Редактирование: ETS1

Protein C-ets-1 (p54) [EWSR2]

==Publications==

{{medline-entry
|title=The transcription factor [[ETS1]] promotes apoptosis resistance of senescent cholangiocytes by epigenetically up-regulating the apoptosis suppressor [[BCL2]]L1.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31659122
|abstract=Primary sclerosing cholangitis (PSC) is an idiopathic, progressive cholangiopathy. Cholangiocyte senescence is important in PSC pathogenesis, and we have previously reported that senescence is regulated by the transcription factor ETS proto-oncogene 1 ([[ETS1]]) and associated with overexpression of [[BCL2]] like 1 ([[BCL2]]L1 or BCL-xL), an anti-apoptotic [[BCL2]]-family member. Here, we further explored the mechanisms regulating BCL-xL-mediated, apoptosis resistance in senescent cholangiocytes and uncovered that [[ETS1]] and the histone acetyltransferase E1A-binding protein P300 (EP300 or p300) both promote [i]BCL-xL[/i] transcription. Using immunofluorescence, we found that BCL-xL protein expression is increased both in cholangiocytes of livers from individuals with PSC and a mouse model of PSC. Using an [i]in vitro[/i] model of lipopolysaccharide-induced senescence in normal human cholangiocytes (NHCs), we found increased BCL-xL mRNA and protein levels, and ChIP-PCRs indicated increased occupancy of [[ETS1]], p300, and histone 3 Lys-27 acetylation (H3K27Ac) at the [i]BCL-xL[/i] promoter. Using co-immunoprecipitation and proximity ligation assays, we further demonstrate that [[ETS1]] and p300 physically interact in senescent but not control NHCs. Additionally, mutagenesis of predicted [[ETS1]]-binding sites within the [i]BCL-xL[/i] promoter blocked luciferase reporter activity, and CRISPR/Cas9-mediated genetic deletion of [i][[ETS1]][/i] reduced senescence-associated BCL-xL expression. In senescent NHCs, TRAIL-mediated apoptosis was reduced ∼70%, and [[ETS1]] deletion or RNAi-mediated BCL-xL suppression increased apoptosis. Overall, our results suggest that [[ETS1]] and p300 promote senescent cholangiocyte resistance to apoptosis by modifying chromatin and inducing BCL-xL expression. These findings reveal [[ETS1]] as a central regulator of both cholangiocyte senescence and the associated apoptosis-resistant phenotype.
|mesh-terms=* ATP Binding Cassette Transporter, Subfamily B
* Animals
* Apoptosis
* Cellular Senescence
* Hepatocytes
* Humans
* Lipopolysaccharides
* Liver
* Mice
* Proto-Oncogene Protein c-ets-1
* Transcription Factors
* bcl-X Protein
|keywords=* BCL2 like 1 (BCL2L1)
* apoptosis
* cholangiocyte
* chromatin modification
* epigenetics
* gene expression
* primary sclerosing cholangitis (PSC)
* senescence
* transcription factor
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901313
}}
{{medline-entry
|title=G protein-coupled receptor kinase 4-induced cellular senescence and its senescence-associated gene expression profiling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28912086
|abstract=Senescent cells have lost their capacity for proliferation and manifest as irreversibly in cell cycle arrest. Many membrane receptors, including G protein-coupled receptors (GPCRs), initiate a variety of intracellular signaling cascades modulating cell division and potentially play roles in triggering cellular senescence response. GPCR kinases (GRKs) belong to a family of serine/threonine kinases. Although their role in homologous desensitization of activated GPCRs is well established, the involvement of the kinases in cell proliferation is still largely unknown. In this study, we isolated [[GRK4]]-GFP expressing HEK293 cells by fluorescence-activated cell sorting (FACS) and found that the ectopic expression of [[GRK4]] halted cell proliferation. Cells expressing [[GRK4]] ([[GRK4]]( )) demonstrated cell cycle G1/G0 phase arrest, accompanied with significant increase of senescence-associated-β-galactosidase (SA-β-Gal) activity. Expression profiling analysis of 78 senescence-related genes by qRT-PCR showed a total of 17 genes significantly changed in [[GRK4]]( ) cells (≥ 2 fold, p < 0.05). Among these, 9 genes - [[AKT1]], p16 , p27 , p19 , [[IGFBP3]], [[MAPK14]], [[PLAU]], [[THBS1]], [[TP73]] - were up-regulated, while 8 genes, Cyclin A2, Cyclin D1, [[CDK2]], [[CDK6]], [[ETS1]], [[NBN]], [[RB1]], [[SIRT1]], were down-regulated. The increase in cyclin-dependent kinase inhibitors (p16, p27) and p38 MAPK proteins ([[MAPK14]]) was validated by immunoblotting. Neither p53 nor p21  protein was detectable, suggesting no p53 activation in the HEK293 cells. These results unveil a novel function of [[GRK4]] on triggering a p53-independent cellular senescence, which involves an intricate signaling network.
|mesh-terms=* Cell Division
* Cell Line, Tumor
* Cell Proliferation
* Cellular Senescence
* Flow Cytometry
* G-Protein-Coupled Receptor Kinase 4
* Gene Expression Profiling
* Gene Expression Regulation
* HEK293 Cells
* Humans
* MCF-7 Cells
* Transcriptome
* Tumor Suppressor Protein p53
|keywords=* Cellular senescence
* G protein-coupled receptor kinase 4
* Gene expression profiling
* p53-independent senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944352
}}
{{medline-entry
|title=ETS Proto-oncogene 1 Transcriptionally Up-regulates the Cholangiocyte Senescence-associated Protein Cyclin-dependent Kinase Inhibitor 2A.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28184004
|abstract=Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory cholangiopathy (disease of the bile ducts) of unknown pathogenesis. We reported that cholangiocyte senescence features prominently in PSC and that neuroblastoma RAS viral oncogene homolog ([[NRAS]]) is activated in PSC cholangiocytes. Additionally, persistent microbial insult ([i]e.g.[/i] LPSs) induces cyclin-dependent kinase inhibitor 2A ([[[[CDKN2A]]]]/p16 ) expression and senescence in cultured cholangiocytes in an [[NRAS]]-dependent manner. However, the molecular mechanisms involved in LPS-induced cholangiocyte senescence and [[NRAS]]-dependent regulation of [[[[CDKN2A]]]] remain unclear. Using our [i]in vitro[/i] senescence model, we found that LPS-induced [i][[[[CDKN2A]]]][/i] expression coincided with a 4.5-fold increase in [i][[ETS1]][/i] ([i]ETS proto-oncogene 1[/i]) mRNA, suggesting that [[ETS1]] is involved in regulating [i][[[[CDKN2A]]]][/i] This idea was confirmed by RNAi-mediated suppression or genetic deletion of [[ETS1]], which blocked [[[[CDKN2A]]]] expression and reduced cholangiocyte senescence. Furthermore, site-directed mutagenesis of a predicted ETS-binding site within the [i][[[[CDKN2A]]]][/i] promoter abolished luciferase reporter activity. Pharmacological inhibition of RAS/MAPK reduced [[ETS1]] and [[[[CDKN2A]]]] protein expression and [i][[[[CDKN2A]]]][/i] promoter-driven luciferase activity by ∼50%. In contrast, constitutively active [[NRAS]] expression induced [[ETS1]] and [[[[CDKN2A]]]] protein expression, whereas [[ETS1]] RNAi blocked this increase. Chromatin immunoprecipitation-PCR detected increased [[ETS1]] and histone 3 lysine 4 trimethylation (H3K4Me3) at the [i][[[[CDKN2A]]]][/i] promoter following LPS-induced senescence. Additionally, phospho-[[ETS1]] expression was increased in cholangiocytes of human PSC livers and in the [i]Abcb4[/i] ([i]Mdr2[/i])  mouse model of PSC. These data pinpoint [[ETS1]] and H3K4Me3 as key transcriptional regulators in [[NRAS]]-induced expression of [i][[[[CDKN2A]]]][/i], and this regulatory axis may therefore represent a potential therapeutic target for PSC treatment.
|mesh-terms=* Animals
* Cell Line
* Cellular Senescence
* Cholangitis, Sclerosing
* Cyclin-Dependent Kinase Inhibitor p16
* Humans
* Lipopolysaccharides
* Liver
* Mice
* Proto-Oncogene Protein c-ets-1
* RNA, Messenger
* Transcriptional Activation
* Up-Regulation
|keywords=* CDKN2A
* Cholangiocytes
* ETS1
* cell signaling
* epigenetics
* epithelial cell
* senescence
* transcription
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377799
}}