological Process 1.76e-06 9.36e-04 1.02e-05
GO:0044843 cell cycle G1/S phase transition Biological Process 1.88e-06 1.00e-03 1.05e-05
GO:0090068 positive regulation of cell cycle process Biological Process 1.98e-06 1.06e-03 1.07e-05
GO:0072332 intrinsic apoptotic signaling pathway by p53 class mediator Biological Process 2.22e-06 1.18e-03 1.12e-05
GO:0044389 ubiquitin-like protein ligase binding Molecular Function 2.23e-06 1.19e-03 1.12e-05
GO:0034644 cellular response to UV Biological Process 2.40e-06 1.28e-03 1.16e-05
GO:2001021 negative regulation of response to DNA damage stimulus Biological Process 2.59e-06 1.38e-03 1.21e-05
GO:0045930 negative regulation of mitotic cell cycle Biological Process 3.20e-06 1.71e-03 1.44e-05
GO:0090400 stress-induced premature senescence Biological Process 3.26e-06 1.74e-03 1.44e-05
GO:0010948 negative regulation of cell cycle process Biological Process 4.17e-06 2.22e-03 1.78e-05
GO:0045787 positive regulation of cell cycle Biological Process 6.67e-06 3.56e-03 2.77e-05
GO:0007569 cell aging Biological Process 7.66e-06 4.08e-03 3.09e-05
GO:0071482 cellular response to light stimulus Biological Process 1.03e-05 5.48e-03 4.04e-05
GO:0009411 response to UV Biological Process 1.29e-05 6.87e-03 4.88e-05
GO:1901987 regulation of cell cycle phase transition Biological Process 1.31e-05 6.99e-03 4.88e-05
GO:0042772 DNA damage response, signal transduction resulting in transcription Biological Process 1.58e-05 8.43e-03 5.75e-05
GO:0046827 positive regulation of protein export from nucleus Biological Process 2.44e-05 1.30e-02 8.65e-05
GO:1901796 regulation of signal transduction by p53 class mediator Biological Process 2.81e-05 1.50e-02 9.72e-05
GO:0071157 negative regulation of cell cycle arrest Biological Process 2.94e-05 1.57e-02 9.93e-05
GO:2001020 regulation of response to DNA damage stimulus Biological Process 4.59e-05 2.45e-02 1.52e-04
GO:0010165 response to X-ray Biological Process 5.40e-05 2.88e-02 1.74e-04
GO:0097718 disordered domain specific binding Molecular Function 5.76e-05 3.07e-02 1.82e-04
GO:0046825 regulation of protein export from nucleus Biological Process 9.04e-05 4.82e-02 2.77e-04
GO:0031668 cellular response to extracellular stimulus Biological Process 9.15e-05 4.88e-02 2.77e-04

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out USP38 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
IFIT3 interferon induced protein with tetratricopeptide repeats 3 6.29e-01 3.83e-07 4.23e-03
UBC ubiquitin C 3.38e-01 3.28e-07 4.23e-03
HMGB2 high mobility group box 2 -4.77e-01 4.22e-06 3.10e-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 USP38 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
USP38 deubiquitinates TBK1. 1 / 1
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Here we report that USP38 negatively regulates type I IFN signaling by targeting the active form of TBK1 for degradation in vitro and in vivo.
USP38 leads to the deubiquitination of MYC. 1 / 1
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USP38 can inhibit the polyubiquitination of c-Myc, thereby increasing c-Myc stability.

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
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eidos
USP38 Inhibits Zika Virus Infection by Removing Envelope Protein Ubiquitination .

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In addition, we found that the deubiquitinase activity of USP38 was essential to inhibit ZIKV infection, and the mutant that lacked the deubiquitinase activity of USP38 lost the ability to inhibit infection.

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USP38 Inhibits Zika Virus Infection by Removing Envelope Protein Ubiquitination Zika virus ( ZIKV ) is a mosquito-borne flavivirus , and its infection may cause severe neurodegenerative diseases .
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USP38 Inhibits Zika Virus Infection by Removing Envelope Protein Ubiquitination.

eidos
These results demonstrate that ZIKV infection was repressed by USP38 .
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USP38 Binds to E Protein through Its C-Terminal Domain Next , the mechanism by which USP38 represses ZIKV infection was explored .
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The deubiquitinase USP38 promotes cell proliferation through stabilizing c-Myc.

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Functionally , USP38 is able to promote cell proliferation via a c-Myc dependent manner .

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Functionally, USP38 is able to promote cell proliferation via a c-Myc dependent manner.
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Pirinixic acid increases the amount of USP38. 2 / 2
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No evidence text available
Bisphenol A affects USP38
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Bisphenol A increases the amount of USP38. 2 / 2
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USP38 affects JUNB
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USP38 activates JUNB. 2 / 2
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USP38 critically promotes asthmatic pathogenesis by stabilizing JunB protein.

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Mechanistically, USP38 directly associated with JunB, deubiquitinated Lys-48-linked poly-ubiquitination of JunB, and consequently blocked TCR induced JunB turnover.
USP38 affects Interferon
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USP38 Inhibits Type I Interferon Signaling by Editing TBK1Ubiquitination through NLRP4 Signalosome.

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Here we report that USP38 negatively regulates type I IFN signaling by targeting the active form of TBK1 for degradation invitro and invivo.
USP38 affects Histone
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USP38 activates Histone. 2 / 2
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Taken together, our data demonstrated that HDAC3 is functional responsible for USP38 mediated histone modifications, which further controls the expression of cancer stem cell related genes.

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Next, we analyzed the expression level of HDACs in control, USP38 knockdown, and overexpressing HCT116 cells to determine which HDAC is responsible for USP38 mediated histone modification.
1,2-dichloroethane decreases the amount of USP38. 2 / 2
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No evidence text available

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Methylmercury chloride increases the amount of USP38.
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Methylmercury chloride increases the amount of USP38. 1 / 1
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No evidence text available
Methylmercury chloride decreases the amount of USP38.
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Methylmercury chloride decreases the amount of USP38. 1 / 1
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No evidence text available
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Valproic acid increases the amount of USP38. 1 / 1
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No evidence text available
Urethane affects USP38
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Urethane increases the amount of USP38. 1 / 1
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No evidence text available
Trimellitic anhydride increases the amount of USP38. 1 / 1
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No evidence text available
Topotecan affects USP38
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Topotecan decreases the amount of USP38. 1 / 1
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No evidence text available
Tetrachloromethane decreases the amount of USP38. 1 / 1
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No evidence text available
Sunitinib affects USP38
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Sunitinib increases the amount of USP38. 1 / 1
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No evidence text available
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Sodium arsenite increases the amount of USP38. 1 / 1
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No evidence text available
Silver(0) affects USP38
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Silver(0) decreases the amount of USP38. 1 / 1
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No evidence text available
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Pirimiphos-methyl decreases the amount of USP38. 1 / 1
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No evidence text available
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No evidence text available
Oxaliplatin affects USP38
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Oxaliplatin decreases the amount of USP38. 1 / 1
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No evidence text available
Leflunomide affects USP38
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Leflunomide increases the amount of USP38. 1 / 1
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No evidence text available
Jinfukang affects USP38
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Jinfukang decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-miR-98-5p decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-miR-7856-5p decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-miR-6831-5p decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-miR-590-3p decreases the amount of USP38. 1 / 1
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No evidence text available
Hsa-miR-587 affects USP38
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Hsa-miR-587 decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-miR-5581-3p decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-miR-548e-5p decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-miR-4694-3p decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-miR-4500 decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-miR-4458 decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-miR-3927-3p decreases the amount of USP38. 1 / 1
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biopax:mirtarbase
No evidence text available
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Hsa-miR-376a-2-5p decreases the amount of USP38. 1 / 1
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biopax:mirtarbase
No evidence text available
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Hsa-miR-3658 decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-miR-17-5p decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-miR-148a-3p decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-miR-124-3p decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-let-7i-5p decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-let-7g-5p decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-let-7f-5p decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-let-7e-5p decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-let-7d-5p decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-let-7c-5p decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-let-7b-5p decreases the amount of USP38. 1 / 1
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No evidence text available
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Hsa-let-7a-5p decreases the amount of USP38. 1 / 1
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No evidence text available
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Formaldehyde decreases the amount of USP38. 1 / 1
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Fenofibrate affects USP38
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Fenofibrate increases the amount of USP38. 1 / 1
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Copper(II) sulfate increases the amount of USP38. 1 / 1
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Cobalt dichloride increases the amount of USP38. 1 / 1
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Cadmium dichloride increases the amount of USP38. 1 / 1
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Bis(2-ethylhexyl) phthalate increases the amount of USP38. 1 / 1
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Atrazine affects USP38
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Atrazine decreases the amount of USP38. 1 / 1
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USP38 Inhibits Zika Virus Infection by Removing Envelope Protein Ubiquitination.
USP38 affects cell growth
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USP38 inhibits colorectal cancer cell growth in vivo and in vitro.
USP38 affects TBK1
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USP38 inhibits TBK1. 1 / 1
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Similarly, USP38 negatively regulates IFN-I signaling by targeting the active form of TBK1 for degradation in vitro and in vivo (101).
USP38 affects SOX2
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USP38 activates SOX2. 1 / 1
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Furthermore, we examined the protein levels of cancer stem cell related genes and found that downregulation of USP38 caused significant upregulation of cancer stem cell marker genes SOX2, NANOG, OCT4, BIM1, SNAIL, CD133, ABCG2, and CD44, suggesting that USP38 restrains cancer stem cell population of colorectal cancer cells.
USP38 affects HDAC3
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Modified USP38 decreases the amount of HDAC3. 1 / 1
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Importantly, we found that USP38 overexpression significantly decreased the ubiquitination level of HDAC3 but not HDAC1 and had no effect on the overall protein level of HDAC3 and HDAC1.
USP38 affects HDAC1
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Modified USP38 inhibits HDAC1. 1 / 1
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Importantly, we found that USP38 overexpression significantly decreased the ubiquitination level of HDAC3 but not HDAC1 and had no effect on the overall protein level of HDAC3 and HDAC1.
USP38 affects HDAC
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USP38 activates HDAC. 1 / 1
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Hence, we detected the global histone deacetylase (HDAC) activity in HCT116 cells with downregulated, normal, and upregulated levels of USP38, respectively and found that the global HDAC activities were significantly induced by downregulation of USP38 in HCT116 cells and SW620 cells while the global HDAC activities were inhibited in USP38 overexpressing HCT116 cells.

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It has been shown that USP38 affects DNA damage repair by regulating the activity of HDAC1 , meanwhile , a low expression of USP38 causes genome instability , which may lead to tumorigenesis [ 18 ] .
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USP38 affects CD44
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USP38 inhibits CD44. 1 / 1
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In both HCT116 and SW620 cells, simultaneous knockdown of USP38 and HDAC3 attenuated the decreased H3K27ac level and increased CD44 and CD133.
TCR affects USP38
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TCR increases the amount of USP38. 1 / 1
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TCR stimulation up-regulated the USP38 level, and USP38 in turn mediated the protein stabilization of JunB, a transcription factor specific for Th2 development.
Soman affects USP38
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Soman increases the amount of USP38. 1 / 1
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No evidence text available
CD44 affects USP38
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CD44 inhibits USP38. 1 / 1
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Importantly, flow cytometry analysis of cell surface markers revealed that the number of CD133 and CD44 double positive cells was significantly elevated in colorectal cancer cells transfected with shRNA targeting USP38 and the number of CD133 and CD44 double positive cells was significantly reduced in colorectal cancer cells overexpressing USP38.
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Firstly, we analyzed the number of apoptotic cells in USP38 knock down and USP38 overexpressing HCT116 cells treated with 5-fluorouracil (5-FU), oxaliplatin (Oxal) or 5-FU plus Oxal (5-FU/Oxal).
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2-hydroxypropanoic acid decreases the amount of USP38. 1 / 1
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No evidence text available