Редактирование: BCL2L1 (раздел)

==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=[[SIRT6]] histone deacetylase functions as a potential oncogene in human melanoma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29234488
|abstract=Melanoma is an aggressive skin cancer that can rapidly metastasize to become fatal, if not diagnosed early. Despite recent therapeutic advances, management of melanoma remains difficult. Therefore, novel molecular targets and strategies are required to manage this neoplasm. This study was undertaken to determine the role of the sirtuin [[SIRT6]] in melanoma. Employing a panel of human melanoma cells and normal human melanocytes, we found significant [[SIRT6]] mRNA and protein upregulation in melanoma cells. Further, using a tissue microarray coupled with quantitative Vectra analysis, we demonstrated significant [[SIRT6]] overexpression in human melanoma tissues. Lentiviral short hairpin RNA-mediated knockdown of [[SIRT6]] in A375 and Hs 294T human melanoma cells significantly decreased cell growth, viability, and colony formation, induced G1-phase arrest and increased senescence-associated beta-galactosidase staining. As autophagy is important in melanoma and is associated with [[SIRT6]], we used a qPCR array to study [[SIRT6]] knockdown in A375 cells. We found significant modulation in several genes and/or proteins (decreases in [[AKT1]], [[ATG12]], [[ATG3]], [[ATG7]], [[BAK1]], [[BCL2L1]], [[CLN3]], [[CTSB]], [[CTSS]], [[DRAM2]], [[HSP90AA1]], [[IRGM]], [[NPC1]], [[SQSTM1]], [[TNF]], and BECN1; increases in [[GAA]], ATG10). Our data suggests that increased [[SIRT6]] expression may contribute to melanoma development and/or progression, potentially via senescence-and autophagy-related pathways.

|keywords=* SIRT6
* autophagy
* melanoma
* senescence
* sirtuins
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724804
}}