ATXN3L Data Analysis

HGNC Gene Name
ataxin 3 like
HGNC Gene Symbol
ATXN3L
Identifiers
hgnc:24173 NCBIGene:92552 uniprot:Q9H3M9
Orthologs
mgi:1099442
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for ATXN3L
Number of Papers
7 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 ATXN3Lusing 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

Literature Mining

INDRA was used to automatically assemble known mechanisms related to ATXN3L 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
ATXN3L deubiquitinates KLF5. 8 / 8
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ATXN3L deubiquitinates KLF5.

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We then sought to determine whether ATXN3L directly decreases the KLF5 ubiquitination.

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The ATXN3L protein interacted with the KLF5 protein and decreased the KLF5 polyubiquitination.

ubibrowser
Ataxin-3 like (ATXN3L), a member of the Josephin family of deubiquitinating enzymes, promotes breast cancer proliferation by deubiquitinating Kruppel-like factor 5 (KLF5). Ge F(1)(2), Chen W(3), Qin J(1), Zhou Z(1), Liu R(1), Liu L(4), Tan J(3), Zou T(3), Li H(2), Ren G(2), Chen C(1). Author information: (1)Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. (2)Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. (3)Department of Breast Surgery, The 3rd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China. (4)Laboratory for Conservation and Utilization of Bioresource, Yunnan University, Kunming, China. The Kr眉ppel-like factor 5 (KLF5) has been suggested to promote breast cell proliferation, survival and tumorigenesis.

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GST-ATXN3L, but not GST-ATXN3L (M4), dramatically decreased the KLF5 protein polyubiquitination.

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Whether the deubiquitination of KLF5 protein by ATXN3L is regulated is unknown at present.

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Although ATXN3L decreases the KLF5 protein ubiquitination, ATXN3L may have other substrate proteins.

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As shown in Figure XREF_FIG, ATXN3L silencing increased the endogenous KLF5 protein ubiquitination.

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
ATXN3L affects KLF5
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ATXN3L activates KLF5.
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ATXN3L activates KLF5. 5 / 11
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To further determine whether ATXN3L increases the KLF5 protein stability, we measured the KLF5 protein half-lives by the cycloheximide (CHX) chase assays [XREF_BIBR].

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Collectively, these results suggest that ATXN3L is a specific DUB for KLF5 and that ATXN3L increases KLF5 protein stability through deubiquitination.

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As expected, ATXN3L over-expression blocked the KLF5 protein degradation induced by WWP1 and FBW7.

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To test whether ATXN3L can antagonize E3 ligase mediated KLF5 degradation, we transfected WWP1, Myc-FBW7, KLF5 and ATXN3L into HEK293FT cells.

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To further confirm whether ATXN3L knockdown decreases KLF5 protein stability in human breast cancer cells, we knocked down ATXN3L in HCC1806 and SUM1315 (two basal type triple negative breast cancer cell lines), in which KLF5 is highly expressed.
ATXN3L increases the amount of KLF5.
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ATXN3L increases the amount of KLF5. 3 / 3
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We identified ATXN3L as a candidate KLF5 DUB because knockdown of ATXN3L decreased KLF5 protein levels and inhibited breast cancer cell proliferation.

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As expected, knockdown of ATXN3L dramatically decreased the endogenous KLF5 protein levels in both cell lines.

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As described above, knockdown of ATXN3L decreased the endogenous KLF5 protein levels in both HCC1806 and SUM1315 cell lines.
ATXN3L decreases the amount of KLF5.
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ATXN3L decreases the amount of KLF5. 3 / 3
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Knockdown of ATXN3L decreased KLF5 protein levels and inhibited the proliferation of breast cancer cells [XREF_BIBR].

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Nevertheless, ATXN3L increased the KLF5 protein stability and inhibited the expression of KLF5 downstream target genes, such as p21 and p27, and promote basal type breast cancer cell proliferation.

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ATXN3L was identified as a candidate KLF5 DUB because the siRNA pool, and 2 out of 3 individual siRNA, against ATXN3L dramatically decreased the KLF5 protein level in HeLa.

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These results indicate that endogenous ATXN3L promotes breast cancer cell proliferation partially through stabilizing KLF5.

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Since ATXN3L stabilizes KLF5 and inhibits the expression of p27 and p21, it is plausible that ATXN3L also promotes breast cancer cell proliferation.

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Consistently, knockdown of ATXN3L by shRNAs significantly decreased cell proliferation in both breast cancer cell lines, as measured by CCK-8.

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Our findings in this study suggest that ATXN3L promotes cell proliferation but not cell migration.

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Functionally, knockdown of ATXN3L inhibits breast cancer cell proliferation partially through KLF5.

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In summary, our study identified ATXN3L as a KLF5 DUB in breast cancer and found that ATXN3L stabilized the KLF5 protein and promoted cell proliferation partially through KLF5.

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ATXN3L promotes breast cancer cell proliferation partially through KLF5.
ATXN3L affects CDKN1A
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ATXN3L decreases the amount of CDKN1A.
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ATXN3L decreases the amount of CDKN1A. 2 / 2
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Furthermore, knockdown of ATXN3L by two different siRNAs also upregulated p27 and p21 protein levels in these cell lines.

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Since ATXN3L stabilizes KLF5 and inhibits the expression of p27 and p21, it is plausible that ATXN3L also promotes breast cancer cell proliferation.
ATXN3L increases the amount of CDKN1A.
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ATXN3L increases the amount of CDKN1A. 1 / 1
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Functionally, depletion of ATXN3L increased the p27 and p21 protein levels and suppressed breast cancer cell proliferation.
ATXN3L affects CDKN1B
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ATXN3L decreases the amount of CDKN1B. 2 / 2
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Furthermore, knockdown of ATXN3L by two different siRNAs also upregulated p27 and p21 protein levels in these cell lines.

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Since ATXN3L stabilizes KLF5 and inhibits the expression of p27 and p21, it is plausible that ATXN3L also promotes breast cancer cell proliferation.
Rotenone affects ATXN3L
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Rotenone increases the amount of ATXN3L. 1 / 1
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ctd
No evidence text available
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Hsa-miR-6891-3p decreases the amount of ATXN3L. 1 / 1
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biopax:mirtarbase
No evidence text available
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Hsa-miR-670-3p decreases the amount of ATXN3L. 1 / 1
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biopax:mirtarbase
No evidence text available
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Hsa-miR-6072 decreases the amount of ATXN3L. 1 / 1
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biopax:mirtarbase
No evidence text available
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Hsa-miR-548g-3p decreases the amount of ATXN3L. 1 / 1
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biopax:mirtarbase
No evidence text available
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Hsa-miR-548e-5p decreases the amount of ATXN3L. 1 / 1
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biopax:mirtarbase
No evidence text available
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Hsa-miR-514b-3p decreases the amount of ATXN3L. 1 / 1
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biopax:mirtarbase
No evidence text available
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Hsa-miR-514a-3p decreases the amount of ATXN3L. 1 / 1
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biopax:mirtarbase
No evidence text available
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Hsa-miR-4753-3p decreases the amount of ATXN3L. 1 / 1
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biopax:mirtarbase
No evidence text available
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Hsa-miR-130b-5p decreases the amount of ATXN3L. 1 / 1
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biopax:mirtarbase
No evidence text available
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Hsa-miR-1238-3p decreases the amount of ATXN3L. 1 / 1
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biopax:mirtarbase
No evidence text available
Butanal affects ATXN3L
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Butanal decreases the amount of ATXN3L. 1 / 1
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ctd
No evidence text available
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MT19c compound increases the amount of ATXN3L. 1 / 1
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ctd
No evidence text available
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As expected, ATXN3L over-expression blocked the KLF5 protein degradation induced by WWP1 and FBW7.
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Our findings in this study suggest that ATXN3L promotes cell proliferation but not cell migration.