BAP1 Data Analysis

HGNC Gene Name: BRCA1 associated protein 1
HGNC Gene Symbol: BAP1
Identifiers: hgnc:950 NCBIGene:8314 uniprot:Q92560
Orthologs: mgi:1206586 rgd:1311938
INDRA Statements: deubiquitinations all statements
Pathway Commons: Search for BAP1
Number of Papers: 1702 retrieved on 2023-02-19

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)
UBE2E3	ubiquitin conjugating enzyme E2 E3	-0.199	Reactome (2)	-0.16	-0.96	1.19e-01
NCOA6	nuclear receptor coactivator 6	0.193		-0.04	-0.33	5.18e-01
PTPN1	protein tyrosine phosphatase non-receptor type 1	0.189		0.18	0.90	1.87e-03
KMT2C	lysine methyltransferase 2C	0.187	BioGRID INDRA (3)	0.16	0.80	5.52e-03
KANSL1	KAT8 regulatory NSL complex subunit 1	0.178		0.35	1.84	8.91e-11
ASXL1	ASXL transcriptional regulator 1	0.171	BioGRID IntAct INDRA (24) Reactome (4)	0.31	1.64	3.25e-07
PPP4R2	protein phosphatase 4 regulatory subunit 2	0.167	Reactome (2)	0.10	0.48	9.19e-02

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with BAP1using 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:0035097	histone methyltransferase complex	Cellular Component	3.44e-06	7.68e-04	3.23e-04
GO:0034708	methyltransferase complex	Cellular Component	7.66e-06	1.71e-03	3.59e-04
GO:0042974	retinoic acid receptor binding	Molecular Function	3.49e-05	7.77e-03	1.09e-03
GO:0003713	transcription coactivator activity	Molecular Function	1.54e-04	3.43e-02	3.60e-03

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out BAP1 using CRISPR-Cas9.

Knockout Differential Expression

Symbol	Name	log₂-fold-change	p-value	p-value (adj.)
RPS28	ribosomal protein S28	1.12e+00	4.07e-09	3.24e-05
RPS28P7	ribosomal protein S28 pseudogene 7	1.10e+00	2.20e-07	5.83e-04
RPS9	ribosomal protein S9	1.23e+00	2.08e-07	5.83e-04
GSTP1	glutathione S-transferase pi 1	-4.03e-01	1.01e-06	2.00e-03
FTL	ferritin light chain	3.39e-01	6.56e-06	8.69e-03
SAA1	serum amyloid A1	-7.63e-01	1.19e-05	1.35e-02
NQO1	NAD(P)H quinone dehydrogenase 1	3.46e-01	5.48e-05	4.36e-02
G0S2	G0/G1 switch 2	-3.64e-01	6.20e-05	4.48e-02
ATAD2	ATPase family AAA domain containing 2	-5.75e-01	7.10e-05	4.70e-02
HMGB3	high mobility group box 3	3.28e-01	7.92e-05	4.84e-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 BAP1 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

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BAP1 leads to the deubiquitination of KLF5. 6 / 6

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Compared with GST and BAP1-C91S, BAP1 specifically decreased KLF5 polyubiquitination (XREF_FIG; XREF_SUPPLEMENTARY).

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BAP1 interacts directly with KLF5 and stabilizes KLF5 via deubiquitination.

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BAP1, but not BAP1-C91S, markedly decreased KLF5 protein polyubiquitination (XREF_FIG, lanes 3 and 4), whereas another DUB, A20, did not decrease KLF5 polyubiquitination (XREF_FIG, lane 5).

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Finally, we demonstrated that knockdown of endogenous BAP1 increased the ubiquitination of endogenous KLF5 in HCC1806 (XREF_FIG).

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Second, BAP1 decreases KLF5 polyubiquitination and increases KLF5 protein stability in a DUB activity dependent manner.

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BAP1 antagonizes WWP1 mediated transcription factor KLF5 ubiquitination and inhibits autophagy to promote melanoma progression.

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BAP1 deubiquitinates INO80. 6 / 6

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In line with this notion, BAP1 depletion resulted in reduced localization of RPA, RAD51 and BRCA1 to IRIF or microlaser irradiation site [100,101], although it remains ambiguous whether either histone[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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In addition to MCRS1, a recent study revealed that BAP1 deubiquitinates and stabilizes Ino80, a key subunit of the INO80 chromatin remodeling complex implicated in DNA replication during stress.

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BAP1 interacts with and deubiquitylates INO80, playing a critical role in stabilizing and targeting the INO80 chromatin remodeling complex to the replication forks.

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Since BAP1 deubiquitinates and stabilizes Ino80, we investigated the relationship between CHIP and BAP1 in Ino80 ubiquitination.

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BAP1 deubiquitylates INO80 and thereby protects the protein from ubiquitin mediated proteolysis.

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BAP1 overexpression also abolished basal Ino80 ubiquitination (XREF_FIG and XREF_FIG, rightmost lanes).

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BAP1 deubiquitinates HCFC1. 6 / 6

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HCF-1 is modified with ubiquitin in vivo, and ectopic studies suggest BAP1 deubiquitinates HCF-1.

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The tumor suppressor BAP1 associates with ASXL1/2 to form the core Polycomb complex PR-DUB, which catalyzes the removal of mono-ubiquitin from several substrates including histone H2A. This complex also mediates the poly-deubiquitination of HCFC1, OGT and PCG1-α, preventing them from proteasomal degradation.

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It has been proposed that ubiquitylation of HCF1 blocks E2F responsive promoter activity, and that HCF1 deubiquitylation by BAP1 would remove this inhibition and promote cell proliferation 33.

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It has been proposed that BAP1 may modulate cell proliferation by deubiquitylating the transcriptional regulator HCF1.

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BAP1 also interacts with and deubiquitinates the transcriptional regulator host cell factor 1 (HCF1).

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SETD2 is a histone H3 lysine 36 (H3K36) methyltransferase that regulates mRNA splicing and transcription elongation; BAP1 interacts with and deubiquitinates host cell factor-1 (HCF-1), a transcription co-activator, that regulates cell proliferation; and KDM5C a histone 3 trimethyl-lysine 4 (H3K4Me3) demethylase that erase active transcription marks.

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BAP1 deubiquitinates TUBG. 4 / 4

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While the mechanism remains to be fully elucidated, it seems that deubiquitylation of gamma-tubulin by BAP1 during mitosis allows proper spindle organisation and function [XREF_BIBR].

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A recent study has linked the deubiquitination of gamma-tubulin by BAP1 to breast cancer.

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Another study showed de-ubiquitination of gamma-tubulin by BAP1 prevents chromosome instability in breast cancer cells [15].

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Deubiquitination of gamma-tubulin by BAP1 prevents chromosome instability in breast cancer cells.

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BAP1 deubiquitinates BRCA1. 3 / 3

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BAP1 also controls G1/S cell cycle progression by regulating BRCA-1 [111], Ying Yang 1 (YY-1), and host cell factor 1 (HCF-1)

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As a possible mechanism of BRCA1 stabilization by BAP1 transduction in this study, we speculated that the ubiquitination of BRCA1 protein might be directly deubiquitinated by BAP1.

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We hypothesized that BAP1 might deubiquitinate BRCA1 and protect it from proteasome mediated degradation; this might explain the BRCA1 stabilization by the mutant BAP1 forms that retained the DUB activity.

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BAP1 deubiquitinates OGT. 3 / 3

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XREF_BIBR, XREF_BIBR, XREF_BIBR BAP1 also deubiquitylates OGT and regulates its levels.

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To investigate whether BAP1 can deubiquitylate and stabilize OGT directly, rather than decreased OGT being secondary to a reduction in HCF-1, we affinity purified ubiquitylated and Myc tagged human OGT from HEK293T cells, and then incubated it with human BAP1 and human ASXL1 residues 2-365 co-purified from Sf9 cells.

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BAP1 leads to the deubiquitination of Histone on A2. 3 / 3

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Further mechanistic studies demonstrated that BAP1 suppresses SLC7A11 expression partly by deubiquitinating histone 2A ubiquitination to promote ferroptosis.

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p53 binds to the SLC7A11 promoter, directly suppressing its transcription; the nuclear deubiquitinase (DUB) BAP1 represses SLC7A11 transcription by removing histone 2A ubiquitination from the SLC7A11 promoter; and KEAP1 represses SLC7A11 transcription through degrading NRF2, a master transcription factor of antioxidant response and regulator of SLC7A11.

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Recently, it has been found that BAP1 can inhibit the expression of SLC7A11 to suppress the uptake of cystine by deubiquitinating histone 2A on the SLC7A11 promoter.

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BAP1 deubiquitinates MCRS1. 2 / 2

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Since BAP1 is a de-ubiquitinating enzyme, we explored whether BAP1 de-ubiquitinates and stabilizes MCRS1.

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Moreover, de-ubiquitination of MCRS1 by BAP1 plays important roles in regulating proper mitotic progression and prevents chromosome instability.The yeast two-hybrid screen was performed with full leng[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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BAP1 deubiquitinates Histone_H2B. 2 / 2

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Subsequent WB using anti-HA and anti- Flag antibodies showed that the BAP1 WT, but not a MT, deubiquitinated H2B in vivo.

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BAP1 affects cell population proliferation

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BAP1 inhibits cell population proliferation.

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BAP1 inhibits cell population proliferation. 10 / 41

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BAP1 enhances BRCA1 mediated suppression of cell proliferation through stabilizing BRCA1 [XREF_BIBR].

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Rescue expression of BAP1, but not BAP1-C91A in two neuroblastoma cells lines reduced the proliferation rate at 48 and 72h, compared with control cells.

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BAP1 suppresses MM cell proliferation.

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In contrast to melanoma cells, stable overexpression of BAP1 into immortalized but non transformed melanocytes did suppress proliferation and reduce survivin.

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Results BAP1 promotes proliferation in HNSCC cells regardless of HPV status Studies of the effects of BAP1 on cell proliferation have shown conflicting results , with some reporting that BAP1 suppresses cell proliferation ( 12 , 13 ) , and others reporting that BAP1 enhances proliferation ( 14 , 15 ) .

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As shown in XREF_FIG, stable introduction of BAP1 into Pmel cells (i.e. Pmel (BAP1)) reduced proliferation, colony forming capacity and survivin levels.

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Wild-type BAP1 but not mutant BAP1 significantly inhibited HCC cell proliferation, invasion, epithelial-mesenchymal transition (EMT) in vitro, and tumor progression and metastasis in vivo.

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Our results suggested that, whereas WT BAP1 suppresses MM cell proliferation and restores cell survival after IR damage, some mutant BAP1 may also moderately retain these functions.

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BAP1 suppresses the proliferation of some cell types.

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BAP1 promotes cell death and suppresses cell proliferation in LAC.

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Mutated BAP1 inhibits cell population proliferation. 1 / 1

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Overexpression of wild-type but not mutant BAP1 significantly suppressed ICC cell proliferation, cell cycle progression, and invasion in vitro, as well as tumor progression in vivo.

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BAP1 activates cell population proliferation.

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BAP1 activates cell population proliferation. 10 / 22

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In agreement with previous work in other cell types [XREF_BIBR, XREF_BIBR, XREF_BIBR], transient BAP1 loss decreased cell proliferation.

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XREF_BIBR showed that BAP1 overexpression in BAP1-null malignant pleural mesothelioma cell lines promoted cell proliferation and that BAP1 knockdown decreased proliferation in three malignant pleural mesothelioma cell lines.

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These results indicate that BAP1 promotes KLF5 positive breast cell proliferation in vitro.

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Our data suggest that BAP1 promotes cell proliferation and migration , and enhances the expression of KLF5 and its downstream genes , including CyclinD1 and FGF-BP1 , in the esophageal carcinoma cell line ECA109 .

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In both cell lines , knockdown of BAP1 significantly inhibited cell proliferation ( P < 0.05 ; Fig. 1A and B ) and clonogenic survival ( Fig. 1C-F ) .

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In both cell lines, knockdown of BAP1 significantly inhibited cell proliferation (P < 0.05; XREF_FIG and XREF_FIG) and clonogenic survival (XREF_FIG - XREF_FIG).

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BAP1 promotes breast cancer cell proliferation and migration in vitro and tumour growth and lung metastasis in vivo.

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BAP1 promotes cell proliferation through KLF5.

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In conclusion, BAP1 is a KLF5 DUB and BAP1 promotes basal breast cell proliferation, migration, tumour growth and metastasis partially through stabilizing KLF5 (XREF_SUPPLEMENTARY).

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42 Kruppel like factor 5 (KLF5) is stabilized by the DUB BRCA1 associated Protein 1 (BAP1), promoting breast cancer cell proliferation.

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Mutated BAP1 activates cell population proliferation. 2 / 2

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In CMML, UTX mutations co-occurred with ASXL1, TET2, or CBL mutations, and in bladder cancer with somatic BAP1 mutations [75] and enhanced in vitro proliferation, in vivo tumor growth and cell migrati[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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In CMML, UTX mutations co-occurred with ASXL1, TET2, or CBL mutations, and in bladder cancer with somatic BAP1 mutations [XREF_BIBR] and enhance in vitro proliferation, in vivo tumor growth and cell migration [XREF_BIBR].

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BAP1 affects BRCA1

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BAP1 inhibits BRCA1.

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BAP1 inhibits BRCA1. 10 / 18

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XREF_BIBR It was initially suggested that BAP1 bound BRCA1 cleaves ubiquitin, and enhances the growth-suppressive effects of BRCA1.

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We further found that BAP1 depletion suppressed the assembly of constitutive BRCA1 foci, which are associated with homologous recombination (HR), but had minimal effect on gamma-H2AX foci and did not affect proteins associated with nonhomologous end joining, suggesting that BAP1 affects radiosensitivity in HNSCC by modifying HR.

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Early experiments found that BAP1 enhanced BRCA1 mediated inhibition of breast cancer cell growth.

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BAP1 enhances BRCA1 mediated suppression of cell proliferation through stabilizing BRCA1 [XREF_BIBR].

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The downregulation of BAP1 expression by BCR-ABL reduces the stability of BRCA1 in chronic myeloid leukemia.

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BAP1 enhances BRCA1 mediated suppression of cell growth in colony formation assays, and this suppression by BAP1 is augmented by its UCH enzymatic domain.

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BAP1 enhances BRCA1 mediated inhibition of breast cancer cell growth and is the first nuclear localized ubiquitin carboxy-terminal hydrolase to be identified.

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Furthermore, the two proteins appeared to interact in a biologically significant manner because BAP1 augmented the growth suppressive properties of BRCA1 in breast cancer cells.

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In our study, we found that BAP1 depletion decreased the assembly of constitutive BRCA1 foci, which are associated with HR, but had minimal effect on gamma-H2AX foci.

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BAP1 bound to BARD1 inhibits BRCA1. 1 / 1

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Here, we report that BAP1 interacts with BARD1 to inhibit the E3 ligase activity of BRCA1 and BARD1.

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BAP1 bound to BRCA1 inhibits BRCA1. 1 / 1

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XREF_BIBR It was initially suggested that BAP1 bound BRCA1 cleaves ubiquitin, and enhances the growth-suppressive effects of BRCA1.

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BAP1 activates BRCA1.

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BAP1 activates BRCA1. 8 / 11

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Surprisingly, BAP1 mediated growth suppression is independent of wild-type BRCA1.

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Interestingly, BRCA1 proteins were decreased in the MM cells with BAP1 deletion, and transduction of the mutants as well as WT BAP1 increased BRCA1 proteins, suggesting that BAP1 may promote DNA repair partly through stabilizing BRCA1.

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The association of BAP1, a Ub carboxy-terminal hydrolase, suggests that BRCA1 mediated ubiquitination is tightly regulated, and there is evidence that BAP1 can potentiate BRCA1 tumor suppressor functi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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It is still not known whether BAP1 functions to modulate BRCA1 ubiquitynating activity and/or to regulate ubiquitin dependent degradation of BRCA1 itself.

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XREF_BIBR suggested that BAP1 could function for HR repair in the BRCA1 related pathway, and they hypothesized that BAP1 enables BRCA1 to readily accumulate DSB sites.

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Initially identified in a yeast two-hybrid screen using the RING-finger domain of the breast cancer type 1 susceptibility protein BRCA1 as bait, BAP1 was shown to enhance BRCA1 mediated growth suppression in MCF7 cells [XREF_BIBR].

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Conceivably, BAP1 might modulate BRCA1 mediated tumor suppression by hydrolyzing ubiquitin moieties from the BRCA1 and BARD1 heterodimer, its associated proteins, or even its substrates [61].

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Although BAP1 has been hypothesized to function in BRCA1 mediated processes, our results, and others ', support the possibility of BRCA1 independent functions of BAP1.

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BAP1 increases the amount of BRCA1.

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BAP1 increases the amount of BRCA1. 5 / 5

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XREF_BIBR previously suggested that BAP1 enhanced BRCA1 mediated inhibition of cancer cell growth, although they did not directly establish the possibility that BAP1 enhances the BRCA1 protein level.

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Although BRCA1 expression significantly decreased in an MM cell line with BAP1 deletion, Y-MESO-25, the transduction of the WT and even mutant forms of BAP1 induced upregulation of the BRCA1 protein level.

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BAP1 mediated growth suppression is independent of wild-type BRCA1 expression.

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Noticeably, we found that exogenous BAP1 significantly increased the BRCA1 protein level.

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It is worth noting that BAP1 can restore the protein expression of BRCA1.

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Modified BAP1 increases the amount of BRCA1. 1 / 1

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The restoration of BAP1 protein expression in BCR-ABL1-expressing UT-7 cells also restores BRCA1 protein expression.

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Mutated BAP1 increases the amount of BRCA1. 1 / 1

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Furthermore, we found that all three mutant BAP1 forms increased BRCA1 protein levels.

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BAP1 affects SLC7A11

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BAP1 decreases the amount of SLC7A11.

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BAP1 decreases the amount of SLC7A11. 10 / 20

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SLC7A11 is an essential BAP1 target in human cancers, and BAP1 represses SLC7A11 expression via reducing H2Aub occupancy on SLC7A11 promoter in a deubiquitinating dependent manner [XREF_BIBR, XREF_BIBR].

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Specifically, our study suggests a model in which the tumor suppressor BAP1 normally functions to repress the expression of SLC7A11 at least partly by deubiquitinating H2Aub on SLC7A11, thereby inhibiting cystine uptake into cells and rendering them more sensitive to ferroptosis.

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However, restoring BAP1 in p53 deficient cells still inhibited SLC7A11 expression (XREF_SUPPLEMENTARY - XREF_SUPPLEMENTARY), and the fold change in SLC7A11 expression by BAP1 restoration in p53 deficient cells was similar to that in p53-proficient cells (XREF_SUPPLEMENTARY), suggesting that BAP1 represses SLC7A11 expression independent of p53.

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Functional studies reveal that BAP1 decreases H2Aub occupancy on the SLC7A11 promoter and represses SLC7A11 expression in a deubiquitinating dependent manner, and that BAP1 inhibits cystine uptake by repressing SLC7A11 expression, leading to elevated lipid peroxidation and ferroptosis.

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In addition, erastin potently induced SLC7A11 expression in BAP1 deficient cells (XREF_SUPPLEMENTARY - XREF_SUPPLEMENTARY), suggesting that BAP1 represses the basal expression of SLC7A11 and that erastin induces SLC7A11 expression likely through BAP1 independent mechanisms.

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Both BAP1 and PRC1 (the main H2Aub ubiquitin ligase) inhibit the expression of SLC7A11 [XREF_BIBR].

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In addition, it 's been found that in renal cancer cell line, as a nuclear deubiquitinating enzyme, the tumour suppressor BRCA1 associated protein 1 decreases SLC7A11 expression, thereby causing lipid peroxidation and ferroptosis [XREF_BIBR].

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Further mechanistic studies demonstrated that BAP1 suppresses SLC7A11 expression partly by deubiquitinating histone 2A ubiquitination to promote ferroptosis.

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Recently, it has been found that BAP1 can inhibit the expression of SLC7A11 to suppress the uptake of cystine by deubiquitinating histone 2A on the SLC7A11 promoter.

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Modified BAP1 decreases the amount of SLC7A11. 2 / 2

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We confirmed that re-expression of BAP1 WT, but not its C91A mutant, in UMRC6 cells decreased SLC7A11 expression (XREF_FIG), suggesting that BAP1 mediated repression of SLC7A11 expression requires BAP1 's DUB activity.

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Similarly, BAP1 re-expression in NCI-H226 cells, a BAP1 deficient mesothelioma cell line with high SLC7A11 expression (see XREF_FIG), also repressed SLC7A11 expression (XREF_SUPPLEMENTARY - XREF_SUPPLEMENTARY).

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BAP1 inhibits SLC7A11.

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BAP1 inhibits SLC7A11. 7 / 7

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Several studies have revealed that BAP1 can inhibit ubiquitinated histone 2A (H2Aub) occupancy on the SLC7A11 promoter (Zhang et al., 2018).

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Further mechanistic studies demonstrated that BAP1 suppresses SLC7A11 expression partly by deubiquitinating histone 2A ubiquitination to promote ferroptosis .

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In addition, we studied how BAP1 coordinates with other transcription factors to regulate SLC7A11 expression and show that BAP1 mediated SLC7A11 repression does not require NRF2 and ATF4 transcription factors.

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Analysis of our H2Aub ChIP-seq data revealed that restoration of BAP1 WT, but not BAP1 C91A, markedly decreased H2Aub occupancy at both the promoter and gene body of SLC7A11 (XREF_FIG), which was further confirmed by H2Aub ChIP assay on the SLC7A11 promoter and representative exons (XREF_FIG and XREF_SUPPLEMENTARY).

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Both BAP1 and PRC1 ( the main H2Aub ubiquitin ligase ) inhibit the expression of SLC7A11 [ 54 ] .

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Together, our data suggested a model that the BAP1 containing PR and DUB complex binds on the SLC7A11 promoter, where BAP1 removes ubiquitin from H2Aub, and BAP1 dependent H2Aub reduction on SLC7A11 is associated with BAP1 mediated SLC7A11 repression.

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Among these genes, SLC7A11 (encoding the Solute Carrier Family 7 Member 11), an antiporter that imports cystine and exports glutamate, was repressed by BAP1.

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BAP1-C91A inhibits SLC7A11. 1 / 1

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BAP1 increases the amount of SLC7A11.

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The tumor suppressor BRCA1 associated protein 1 (BAP1) represses SLC7A11 expression via reducing H2Aub occupancy on SLC7A11 promoter in a deubiquitinating dependent manner [XREF_BIBR].

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The tumor suppressor BRCA1-associated protein 1 inhibits the growth of cancer cells by regulating the expression of SLC7A11 (Zhang et al., 2019), and its effect is similar to Erastin.

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The tumor suppressor BAP1, an H2A deubiquitinating enzyme, can reduce SLC7A11 expression by inhibiting H2A ubiquitination (H2Aub) on the SLC7A11 promoter, thus controlling ferroptosis (Zhang Y.L.

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As a particular SMG of C1, BAP1 has been certified to block cystine uptake by inhibiting the expression of SLC7A11, leading to lipid peroxidation and ferroptosis, thereby inhibiting tumor progression.

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Conversely, BAP1 deficiency by CRISPR technology increased SLC7A11 expression in several BAP1-proficient renal cancer cells with low SLC7A11 levels, including 786-O, Caki1, and ACHN cells (XREF_FIG - XREF_FIG and XREF_SUPPLEMENTARY - XREF_SUPPLEMENTARY).

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ASXL1 affects BAP1

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ASXL1 activates BAP1.

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ASXL1 activates BAP1. 10 / 29

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In this paper we describe that similar to the homologous UCH-L5 and RPN13 DEU complex, the DEUBAD domains of ASXL1, ASXL2 and ASXL3 can activate BAP1 by increasing BAP1 's affinity specifically for the ubiquitin in the substrate, through a combination of mild effects.

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Therefore we tested whether ASXL1 DEU can activate BAP1 by increasing its affinity for ubiquitin.

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The tumor suppressor BAP1 is activated by ASXL1 to deubiquitinate mono-ubiquitinated H2A at K119 in Polycomb gene repression.

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Like UCH37, BAP1 associates with a partner protein, ASXL1, which activates BAP1 and is required for the BAP1 mediated deubiquitylation of H2A in nucleosomes.

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As part of the Polycomb repression machinery, BAP1 is activated by the deubiquitinase adaptor domain of ASXL1 mediating gene repression by cleaving ubiquitin (Ub) from histone H2A in nucleosomes.

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BAP1 is activated by ASXL1 to deubiquitinate mono-ubiquitinated H2A at K119 in Polycomb gene repression, but the mechanism of this reaction remains poorly defined.

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The ULD is conserved in UCH family member BAP1 that is activated by the ASXL1 DEUBAD domain to deubiquitinate H2A.

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Like on Ub-AMC, ASXL1 1-390 could activate BAP1 to the same extent as ASXL1 DEU (XREF_FIG), but on the nucleosomal substrates the activation observed was much more significant than on the minimal substrate.

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Because of the strong conservation of key elements between UCH-L5 and RPN13 DEU and BAP1 and ASXL1, we anticipate that the ASXL1 DEUBAD domain employs similar strategies to activate BAP1.

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A recent study suggests that ASXL1 might activate Bap1 in a similar manner xref .

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Mutated ASXL1 activates BAP1. 1 / 1

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Monoubiquitination of mutant ASXL1 enhanced the catalytic function of BAP1, resulting in a profound reduction in H2AK119ub by counteracting the PRC1 complex.

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ASXL1 inhibits BAP1.

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ASXL1 inhibits BAP1. 1 / 1

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ASXL1 Modulates DUB Activity of BAP1 and RAR Repression In Vivo The physiological relevance of ASXL1 cooperation with BAP1 was addressed by using MEFs derived from Asxl1 null mice.

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BAP1 affects Neoplasm Metastasis

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BAP1 activates Neoplasm Metastasis.

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BAP1 activates Neoplasm Metastasis. 10 / 15

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Furthermore, BAP1 knockdown inhibits tumorigenicity and lung metastasis, which can be rescued partially by ectopic expression of KLF5.

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Finally, we wondered whether BAP1 and KLF5 promoted metastasis in vivo.

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In conclusion, BAP1 is a KLF5 DUB and BAP1 promotes basal breast cell proliferation, migration, tumour growth and metastasis partially through stabilizing KLF5 (XREF_SUPPLEMENTARY).

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BAP1 promotes breast cancer cell proliferation and metastasis by deubiquitinating KLF5.

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How BAP1 and KLF5 promote metastasis requires further investigation.

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BAP1 and KLF5 promote breast cancer migration, invasion and metastasis may not through p27; however, KLF5 is a transcription factor regulating numerous downstream target genes, such as FGF-BP and mPGES1.

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Nevertheless, our results suggest that BAP1 promotes breast tumour growth and metastasis partially through stabilizing KLF5.

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BAP1 and KLF5 promote breast cancer lung metastasis.

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Therefore, these findings clearly indicate that BAP1 promotes breast cancer lung metastasis partially through stabilizing KLF5.

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Furthermore, BAP1 loss abrogates tumor growth and lung metastasis in murine syngeneic tumor models.

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Mutated BAP1 activates Neoplasm Metastasis. 3 / 3

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XREF_BIBR Therefore, both somatic mutation of BAP1 in primary UM tumors and germline mutations increase the risk of metastasis and impart low survival rate.

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Germline BAP1 mutations increased risk of metastasis independent of ciliary body involvement (P =.02).

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37 Therefore, both somatic mutation of BAP1 in primary UM tumors and germline mutations increase the risk of metastasis and impart low survival rate.

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BAP1 inhibits Neoplasm Metastasis.

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BAP1 inhibits Neoplasm Metastasis. 10 / 12

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19 However, GNA11 mutations are also more common in tumors involving the ciliary body, which is an independent risk factor for metastasis, and in tumors with mutations in the metastasis suppressor BAP1 (Breast cancer 1, early onset (BRCA1)-associated protein 1) (see below), so it remains possible or even likely that the association between GNA11 and metastasis is not causal.

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Finally, to elucidate the mechanism by which BAP1 suppresses invasion and metastasis in LAC cells, we analyzed the expression levels of metastasis related proteins in transfected H1299 cells and H1650 cells using IB, respectively.

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It will be important to elucidate how this effect of BAP1 loss promotes metastasis and how to reverse this effect therapeutically.

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We find that this process requires VCAM mediated adhesion between UM cells and ECs and that loss of the metastasis suppressor BAP1 enhances TEM.

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26 The exact mechanism (s) by which loss of BAP1 mediates primary uveal melanoma metastasis is currently being investigated.

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Knockdown of BAP1 in TNBC cells inhibited tumorigenesis and metastasis, which could be partially rescued by restoration of KLF5 expression, suggesting that KLF5 mediates, at least in part, the breast cancer promoting function of BAP1 [XREF_BIBR].

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There was a low transcript number for BRCA1 associated protein 1 (BAP1), which when highly expressed suppresses metastasis [XREF_BIBR].

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Prompted by these transcriptomic findings, we wished to explore further the possibility that BAP1 inhibits metastasis of uveal melanoma cells by maintaining their differentiated state and impeding their reversion to a stem like state.

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The authors concluded that loss of BAP1 might increase susceptibility to uveal melanoma metastasis and serve as a valuable therapeutic target.

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Our results reveal a novel route of transendothelial migration for uveal melanoma cells, and they provide insight into the mechanism by which loss of BAP1 promotes metastasis.

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BAP1 affects cell death

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BAP1 activates cell death.

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BAP1 activates cell death. 10 / 19

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Reduced BAP1 levels impair DNA repair as well as different forms of cell death and induce metabolic alterations that together favor cancer development and growth.

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BAP1 induces cell death via interaction with 14-3-3 in neuroblastoma.

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- If BAP1 triggers cell death as discussed by the authors , could the authors be selecting for cells with reduced BAP1 knockdown in Fig. S2B ?

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Two different strategies were applied to analyze the mechanism of BAP1 inducing cell death in neuroblastoma.

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Among the most common genetic alterations or deregulated pathways identified in MM, deletions in the cyclin dependent kinase inhibitor 2A (CDKN2A) locus, inactivation of the retinoblastoma (RB) pathway, mutations in the BRCA1 associated protein 1 (BAP1) and neurofibromatosis type 2 (NF2) genes, and aberrant regulation of phosphatidylinositol-4,5- bisphosphate 3-kinase (PI3K)/AKT pathway are all related to MM uncontrolled growth and resistance to treatment induced cell death.

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Conversely, silencing BAP1 expression reduced the early stage apoptotic cell population to 2.71%, significantly lower than that of the control (5.25%, p < 0.05), suggesting that BAP1 promotes tumor cell death by apoptosis and necrosis.

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Processes other than apoptosis could be also involved in the cell death mechanism mediated by BaP1 on BAEC and HeLa cell lines [[XREF_BIBR]].

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More in-depth analysis of BAP1 mediated cell death is warranted in order to determine the specific mechanism of BAP1 mediated growth inhibition.

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The mechanism that BAP1 induces cell death is mediated via an interaction with 14-3-3 protein.

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24 For example, BAP1 has been shown to enhance progression through the G1-S checkpoint and subsequently induce cell death by a process with similarities to both apoptosis and necrosis.

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BAP1 inhibits cell death.

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BAP1 inhibits cell death. 7 / 7

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Here we show that BAP1 inhibits cell death induced by unresolved metabolic stress.

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Arabidopsis C2 domain proteins, BAP1, and its homologue BAP2, negatively regulate biotic and abiotic cell death.

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The powerful activity of heterozygous germline BAP1 mutations to facilitate asbestos induced transformation and cause mesothelioma has been linked to the alterations in the mechanisms that regulate DNA repair and cell death caused by decreased BAP1 protein levels.

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Thus, BAP1 might suppress tumorigenesis by facilitating tumor cell death by activation of both these pathways.

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Here we show that BAP1 inhibits cell death induced by unresolved metabolic stress.

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XREF_BIBR reported that BAP1 overexpression in the BAP1-null NCI-H226 human non-small-cell lung cancer cell line suppressed growth in DUB activity- and nuclear localization dependent manners by accelerating the cell cycle G1/S transition and inducing cell death.

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The group of flg22 induced MPK4 dependent genes encode important regulators of plant defence such as the cell death inhibitor BAP1 [XREF_BIBR], the calcium dependent protein kinase CPK5 [XREF_BIBR], the exocyst complex subunit EXO70B2 [XREF_BIBR], the cyclic nucleotide gated ion channel CNGC11 [XREF_BIBR] or the BAK1 like receptor kinase BKK1 and SERK4 [XREF_BIBR].

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Mutated BAP1 inhibits cell death. 1 / 1

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Based on epidemiological and genetic studies, a carcinogenic model has been proposed in which BRCA1-associated protein 1 mutations are able to suppress cell death in mesothelial cells and increase genomic instability in the mutagenic microenvironment.

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BAP1 affects apoptotic process

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BAP1 activates apoptotic process.

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BAP1 activates apoptotic process. 10 / 20

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For example, BAP1 can enhance progression through the G1-S checkpoint and subsequently induce cell death by a process with similarities to both apoptosis and necrosis [XREF_BIBR].

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Likewise, A549 cells transfected with the BAP1 siRNA showed suppression of cell apoptosis (XREF_SUPPLEMENTARY), whereas overexpression of BAP1 significantly promoted cell apoptosis (XREF_SUPPLEMENTARY).

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It is also prudent to note that expression of BAP1 increased the population of cells that stain positive for both AnnexinV and PI, an indication of late apoptosis and/or necrosis.

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Functionally, BAP1 promotes apoptosis and necrosis, and down-regulates the migration and invasion abilities of LAC cells.

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We also provided evidence that BAP1 suppressed cell proliferation and promoted cell apoptosis, suggesting that BAP1 tended to function as a tumor suppressor in lung cancer.

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Interestingly B. lanceolatus venom results reproduced the in vivo observations of Jiménez et al [45]; in a murine model of cutaneous tissue damage, class I SVMP, BaP1, causes the apoptosis of keratinocytes without affecting the viability of endothelial cells.

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In functional experiments, BAP1 has been shown to suppress lung cancer tumorigenesis in athymic nude mice, promote the cell cycle and induce both apoptosis and necrosis.

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We show that BAP1 inactivation causes apoptosis in mouse embryonic stem cells, fibroblasts, liver, and pancreatic tissue but not in melanocytes and mesothelial cells.

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Genetic depletion of BAP1 in melanoma cells reduced proliferation and colony forming capability, induced apoptosis and inhibited melanoma tumor growth in vivo.

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Inactivation of BAP1 causes apoptosis in mouse ES cells, fibroblasts, liver and pancreatic tissue but not melanocytes and mesothelial cells [12].

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BAP1 inhibits apoptotic process.

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BAP1 inhibits apoptotic process. 3 / 3

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For instance, while loss of Bap1 activates intrinsic apoptosis in several mouse cell types (hepatocytes, keratinocytes, fibroblasts, and embryonic stem cells) in an RNF2 dependent fashion, the Bap1 loss enhances proliferation of melanocytes in association with upregulation of lineage specific oncogenes MITF and BCL2, independently of RNF2.

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Thus , loss of BAP1 activity prevents Bcl2 and Mcl1 expression and triggers apoptosis .

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The Arabidopsis BAP1 and BAP2 genes are general inhibitors of programmed cell death.

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BAP1 affects cell growth

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BAP1 inhibits cell growth.

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BAP1 inhibits cell growth. 10 / 16

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That study also showed that BAP1 slows cell growth through altered G1-S checkpoint regulation.

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Restoration of BAP1 inhibits cell growth in cancer cell lines that lack BAP1 (NCI-H226 cells) or express defective BAP1 (769-P cells) [XREF_BIBR, XREF_BIBR].

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In the absence of a carcinogenic insult however, BAP1 loss may not promote cell growth.

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Early experiments found that BAP1 enhanced BRCA1 mediated inhibition of breast cancer cell growth.

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BAP1 was originally discovered as a binding partner for BRCA1 [XREF_BIBR] and shown to inhibit cancer cell growth.

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BAP1 knockdown in vitro has resulted in decreased cell proliferation and mediation of apoptosis in MSTO211H, HMeso, and H2373 mesothelioma cell lines, and reintroduction of wild-type BAP1 in BAP1-null cell line NCI-H226 promoted cell growth, yet another study reported that this was counterbalanced by increased apoptosis, indicating that the consequences of in vitro manipulation may be cell type dependent [XREF_BIBR, XREF_BIBR].

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BAP1 enhances BRCA1 mediated inhibition of breast cancer cell growth and is the first nuclear localized ubiquitin carboxy-terminal hydrolase to be identified.

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With the colony formation assay, we also found that WT BAP1 suppressed the anchorage independent cell growth of the MM cells with BAP1 deletion, whereas mutant BAP1 showed little or no reduced effect.

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Heterozygous loss of BAP1 would reduce overall levels of BAP1 protein, disfavouring bidentate complex assembly and decreasing specific activity.

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Pathogenic germline variants in the BRCA1 associated protein 1 (BAP1) gene cause the BAP1 tumor predisposition syndrome (BAP1-TPDS) with increased risk of several cancers, the most frequent of which is uveal melanoma (UM).

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The BAP1 cancer syndrome (Mendelian Inheritance in Man Tumor Predisposition Syndrome # 614327) is caused by heterozygous germline mutation in the BRCA1 associated protein-1 gene (BAP1) located at chromosome 3p21.1.

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While ubiquitination enzyme UBE2O monoubiquitinates the NLS of BAP1 and induces translocation (inactivation) of BAP1 from the nucleus to the cytoplasm, DUB activity of the UCH-domain of BAP1 counteracts the UBE2O activity mediated through the intramolecular interaction between the UCH-domain and COOH-terminal domain of BAP1.

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Germline pathogenic variants in the BRCA1 associated protein-1 (BAP1) gene cause the BAP1 tumor predisposition syndrome (TPDS).

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Identified in 2011, the inherited cancer predisposition syndrome caused by germline mutations in the tumor suppressor gene BAP1 (BRCA1 Associated Protein 1) has shed light for the first time on monoge[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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BAP1 inhibits BAP1.

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BAP1 inhibits BAP1. 3 / 5

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In these haplo-insufficient cells (designated as HAP1 BAP1 KO), there was a complete loss of BAP1 compared with the parental HAP1 WT cells.

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There were no chromosomal losses in either the Bap1 or Nf2 regions.

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Tumors with both miR-31 and BAP1 overexpression exhibited significantly higher levels of BAP1 compared to tumors with miR-31 overexpression, suggesting that BAP1 overexpression could rescue the BAP1 suppression caused by miR-31.

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BAP1 increases the amount of BAP1.

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BAP1 increases the amount of BAP1. 5 / 5

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Genetic mutations in BAP1 could modulate BAP1 protein expression or could alter BAP1 function in the absence of alterations in protein expression.

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BAP1-IP3R3 CoIP was barely detectable in BAP1 +/- fibroblasts; BAP1 rescue significantly increased the amount of BAP1 that CoIP with IP3R3 (XREF_FIG).

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Deletion of chromosome 3 and BAP1 inactivating mutations cause loss of BAP1 expression and function in cancer.

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We also detect the mRNA and protein expression level of BAP1, tumors with BAP1 plasmid transfected group exhibited higher BAP1 mRNA and protein expression compared with the control group, suggesting that BAP1 plasmid overexpression could rescue the expression of BAP1 suppressed by miR-31.

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Mechanically, we show that BAP1 represses metabolic stress induced UPR and cell death through activating transcription factor 3 (ATF3) and C/EBP homologous protein (CHOP), and reveal that BAP1 binds to ATF3 and CHOP promoters and inhibits their transcription.

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BAP1 decreases the amount of BAP1.

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BAP1 decreases the amount of BAP1. 2 / 3

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This result is perhaps surprising given that BAP1 inactivation or loss of BAP1 expression has been detected using IHC and whole-exome sequencing in approximately 25% of the intrahepatic CCAs [XREF_BIBR, XREF_BIBR, XREF_BIBR].

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Using patient derived lymphoblastoid cell lines, we found that carriers of pathogenic BAP1 germline variants (c. 852_del and c. 1358_1359del) had reduced expression of full-length BAP1, Vimentin and Snail, as compared to controls with wild-type BAP1 (BAP1 WT), whereas BAP1 germline VUS (c. 299T> C and c. 551A> G) or likely benign carriers were not significantly different from wild-type BAP1 WT.

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BAP1 affects Multiple Myeloma

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BAP1 activates Multiple Myeloma.

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BAP1 activates Multiple Myeloma. 7 / 7

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Importantly, however, our data suggest that dysregulation of the Rb path way may be required for Bap1 driven MM pathogenesis, at least in an experimental model.

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While homozygous CKO of Bap1, Cdkn2a, or Nf2 alone gave rise to few or no MMs, inactivation of Bap1 cooperated with loss of either Nf2 or Cdkn2a to drive development of MM in ~ 20% of double-CKO mice, and a high incidence (22/26, 85%) of MMs was observed in Bap1; Nf2; Cdkn2a (triple)-CKO mice.

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Rather, the presence of a wild type allele in most studied cases, suggests that BAP1 haplo-insufficiency may lead to peritoneal MM.

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Recently, Bap1 +/- knockout mice were found to have increased susceptibility to asbestos induced MM compared to wild type litter mates (Xu et al., 2014).

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There was no association between total SNV and survival; ever versus never smokers; or patients with epithelioid versus non epithelioid histologies.The three archetypical somatic drivers of MM - BAP1,[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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BAP1 stabilizes BRCA1 protein and restores cell survival rates of MM cells with BAP1 deletion after IR.

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While most human MMs exhibit somatic alterations of BAP1, NF2 and/or CDKN2A, currently it is not known if inactivation of BAP1 cooperates with loss of NF2 and/or CDKN2A to drive a more aggressive MM phenotype.

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A possible explanation is that germline BAP1 mutations alone can cause MM and many other tumor types.

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We recently reported in vivo genetic evidence that germline heterozygous mutation of Bap1 accelerates development of asbestos induced MM.

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We are investigating how germline BAP1 mutations on one hand promote MM development, while on the other hand they are associated to reduce disease aggressiveness.

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BAP1 is the most promising driver gene in MM pathogenesis, because more than 60% of MM biopsies contain BAP1 mutations and inactivation [XREF_BIBR, XREF_BIBR] and germline BAP1 mutations cause a cancer syndrome with high incidence of MM [XREF_BIBR, XREF_BIBR].

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BAP1 inhibits Multiple Myeloma.

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BAP1 inhibits Multiple Myeloma. 7 / 7

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BAP1 suppresses MM cell proliferation.

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Loss of BAP1 is frequently observed in MM and has been proven to increase the risk of MM [XREF_BIBR - XREF_BIBR].

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Transduction of the WT BAP1 vector inhibited cell proliferation of the Y-MESO-25 MM cell line with BAP1 deletion by approximately 50% compared to the cells with control vector (GFP).

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In effusions with mesotheliomatous cells or atypical mesothelial cells of uncertain significance, negative BAP1 IHC strongly supports a diagnosis of MM.

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Bap1 deletion alone does not cause MM but dramatically accelerates MM development when combined with Nf2 and Cdkn2ab (hereafter BNC) disruption.

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Our results suggested that, whereas WT BAP1 suppresses MM cell proliferation and restores cell survival after IR damage, some mutant BAP1 may also moderately retain these functions.

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BAP1 affects cell differentiation

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BAP1 inhibits cell differentiation.

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BAP1 inhibits cell differentiation. 8 / 8

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The recent finding that BAP1 loss leads to defective differentiation and an arrested primitive phenotype in vertebrate development and uveal melanoma suggests that BAP1 loss can promote tumor progression by inducing cell dedifferentiation and stem like behavior.

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However, as previously reported, depletion of BAP1 in UM cells induced loss of melanocytic differentiation together with acquisition of a gene expression profile seen in advanced metastasizing tumors.

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Consistent with those results, treatment of BAP1 deficient uveal melanoma cells with an HDAC inhibitor restored the expression of the melanocyte differentiation markers, which were down-regulated by BAP1 depletion, in a dose dependent manner.

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Studies suggest that down regulated expression of BAP1 led to impaired differentiation in UM cells.

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ASXL1-MT alone modestly, and coexpression of ASXL1-MT and BAP1 dramatically blocked G-CSF-induced granulocytic differentiation of 32Dcl3.

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In functional studies, depletion of BAP1 protein in the 92.1 UM cell line using siRNAs led to a change in cell morphology from spindle to a more epithelioid phenotype, loss of melanocytic differentiation and transition from a ' class 1 ' to a ' class 2 ' gene expression profile.

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Depletion of BAP1 in cultured class 1 UM cells induced a loss of melanocytic differentiation and acquisition of a class 2 gene expression profile, suggesting that the loss of BAP1 may be mechanistically linked to metastasis.

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ASXL1-MT and BAP1 impairs multilineage differentiation of HSPCs.

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BAP1 activates cell differentiation.

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BAP1 activates cell differentiation. 8 / 8

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Both ASXL1 and BAP1 were downregulated during RA induced P19 cell differentiation with concomitant increase of ubiquitinated H2B, leading to activation of Hox genes.

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Concomitant Bap1 and Ezh2 loss reduced myeloid progenitor expansion, reduced the proportion of Mac1 + Gr1 + myeloid cells, restored erythroid differentiation (CD71 + Ter119 +) and decreased proliferation of Bap1 and Ezh2 deficient progenitors (XREF_FIG and XREF_SUPPLEMENTARY).

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6 In line with these findings, several reports have indicated that truncated ASXL1 enhances BAP1 complex activity, thereby promoting depletion of the H2AK119Ub mark and aberrant myeloid differentiation.

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Interestingly, ASXL1-MT and BAP1 promotes monocyte differentiation, while it inhibits terminal differentiation to macrophage, which may account for the frequent (40-50%) detection of ASXL1 mutations in CMML patients.

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In the monocyte and macrophage differentiation assay, coexpression of ASXL1-MT and BAP1 substantially promoted differentiation toward CD115 + monocytes while inhibiting their terminal differentiation to CD115 + F4/80 + macrophages.

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Downregulation of ASXL1 and BAP1 Promotes Hox Gene Exp (A) Downregulation of ASXL1 and BAP1 during RA induced differentiation.

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BAP1 depletion caused a reduction in mRNA levels of neural crest migration genes (ROBO1), melanocyte differentiation genes (CTNNB1, EDNRB and SOX10) and other genes that are down-regulated in class 2 tumors (LMCD1 and LTA4H).

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Paradoxically, recent findings have confirmed that BAP1 also promotes growth and differentiation even in uveal melanomas where loss of BAP1 expression is a common event.

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BAP1 affects Neoplasm Invasiveness

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BAP1 inhibits Neoplasm Invasiveness.

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BAP1 inhibits Neoplasm Invasiveness. 8 / 8

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In functional assays, BAP1 was found to inhibit the migration and invasion of LAC cells, and promoted their apoptosis and necrosis.

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Early changes resulting in gain of chromosome 8q may activate macrophage infiltration, while sequential loss of BAP1 expression seems to drive T cell infiltration in UM.

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Wild-type BAP1 but not mutant BAP1 significantly inhibited HCC cell proliferation, invasion, epithelial-mesenchymal transition (EMT) in vitro, and tumor progression and metastasis in vivo.

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Importantly, loss of BAP1 decreased the formation of stress fibers and membrane protrusions and induced migration and invasion defects.

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BAP1 inhibits migration and invasion abilities of cells in vitro.

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Functionally, BAP1 promotes apoptosis and necrosis, and down-regulates the migration and invasion abilities of LAC cells.

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Importantly, loss of BAP1 decreased the formation of stress fibers and membrane protrusions and induced migration and invasion defects.

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Overexpression of wild-type but not mutant BAP1 significantly suppressed ICC cell proliferation, cell cycle progression, and invasion in vitro, as well as tumor progression in vivo.

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BAP1 activates Neoplasm Invasiveness.

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Consistently, silence of BAP1 or KLF5 expression significantly decreased the invasion of HCC1937 cells in transwell matrigel invasion assays (XREF_FIG).

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We also report a positive correlation between BAP1 and patient outcome and provide evidence that BAP1 overexpression promotes migration and invasion of adenocarcinoma.

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BRCA1 associated protein 1 deficiency in lung adenocarcinoma predicts poor outcome and increased tumor invasion.

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BAP1 may inhibit the progression of LAC by attenuating tumor invasiveness, a function that was supported by the findings of the Transwell assay.

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BAP1 mutation increased the infiltration degree of Treg cells.

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BAP1 affects EZH2

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BAP1 inhibits EZH2.

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BAP1 loss leads to reduced L3MBTL2 stability and increased EZH2 transcriptional output (XREF_FIG).

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Indeed , we observed that loss of BAP1 results in elevated EZH2 expression and increased H3K27me3 levels , and knock-down of Ezh2 leads to decreased H3K27me3 levels in BNC cells ( Fig. 5 , B and C ; and Fig. S2 J ) .

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Loss of BAP1 leads to reduced L3MBTL2 stability and increased EZH2 transcriptional output in mesothelioma [XREF_BIBR].

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To that end, a systematic literature review was performed of articles dealing with a loss of BRCA1-associated protein 1 (BAP1), methylthioadenosine (MTAP), 5-hydroxymethylcitosine (5-hmC), glucose transporter 1 (GLUT1), insulin like-growth factor II messenger RNA-binding protein 3 (IMP3), enhanced zeste homologue 2 (EZH2) staining, cyclin-dependent kinase inhibitor 2A (CDKN2A) homozygous deletion (HD) testing, soluble mesothelin, and microRNA quantification in cytological samples for the diagnosis of MPM versus reactive atypical mesothelial cells.

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As for the reported tumor suppressive mechanism, BAP1 can antagonize EZH2 and PRC2 or RING1B (RNF2)/PRC1 in a tissue specific manner.

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LaFave et al. [XREF_BIBR] reported that loss of BAP1 promotes MPM cell proliferation by upregulating EZH2.

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BAP1 decreases the amount of EZH2.

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Re-expression of BAP1 in Bap1 KO bone marrow cells reduced Ezh2 mRNA expression to normal levels (XREF_SUPPLEMENTARY).

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This could represent a possible connection between BAP1 and expression of HLA in uveal melanoma, as study in mice showed that loss of BAP1 leads to increased levels of EZH2 (and PRC2) with repressed expression of its targets [XREF_BIBR], including thus CIITA, leading ultimately to less HLA class II expression.

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Recurrent BAP1 mutations have also been observed in intrahepatic cholangiocarcinoma 25, and a recent study showed that loss of Bap1 in mice increases expression of H3K27me3 and Ezh2 while suppressing expression of PRC2 targets 26.

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BAP1 activates EZH2.

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Frequent loss-of-function mutations in epigenetic factors, such as ARID1A, SMARCA4, SMARCB1, BAP1, and KDM6A, are likely to elicit the EZH2 and PRC2 addicted situation.

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In line with the observations in myeloid cells, Bap1 deleted mouse MM cell proliferation is impaired upon shRNA mediated down-regulation of Ezh2.

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99 In addition, RCC derived cell lines deficient in BAP1 overexpress EZH2, and are sensitive to EZH2 inhibitors in vitro.

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BAP1 affects KLF5

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BAP1 activates KLF5.

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BAP1 activates KLF5. 7 / 7

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To test whether BAP1 can antagonize E3 ligase mediated KLF5 degradation, we transfected KLF5 E3 ligases and BAP1 into HEK293FT cells and detected the KLF5 protein levels.

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Collectively, these results suggest that BAP1 is a specific DUB for KLF5 and that BAP1 increases KLF5 protein stability in a DUB activity dependent manner.

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To further confirm whether BAP1 increases KLF5 protein stability, we transfected two different siRNAs targeting different regions of BAP1 into MCF10A and breast cancer cell lines (HCC1806 and HCC1937).

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These results indicate that BAP1 promotes KLF5 positive breast cell proliferation in vitro.

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Besides, BAP1 promoted KLF5 mediated growth of melanoma in vivo.

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Taken together, these results demonstrate that BAP1 promotes HCC1806 breast cancer tumorigenesis partially by stabilizing KLF5.

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However, BAP1 positively regulates KLF5 at the protein level.

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BAP1 increases the amount of KLF5.

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BAP1 knockdown decreased the endogenous protein levels of KLF5 and its downstream target gene FGF-BP XREF_BIBR (XREF_FIG).

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The KLF5 mRNA levels were not decreased by BAP1 knockdown in the MCF10A and HCC1806 cells (XREF_SUPPLEMENTARY).

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Our data suggest that BAP1 promotes cell proliferation and migration, and enhances the expression of KLF5 and its downstream genes, including CyclinD1 and FGF-BP1, in the esophageal carcinoma cell line ECA109.

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In addition, expression of KLF5, CyclinD1, and FGF-BP1 was increased by BAP1 overexpression and decreased by BAP1 knockdown.

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As shown in XREF_SUPPLEMENTARY, BAP1 overexpression elevated the KLF5 protein level, decreased the p27 protein level and significantly promoted cell growth.

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BAP1 affects Neoplasms

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These cases demonstrate the importance of routine BAP1 tumor testing in meningioma with rhabdoid features regardless of grade, germline testing for patients with BAP1 inactivated tumors, and tailored cancer screening in this population.

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The BAP1 gene encodes BRCA1-associated protein 1 , which suppresses tumors by promoting the activity of the Hippo tumor suppressor pathway [ 20 ] .

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Novel insights into the BAP1-inactivated melanocytic tumor.

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It is worth noticing that, through 3p loss, cancer cells also delete other important tumor suppressors such as VHL, SETD2,BAP1, and PBRM1.

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The BAP1 gene encodes BRCA1-associated protein 1, which suppresses tumors by promoting the activity of the Hippo tumor suppressor pathway[20].

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BAP1-inactivated melanocytic tumor (BIMT) is a group of melanocytic neoplasms with epithelioid cell morphology molecularly characterized by the loss of function of BAP1, a tumor suppressor gene located on chromosome 3p21, and a mutually exclusive mitogenic driver mutation, more commonly BRAF.

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BAP1 affects transcription, DNA-templated

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BAP1 activates transcription, DNA-templated.

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In addition, melanoma specific network analysis followed by Kaplan-Meier analysis along with log-rank tests identified tyrosinase, hedgehog acyltransferase, BRCA1 associated protein 1 and melanocyte inducing transcription factor as potential therapeutic targets for melanoma.

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BAP1 activates transcription in an enzymatic-activity-dependent manner and regulates the expression of a variety of genes involved in numerous cellular processes.

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These included the SETD1A, KMT2C and MLL3, KMT2E and MLL5, and KMT2A and MLL1 methyltransferases that install activating histone H3-lysine 4 trimethylation (H3K4me3) marks; OGT (O-GlcNac transferase), a protein that modulates multiple cell pathways but more recently has been implicated in promoting promoter occupancy of RNAPII; and BAP1 (BRCA1 Associated Protein 1), a deubiquitinase that stimulates transcription, at least in part, by removing repressive histone H2A-K119 monoubiquitin.

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RNA sequencing and chromatin immunoprecipitation coupled with quantitative PCR analyses revealed that reduced BAP1 expression suppressed upregulation of the transcription factors AP-1 and EGR1/2, as well as myeloid dysplasia associated genes, by retarding H2AK119Ub removal caused by ASXL1 mutation.

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BAP1 complex promotes transcription by opposing PRC1 mediated H2A ubiquitylation.

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BAP1 activates transcription in an enzymatic-activity-dependent manner and regulates the expression of a variety of genes involved in numerous cellular processes.

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BAP1 inhibits transcription, DNA-templated.

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Moreover , ZEB1 promoted down-regulation of crucial genes involved in melanocyte differentiation , including BAP1 , melanocyte inducing transcription factor ( MITF9 ) , tyrosinase ( TYR ) , and tyrosinase-related protein 1 ( TYRP ) .

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Under glucose starvation , BAP1 can directly bind to the promoter of ATF3 and CHOP , inhibit its transcription , and thus inhibit the UPR and cell death induced by the ER stress ( Figure 2p ) .

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BAP1 affects Cell Survival

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BAP1 activates Cell Survival.

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Our results suggested that, whereas WT BAP1 suppresses MM cell proliferation and restores cell survival after IR damage, some mutant BAP1 may also moderately retain these functions.

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Further, downregulation of BAP1 in SK-N-FI cells by using small interfering RNA (siRNA) enhanced cell survival compared to siRNA treated control cells.

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BAP1 promotes stalled fork restart and cell survival via INO80 in response to replication stress.

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BAP1 stabilizes BRCA1 protein and restores cell survival rates of MM cells with BAP1 deletion after IR.

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BAP1 inhibits Cell Survival.

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In summary, it seems that loss of BAP1 foster genomic instability in tumor pathogenesis, however, the activity of BAP1 promotes tumor cell survival and contributes to therapeutic resistance during irradiation.

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BAP1 suppresses cell viability and growth.

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Crucially, concomitant BAP1 and HDAC2 depletion did not additively reduce cell viability in the presence of vorinostat.

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BAP1 affects 2'-O-methyluridine

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BAP1 activates 2'-O-methyluridine.

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XREF_BIBR UM in BAP1 germ line mutants is usually diagnosed between the ages of 30 and 59 years, and is driven by inactivating mutations in the lone functional BAP1 gene, analogous to the frequent loss of chromosome 3 observed in high-risk sporadic disease.

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The results suggest that knowledge of mutations in BAP1 and EIF1AX can enhance prognostication of UM beyond that determined by chromosome 3 and tumor characteristics.

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BAP1 loss-of-function mutations promote the metastatic spread of UM cancers in patients XREF_BIBR, and TEM should be a rate limiting step of metastasis.

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This technique has generated a new and expanded list of BAP1 targets in UM that provides important insight into metastasis pathways and identifies novel potential therapeutic targets.

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BAP1 depletion appears to promote UM cell migration underneath the monolayer.

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BAP1 inhibits 2'-O-methyluridine.

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Next, we used movie analysis of living cells to examine BAP1 depleted UM cells interacting with EC monolayers.

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Early changes resulting in gain of chromosome 8q may activate macrophage infiltration, while sequential loss of BAP1 expression seems to drive T cell infiltration in UM.

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Therefore, we hypothesized that decreasing BAP1 might increase the ability of UM cells to perform TEM in our model system.

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Loss of BAP1 enhances UM transmigration.

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BAP1 affects INO80

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BAP1 activates INO80.

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BAP1 activates INO80. 6 / 7

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One reason for this could be that the simultaneous knockdown of CHIP and BAP1 decreased Ino80 only marginally compared to the individual knockdown, which is likely due to a limitation of siRNA knockdown.

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Importantly, Ino80 levels are often reduced in BAP1-null mesothelioma cells, which lack a BAP1 mediated Ino80 stabilization mechanism, and downregulated in BAP1 defective cancer cells in mesothelioma patients [XREF_BIBR].

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By recruiting INO80 to the stalled forks, BAP1 allows stress induced stalled replication forks to restart, a mechanism that suppresses genome instability and thus cancer development.

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Ino80 is downregulated in BAP1 defective mesothelioma, owing to the lack of a BAP1 mediated Ino80 stabilization mechanism, thus raising the possibility of a tumorigenic role for INO80 in this cancer.

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While individual expression of CHIP and BAP1 increased Ino80, as expected, coexpression of these proteins increased endogenous Ino80 (XREF_FIG) and transfected Flag-Ino80 beyond the levels achieved by individual expression of either protein (XREF_FIG).

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Conversely, knockdown of CHIP, BAP1, or both decreased Ino80 preferentially in the chromatin fractions (XREF_FIG).

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BAP1 inhibits INO80.

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BAP1 depletion abrogates the binding of INO80 to replication forks and increases the formation of RAD51 foci following HU treatment.

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BAP1 affects cell cycle

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BAP1 activates cell cycle.

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BAP1 loss causes transient cell cycle inhibition.

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In functional experiments, BAP1 has been shown to suppress lung cancer tumorigenesis in athymic nude mice, promote the cell cycle and induce both apoptosis and necrosis.

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In sharp contrast, RNA interference mediated depletion of BAP1 induced cell cycle progression defects and inhibited cell proliferation in vitro XREF_BIBR XREF_BIBR, suggesting that BAP1 may have dual roles in cancer development.

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Moreover, RNA mediated depletion of BAP1 promoted cell cycle G1-S progression XREF_BIBR.

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In the spleen, Bap1 deletion reduced cell cycle proteins (p = 6.2e-20), consistent with pancytopenia often observed in myelodysplastic disorders (XREF_FIG).

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To test whether the KLF5, BAP1, and HCF complex promotes cell cycle progression through p27, we knocked down p27 together with KLF5, BAP1, HCF-1 or OGT (XREF_FIG).

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BAP1 inhibits cell cycle.

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Interestingly, there was no substantial difference in cell viability, BrdU incorporation or cell cycle profile between BAP1 deficient and control cells after stable expression of the shRNA constructs for at least 14days, indicating that the initial cell cycle inhibition caused by BAP1 depletion was transient.

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BAP1 affects ITPR3

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BAP1 increases the amount of ITPR3.

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Loss of BAP1 therefore leads to loss of ITPR3, which in turn reduces apoptotic mitochondrial calcium signals [XREF_BIBR].

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Reduced levels of BAP1 in BAP1 +/- carriers caused reduction of both IP3R3 levels and Ca 2+ flux, preventing BAP1 +/- cells that had accumulated DNA damage from executing apoptosis.

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Consequently, heterozygous loss of BAP1 leads to decreased IP3R3 levels and resistance to apoptotic stimuli, as demonstrated in human fibroblasts or mesothelial cells derived from mutant BAP1 +/- carriers and in mesothelioma cell lines 174.

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Remarkably, depletion of BAP1 or IP3R3 promoted crocidolite asbestos and TNF-alpha-induced transformation of primary mesothelial cells, and re-expression of IP3R3 in BAP1 depleted cells partially reverted the phenotype.

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Transduction of BAP1 +/- fibroblasts with adenoviruses encoding BAP1, but not the catalytic inactive mutant BAP1 (C91S) XREF_BIBR, XREF_BIBR, rescued IP3R3 protein levels (XREF_FIG), mitochondrial Ca 2+ uptake (XREF_FIG, XREF_FIG, XREF_SUPPLEMENTARY) and resulted in enhanced apoptosis (XREF_FIG).

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Silencing of BAP1 in BAP1 WT fibroblasts consistently caused a reduction of IP3R3 protein levels (XREF_FIG), with concomitant reduction of mitochondrial Ca 2+ responses (XREF_FIG, and XREF_SUPPLEMENTARY), and protection from apoptosis (XREF_FIG).

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BAP1 activates ITPR3.

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Thus , loss of BAP1 leads to decreased ITPR3 expression , decreased mitochondrial Ca2 + and reduced sensitivity of cancer cells to apoptosis .

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Loss of BAP1 therefore leads to loss of ITPR3 , which in turn reduces apoptotic mitochondrial calcium signals [ 6 ] .

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BAP1 affects DNA repair

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BAP1 activates DNA repair.

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BAP1 activates DNA repair. 6 / 6

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Most of them are involved in DNA repair signaling, including MLH1, BRCA1/2, MUTYH, ATM, PMS2, MSH6, BAP1, and FANCA.

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Reduced BAP1 levels impair DNA repair as well as different forms of cell death and induce metabolic alterations that together favor cancer development and growth.

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Reduced BAP1 levels impair DNA repair ( 11 ) as well as different forms of cell death ( 3 , 12 ) and induce metabolic alterations ( 13-15 ) that together favor cancer development and growth .

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In heterozygous BAP1 +/- conditions, as in family members affected by the BAP1 cancer syndrome, the reduced BAP1 levels impair both DNA repair, making their cells accumulate more DNA damage, and the apoptotic response.

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BAP1 promotes double-strand DNA repair by homologous recombination (HR), a key process to reduce genetic damage and prevent cancer.

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BAP1 inhibits DNA repair.

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Mutated BAP1 inhibits DNA repair. 1 / 1

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Another relevant study demonstrated that BAP1 can transcriptionally promote the expression of HDAC2 .

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The BAP1 knockdown led to a decrease in HDAC2 but an increase in HDAC1 expression .

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BAP1 increases the amount of HDAC2.

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BAP1 increases the amount of HDAC2. 1 / 1

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Another relevant study demonstrated that BAP1 can transcriptionally promote the expression of HDAC2.

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BAP1 affects CDKN1B

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BAP1 increases the amount of CDKN1B.

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Knockdown of KLF5, BAP1 or HCF-1, but not OGT, significantly increased p27 mRNA levels (XREF_FIG).

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Depletion of KLF5, BAP1 or HCF-1 also upregulated p27 mRNA levels (XREF_FIG).

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Knockdown of either KLF5 or BAP1 upregulated p27 protein levels in these breast cell lines as well (XREF_FIG; XREF_SUPPLEMENTARY).

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Indeed, depletion of KLF5, BAP1, HCF-1 or OGT upregulated p27 protein expression and blocked cell cycle progression (XREF_FIG).

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UBE2O activates BAP1.

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The ubiquitin conjugating enzyme UBE2O induces BAP1 sequestration in the cytoplasm by multi monoubiquitylation of its nuclear localization signal (NLS).

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The antagonistic relationship between UBE2O and BAP1 is also observed during adipogenesis, whereby UBE2O promotes differentiation and cytoplasmic localization of BAP1.

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Of note, overexpression of UBE2O, but not its catalytic dead form, also promoted cytoplasmic localization of endogenous BAP1.

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UBE2O inhibits BAP1.

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Given that UBE2O has been shown to inhibit BAP1 function 23, activation of UBE2O may represent an alternative approach to suppress the hyperactivity of the ASXL-MT and BAP1 complex.

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BAP1 affects cell adhesion

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Because exogenously provided Bap1 restored biofilm surface adhesion to a Deltabap1DeltarbmC mutant, we questioned whether Bap1 synthesis could be a joint venture in the biofilm community.

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Two of the proteins, RbmC and Bap1, are seemingly redundant paralogs that coat substrate surfaces and promotes cell adhesion, while another protein RbmA coats cell surfaces and promotes cell-cell cohesion.

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Bap1 mediates adhesion of bystander cells.

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This suggests that communal Bap1 secreted by nearby biofilm cells may also increase surface adhesion of bystanders that have not yet been reprogrammed for biofilm matrix synthesis.

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As shown in XREF_FIG and quantified in XREF_FIG, Bap1 increased surface adhesion of wild-type V. cholerae, a Deltabap1DeltarbmC mutant, and a DeltavpsL mutant in monolayer minimal medium, while a control protein, bovine serum albumin (BSA), had no effect.

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Exogenous Bap1 increases surface adhesion of planktonic bystanders as well.

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BAP1 bound to YY1 and HCFC1 activates cell adhesion. 1 / 1

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Prominent among the positively enriched gene sets were those related to writers of histone H3K27Me3, including PRC2 and SUZ12 (XREF_FIG), as well as genes participating in cell proliferation and transcription regulation involving ubiquitin signaling mediated by the Bap1, HCF1, and YY1 complex, EED related stem cell pluripotency, cytokine signaling, and cell adhesion; 100 of the top pathways differentially affected in MMs from TKO versus DKO mice are presented in XREF_SUPPLEMENTARY.

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BAP1 affects TNFSF10

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BAP1 activates TNFSF10.

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BAP1 activates TNFSF10. 4 / 4

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While we highlight the extrinsic apoptotic pathway and proteins as being significantly altered by BAP1 status, identifying a single factor to explain BAP1 induced TRAIL resistance is extremely challenging.

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To elucidate the mechanism by which BAP1 modulates sensitivity to TRAIL we generated expression vectors containing wild-type or mutant forms of BAP1, each with an inactive functional site or protein binding domain.

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Functionally, BAP1 promotes apoptosis and necrosis, and down-regulates the migration and invasion abilities of LAC cells.

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It is also prudent to note that expression of BAP1 increased the population of cells that stain positive for both AnnexinV and PI, an indication of late apoptosis and/or necrosis.

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In functional experiments, BAP1 has been shown to suppress lung cancer tumorigenesis in athymic nude mice, promote the cell cycle and induce both apoptosis and necrosis.

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In functional assays, BAP1 was found to inhibit the migration and invasion of LAC cells, and promoted their apoptosis and necrosis.

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BAP1 affects DNA damage response, detection of DNA damage

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BAP1 activates DNA damage response, detection of DNA damage. 6 / 6

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BAP1 can modulate the DDR via several different interactions, including deubiquitinylation of histone H2A.

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BAP1 can modulate the DDR via several different interactions , including deubiquitinylation of histone H2A ( 6 , 7 ) .

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In such an environment, an impaired DDR caused by BAP1 deletion, might be expected to favour the accumulation of genetic damage that eventually gives rise to a malignant clone.

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Thus , BAP1 is thought to modulate DDR through H2Aub .

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Thus, BAP1 is thought to modulate DDR through H2Aub.

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Indeed, inhibition of BAP1 by short hairpin RNAs (shRNAs) impaired the DDR and caused HeLa cells to become hypersensitive to ionizing radiation resulting in S-phase retardation, a phenotype similar to BRCA1 deficiency.

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BAP1 affects cell migration

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BAP1 inhibits cell migration.

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However, BAP1 is closely related to lymph node status, suggesting that BAP1 also mediates suppression of cell migration in LAC which is in keeping with the findings of the wound healing assay.

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The overexpression of CAST rescued the cell migration phenotype caused by BAP1 loss.

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Knockdown of BAP1 and KLF5 significantly decreased cell migration compared with the Lucsh negative control in HCC1806 and HCC1937 cells using wound healing and transwell assays (XREF_FIG; XREF_SUPPLEMENTARY).

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BAP1 activates cell migration.

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We found that dual knockdown of BAP1 and miR-31 significantly reversed cell migration ability of HeLa and C33A cells induced by single-knockdown of miR-31.

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Upregulation of miR-31 and Knockdown of BAP1 Promoted Cell Migration In Vitro.

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BAP1 depletion appears to promote UM cell migration underneath the monolayer.

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BAP1 affects HCFC1

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BAP1 activates HCFC1.

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BAP1 activates HCFC1. 4 / 5

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The BAP1 nuclear deubiquitinase is known to target histones (together with ASXL1 as a Polycomb repressor subunit) and the HCF1 transcriptional co-factor, and we show that BAP1 knockdown in MPM cell lines affects E2F and Polycomb target genes.

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BAP1 is a deubiquitinase targeting histones and the host cell factor-1 transcriptional co-factor, and plays a role in transcriptional regulation, chromatin modulation, cell cycle regulation, and DNA repair.

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Among these substrates, OGT and HCF-1 levelswere found to decrease upon Bap1 deletion in mice (Dey et al., 2012), supporting a previous report on the stabilization of HCF-1 by BAP1 (Machida et al., 20[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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In a mouse model, absence of one such shared binding partner, BAP1, led to a lack of HCFC1 protein (since BAP1 normally prevents HCFC1 degradation), and these mice exhibited features of myeloproliferative disease.

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BAP1 increases the amount of HCFC1.

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BAP1 increases the amount of HCFC1. 1 / 1

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OGT and HCF-1 levels were decreased by Bap1 deletion, indicating a critical role for BAP1 in stabilizing these epigenetic regulators.

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BAP1 affects lactose

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BAP1 inhibits lactose. 5 / 5

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In functional assays, BAP1 was found to inhibit the migration and invasion of LAC cells, and promoted their apoptosis and necrosis.

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Functionally, BAP1 promotes apoptosis and necrosis, and down-regulates the migration and invasion abilities of LAC cells.

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However, BAP1 is closely related to lymph node status, suggesting that BAP1 also mediates suppression of cell migration in LAC which is in keeping with the findings of the wound healing assay.

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BAP1 may inhibit the progression of LAC by attenuating tumor invasiveness, a function that was supported by the findings of the Transwell assay.

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BAP1 affects double-strand break repair

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BAP1 activates double-strand break repair.

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BAP1 activates double-strand break repair. 4 / 4

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In addition to a potentially critical role for BAP1 inactivation in epigenetic deregulation in ccRCC, BAP1 has been found to promote DNA double-strand break repair by homologous recombination, thereby adding to its tumor suppressor function [XREF_BIBR].

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BAP1 protein was reported to form a complex with host cell factor-1 (HCF-1) and promotes DNA double-strand break repair.

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The literature suggests that BAP1 promotes DNA double-strand break repair and that its loss leads to homologous recombination repair defects, reminiscent of BRCA1/2 deficiency.

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BAP1 loss impairs HR and double-strand break repair, promoting error-prone nonhomologous end joining, with consequent genomic instability (XREF_FIG).

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BAP1 inhibits double-strand break repair.

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BAP1 inhibits double-strand break repair. 1 / 1

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Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair.

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BAP1 affects RCC

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BAP1 inhibits RCC.

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BAP1 inhibits RCC. 3 / 3

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Modified BAP1 increases the amount of MCRS1. 1 / 1

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As shown in Fig. 3A, ectopic expression of BAP1-WT, but not the BAP1 C91S mutant (lacking catalytic activity), increased the co-expressed MCRS1 protein level in a dose dependent manner, indicating tha[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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BAP1 affects calcium(2+)

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BAP1 activates calcium(2+). 3 / 3

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(ii) The tumor suppressor BRCA1 associated protein 1 (BAP1), a deubiquitylating enzyme, promotes ER-mitochondrial Ca 2+ transfer by stabilizing the IP 3 R3 114.

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In a paper in press in Nature, 19 we report that BAP1 modulates ER-to-mitochondria calcium (Ca 2+) release.

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In a paper in press in Nature, 19 we report that BAP1 modulates ER-to-mitochondria calcium (Ca 2+) release.

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Modified BAP1 activates calcium(2+). 1 / 1

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Reduced levels of BAP1 in BAP1 +/- carriers caused reduction of both IP3R3 levels and Ca 2+ flux, preventing BAP1 +/- cells that had accumulated DNA damage from executing apoptosis.

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BAP1 increases the amount of calcium(2+).

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BAP1 increases the amount of calcium(2+). 1 / 1

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A recent factor that deserves attention is the tumour suppressor BAP1, which has been shown to increase the amount of Ca 2+ released from the ER into the cytosol and mitochondria, promoting apoptosis XREF_BIBR and increasing aerobic glycolysis XREF_BIBR.

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BAP1 affects Ubiquitin

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BAP1 activates Ubiquitin.

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BAP1 activates Ubiquitin. 3 / 3

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BAP1 and the BRCA1 and BARD1 complex BRCA1 participates in several multiprotein complexes, and plays roles in : repair of double stranded DNA (dsDNA) breaks by homologous recombination; chromatin remo[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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As part of the Polycomb repression machinery, BAP1 is activated by the deubiquitinase adaptor domain of ASXL1 mediating gene repression by cleaving ubiquitin (Ub) from histone H2A in nucleosomes.

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The deubiquitinase (DUB) and tumor suppressor BAP1 catalyzes ubiquitin removal from histone H2A Lys 119 and coordinates cell proliferation, but how BAP1 partners modulate its function remains poorly understood.

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BAP1 bound to YY1 and HCFC1 activates Ubiquitin. 1 / 1

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BAP1 inhibits Ubiquitin.

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BAP1 inhibits Ubiquitin. 1 / 1

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Whereas BAP1 encodes for an ubiquitin C-terminal hydrolase (deubiquitinase, DUB) and is therefore able to reverse the ubiquitin linkages formed by E3 ubiquitin ligases, NF2 encodes for a negative regulator of the E3 ubiquitin ligase CRL4 DCAF1.

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BAP1 affects SNAI1

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BAP1 increases the amount of SNAI1.

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Loss of BAP1 has been reported to downregulate the expression of Snail, promoting ccRCC cells towards mesenchymal-epithelial transition 25.

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BAP1 knockout in ccRCC cells also downregulated the expression of transcriptional repressor protein Snail and decreased the activity of Rho family GTPases, promoting the cells to undergo mesenchymal-epithelial transition.

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BAP1 decreases the amount of SNAI1.

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BAP1 decreases the amount of SNAI1. 1 / 1

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BAP1 activates SNAI1.

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BAP1 activates SNAI1. 1 / 1

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Loss of BAP1 has been reported to downregulate the expression of Snail , promoting ccRCC cells towards mesenchymal-epithelial transition25 .

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BAP1 affects IRF8

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BAP1 activates IRF8.

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BAP1 activates IRF8. 3 / 3

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In addition to posterior Hoxa genes, we found that coexpression of ASXL1-MT and BAP1 in c-Kit + cells led to upregulation of Irf8, a master regulator of monocyte differentiation, at both mRNA and protein levels 37.

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We also examined whether ASXL1-MT and BAP1 upregulated posterior HOXA genes and IRF8 in human RUNX1-ETO cells by qRT-PCR.

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ASXL1-MT and BAP1 induces upregulation of HOXA genes and IRF8.

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BAP1 bound to ASXL1 activates IRF8. 1 / 1

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This hyperactive mutant ASXL1 and BAP1 complex induces upregulation of posterior HOXA genes and IRF8 through inhibition of H2AK119ub, impairing multilineage differentiation of haematopoietic progenitors (except for that toward monocytes), and accelerates RUNX1-ETO-induced leukaemogenesis.

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BAP1 increases the amount of IRF8.

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Modified BAP1 increases the amount of IRF8. 1 / 1

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Coexpression of ASXL1-MT-K351R and BAP1 also increased posterior Hoxa gene and Irf8 expression, but to a lesser extent.

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BAP1 affects E3_Ub_ligase

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BAP1 inhibits E3_Ub_ligase.

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BAP1 inhibits E3_Ub_ligase. 3 / 3

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XREF_BIBR suggested that BAP1 inhibits the E3 ligase activity of BRCA1 in a manner independent of its deubiquitination activity.

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The BRCA1 associated protein 1 (BAP1), a de-ubiquitinating enzyme (DUB), also inhibits the E3 ligase activity of BRCA1-BARD1 (Nishikawa et al., 2009).

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In this regard, however, Nishikawa et al . xref suggested that BAP1 inhibits the E3 ligase activity of BRCA1 in a manner independent of its deubiquitination activity.

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Histone deacetylase (HDAC) inhibitors have been shown to reverse the phenotypic effects of BAP1 loss by inducing morphologic differentiation and transition from a high-risk to a low-risk gene expression profile in uveal melanoma cells.

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The Bap1 deficient phenotype can be rescued with human BAP1, by pharmacologic inhibition of histone deacetylase (HDAC) activity or by specific knockdown of Hdac4.

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Histone deacetylase (HDAC) inhibitors, such as the readily available valproic acid, can reverse this effect of BAP1 loss and may play a role in treated patients with high-risk class 2 uveal melanomas in an adjuvant setting prior to the emergence of overt metastatic disease [XREF_BIBR].

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BAP1 affects gemcitabine

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BAP1 activates gemcitabine. 4 / 4

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BAP1 dependent expression of long non coding RNA NEAT-1 contributes to sensitivity to gemcitabine in cholangiocarcinoma.

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Taken together these studies indicate that BAP1 expression modulates sensitivity to gemcitabine.

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BAP1 inhibits TNMD. 2 / 2

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We find that this process requires VCAM mediated adhesion between UM cells and ECs and that loss of the metastasis suppressor BAP1 enhances TEM.

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These results suggest that BAP1 expression favors activation of the RhoA pathway over the Rac1 pathway , such that loss of BAP1 shifts the balance toward Rac1-driven motility and increased TEM .

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BAP1 activates TNMD.

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BAP1 activates TNMD. 2 / 2

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As predicted, shRNA mediated depletion of BAP1 increased the overall rate of TEM by UM cells in transwell assays.

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BAP1 Depletion Enhances TEM.

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BAP1 affects PPARGC1A

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BAP1 increases the amount of PPARGC1A.

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Modified BAP1 increases the amount of PPARGC1A. 2 / 2

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In line with our observation that BAP1 is a deubiquitinase for PGC-1alpha in vitro, hepatic BAP1 overexpression increases the protein level of PGC-1alpha (XREF_FIG).

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BAP1 activates PPARGC1A.

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BAP1 activates PPARGC1A. 2 / 2

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Conversely, knockdown of BAP1 in cells (XREF_SUPPLEMENTARY) decreases the stability of PGC-1alpha (XREF_FIG).

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Bap1 overexpression in the liver slightly enhances gluconeogenesis, possibly by stabilizing Pgc1alpha.

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BAP1 affects FOXK2

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BAP1 inhibits FOXK2.

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BAP1 inhibits FOXK2. 3 / 3

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BAP1 represses FoxK2 target genes, and this effect requires BAP1 DUB activity but not interaction with HCF-1.

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Loss of BAP1 causes the increase of FoxK2 target genes, which is dependent on the Ring1B and Bmi1 complex.

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Moreover, BAP1 is part of a ternary complex bridging FOXK2 and HCF1 and represses FOXK2 target genes, an effect requiring BAP1 DUB activity but not the interaction with HCF1 binding.

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BAP1 activates FOXK2.

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WT BAP1, but not mutant BAP1 C91S, obviously elevated the KLF5 and FGF-BP protein levels and inhibited the p27 protein levels in both cell lines (XREF_FIG).

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ASXL2 affects BAP1

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ASXL2 activates BAP1.

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ASXL2 activates BAP1. 3 / 3

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BAP1 promotes DEUBAD monoubiquitination resulting in an increased stability of ASXL2, which in turn stimulates BAP1 DUB activity.

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The DEUBAD domains of ASXL1, ASXL2 and ASXL3 can activate BAP1 by increasing its affinity for ubiquitin.

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ASXL2 inhibits BAP1.

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ASXL2 inhibits BAP1. 1 / 1

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Moreover, we demonstrated that BAP1 interaction with ASXL2 regulates cell senescence and that ASXL2 cancer associated mutations disrupt BAP1 DUB activity.

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EZH2 affects BAP1

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EZH2 inhibits BAP1.

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EZH2 inhibits BAP1. 2 / 2

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Ezh2 haploinsufficiency reduced, but did not abrogate, Bap1 deficient myeloproliferation (XREF_SUPPLEMENTARY) consistent with a dose dependent requirement for Ezh2.

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EZH2 increases the amount of BAP1.

No evidence text available

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No evidence text available

BAP1 affects TERT

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BAP1 decreases the amount of TERT. 3 / 3

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The DEUBAD domains of ASXL1, ASXL2 and ASXL3 can activate BAP1 by increasing its affinity for ubiquitin.

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Our in vitro analysis indicates that also ASXL3 can bind and activate BAP1, which is not surprising in the light of the high sequence similarity between the DEUBAD domains in the ASXL family.

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SH3PXD2A affects BAP1

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SH3PXD2A decreases the amount of BAP1.

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SH3PXD2A decreases the amount of BAP1. 2 / 2

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BAP1 inhibits metabolic process. 2 / 2

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BAP1 activates mTORC1. 1 / 1

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BAP1 affects HIF1A

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BAP1 activates HIF1A.

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BAP1 activates HIF1A. 2 / 2

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BAP1 inhibits Collagen. 2 / 2

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34641979

BAP1 inhibits Genomic Instability.

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Chromosome 3p21.1-21.3 encoded sequences BAP1, but not SETD2 PARP-3 and PBRM1, repress hTERT transcription within 21NT cells.

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SMAD6 affects BAP1

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SMAD6 activates BAP1. 2 / 2

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Recent biochemical and cell based studies have showed that UBE2O ubiquitinates SMAD6 during bone morphogenetic protein signaling, induces cytoplasmic sequestration of nuclear BAP1, and coordinates endosomal protein trafficking.

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Recent biochemical and cell based studies have shown that UBE2O ubiquitinates SMAD6 during bone morphogenetic protein signaling (Zhang et al., 2013a), induces cytoplasmic sequestration of nuclear BAP1[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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SLC7A11 affects BAP1

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SLC7A11 increases the amount of BAP1. 2 / 2

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A luciferase assay with the SLC7A11 promoter showed that overexpression of BAP1 WT, but not its C91A mutant, decreased luciferase activity, whereas BAP1 knockdown increased it, indicating that BAP1 regulates SLC7A11 transcription (XREF_SUPPLEMENTARY - XREF_SUPPLEMENTARY).

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RAG2 affects BAP1

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RAG2 inhibits BAP1. 2 / 2

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UCHL1, UCHL3, USP2 and USP8 were found to be inhibited by AM146, RA-9, and RA-14, which did not inhibit Ataxin-3, A20, BAP1, Otubain 1 or USP7.

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UCHL1, UCHL3, USP2 and USP8 were found to be inhibited by AM146, RA-9, and RA-14 which did not inhibit Ataxin-3, A20, BAP1, Otubain 1 or USP7 [XREF_BIBR].

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HDAC_I affects BAP1

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HDAC_I inhibits BAP1. 2 / 2

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29497459

CDKN2A affects BAP1

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BAP1 affects DGC

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BAP1 inhibits DGC. 2 / 2

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As in NCI-H226 cells, 25 BAP1 expression suppressed the growth of our DGC cells, suggesting that BAP1 is a novel tumor suppressor candidate in DGC.

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All 4 of the BAP1 somatic mutations found in EODGC-WES were associated with loss of heterozygosity, and BAP1 over-expression suppressed the growth of DGC cells (XREF_FIG).

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BAP1 affects CTNNB1

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PBRM1 inhibits BAP1. 1 / 1

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Genetic markers of ccRCC include biallelic inactivation of Von Hippel-Lindau (VHL) tumor suppressor genes; negative regulators of hypoxia inducible factor (HIF) protein; copy number changes of chromosome 3p, 5q, and 14q genes; and chromatin modifying enzyme high mutation frequencies, such as protein polybromo-1 (PBRM1), SET domain containing 2 (SETD2), and BRCA1 associated protein-1 (BAP1) [XREF_BIBR].

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PBRM1 activates BAP1.

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PBRM1 activates BAP1. 1 / 1

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Modified BRCA1 increases the amount of BAP1. 1 / 1

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Therefore, our data suggest that the reduction of BRCA1 protein levels in a CML context depends on the ability of BCR-ABL to inhibit BAP1 expression.

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BRCA1 activates BAP1.

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BRCA1 activates BAP1. 1 / 1

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The discovery that germline BRCA1 asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested.

BAP1 decreases the amount of SRC. 1 / 1

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We observed that BAP1 re-expression significantly lowered the SRC level in MP65, but increased SRC in MP46 (XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY).

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BAP1 activates SRC.

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BAP1 activates SRC. 1 / 1

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BAP1 inhibits PCV. 1 / 1

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Our results demonstrate that BaP1 is able to disrupt the endothelial barrier in PCV in the in vivo model.

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BAP1 activates PCV.

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BAP1 activates PCV. 1 / 1

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BAP1 inhibits Mesothelioma. 1 / 1

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We investigated whether loss of BAP1 expression can be used to support a diagnosis of mesothelioma in effusion cytology.

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BAP1 activates Mesothelioma.

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Mutated BAP1 activates Mesothelioma. 1 / 1

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High frequency of germline mutations of BAP1 were demonstrated to cause mesothelioma in 2001, when an epidemic spread of cases was reported in a village in Cappadocia (113, 118).

BAP1 inhibits CDKN.

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BAP1 inhibits CDKN. 1 / 1

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BAP1 activates CDKN.

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BAP1 activates CDKN. 1 / 1

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Modified BAP1 decreases the amount of BCL2. 1 / 1

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This result was confirmed by showing that the transient overexpression of BAP1 downregulates the total levels of Bcl-2, 24-48h post transfection.

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BAP1 activates BCL2.

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BAP1 activates BCL2. 1 / 1

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1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine increases the amount of BAP1. 1 / 1

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No evidence text available

20230807

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine decreases the amount of BAP1.

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1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine decreases the amount of BAP1. 1 / 1

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No evidence text available

TFAP4 affects BAP1

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No evidence text available

MTOR affects BAP1

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No evidence text available

M3 affects BAP1

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CDK affects BAP1

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33240524

BAP1 affects UK

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Mutated BAP1 inhibits UK. 1 / 1

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This study therefore suggests that complete loss-of-function germline BAP1 mutations underlie susceptibility to cutaneous melanoma in ~ 0.2% of the population ascertained melanoma cases in the UK.

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BAP1 affects UCH

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BAP1 inhibits UCH. 1 / 1

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BAP1-inactivated melanocytic tumour with borderline histopathological features (BAP1-inactivated melanocytoma) : A case report and a reappraisal.

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BAP1 affects TP53

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BAP1 affects RAS

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BAP1 inhibits RAS. 1 / 1

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BAP1 affects RAD51

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BAP1 activates RAD51. 1 / 1

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BAP1 depletion abrogates the binding of INO80 to replication forks and increases the formation of RAD51 foci following HU treatment.

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BAP1 affects RAB6B

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BAP1 inhibits RAB6B. 1 / 1

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BAP1 affects RAB14

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BAP1 affects LTA4H

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BAP1 activates LTA4H. 1 / 1

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BAP1 affects LOX

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BAP1 increases the amount of LOX. 1 / 1

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Finally, we observed down- regulation of ASXL1 and BAP1 concomitant with increased ubiq- uitinated H2B (ubH2B) levels and Hox gene expression during RA induced P19 cell differentiation.

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BAP1 affects HOXA9

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BAP1 inhibits HOXA9. 1 / 1

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Despite these findings, BAP1 knockdown did not result in upregulation of HOXA5 and HOXA9 in UKE1 cells, although a similar extent of ASXL1 knockdown in the same cells reproducibly increased HOXA5 and HOXA9 expression (XREF_FIG).

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BAP1 affects HOXA5

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No evidence text available

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