Редактирование: BMI1

Polycomb complex protein BMI-1 (Polycomb group RING finger protein 4) (RING finger protein 51) [PCGF4] [RNF51]

==Publications==

{{medline-entry
|title=Senescence Induced by [[BMI1]] Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33086074
|abstract=Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component [[BMI1]] as a critical factor for DIPG tumor maintenance in vivo. [[BMI1]] chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of [[BMI1]] decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged [[BMI1]] inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with [[BMI1]] inhibition to enhance tumor cell killing in vivo.

|keywords=* BH3 mimetics
* BMI1
* DIPG
* H3K27M mutant
* H3WT
* PTC 028
* RNAi screen
* SASP
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574900
}}
{{medline-entry
|title=microRNA-31 inhibition partially ameliorates the deficiency of bone marrow stromal cells from cleidocranial dysplasia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30506733
|abstract=Cleidocranial dysplasia (CCD) in humans is an autosomal-dominant skeletal dysplasia caused by heterozygous mutations of the runt-related transcription factor 2 ([[RUNX2]]) and significantly increases the risk of osteoporosis. Increasing evidence demonstrates that the dysfunction of bone marrow stromal cells from CCD patients (BMSCs-CCD) contributes to the bone deficiency, but the characteristics of BMSCs-CCD and the mechanisms that underlie their properties remain undefined. The clinical manifestations of three CCD patients were collected and the mutations of [[RUNX2]] were analyzed. The properties of proliferation, osteogenesis, stemness, and senescence of BMSCs-CCD were compared with that of BMSCs from healthy donors. The expression of microRNA-31 ( miR-31) between BMSCs-CCD and BMSCs was measured and lentivirus-carried miR-31 inhibitor was used to determine the role of miR-31 in BMSCs-CCD both in vitro and in vivo. The molecular mechanisms underlying [[RUNX2]]-miR31 and miR-31 targeting stemness and senescence of BMSCs-CCD were also explored. We identified two mutation sites of [[RUNX2]] via exome sequencing from 2 of 3 Chinese CCD patients with typical clinical presentations. Compared with BMSCs from healthy donors, BMSCs-CCD displayed significantly attenuated proliferation, osteogenesis and stemness, and enhanced senescence. Meanwhile, miR-31 knockdown could ameliorate these deficiency phenotypes of BMSCs-CCD by regulating [[SATB2]], [[BMI1]], CDKN, and [[SP7]]. Mechanistically, [[RUNX2]] directly repressed miR-31 expression, and therefore [[RUNX2]] haploinsufficiency in CCD leading to miR-31 upregulation contributed to the deficiency of BMSCs-CCD. miR-31 inhibition in BMSCs-CCD showed enhanced osteogenesis through heterotopic subcutaneous implantation in the nude mice. Our results show the functional deficiencies of BMSCs-CCD and a potential role of miR-31 in BMSCs-CCD deficiencies. The application of miR-31 inhibitor in BMSCs-CCD might lend hope for developing BMSC-based therapeutic approaches against CCD-associated skeletal diseases.
|mesh-terms=* Adolescent
* Animals
* Base Sequence
* Cell Proliferation
* Child
* Choristoma
* Cleidocranial Dysplasia
* Core Binding Factor Alpha 1 Subunit
* Haploinsufficiency
* Humans
* Mesenchymal Stem Cells
* Mice, Inbred BALB C
* Mice, Nude
* MicroRNAs
* Mutation
* Organ Size
* Osteogenesis
* Up-Regulation
* Young Adult
|keywords=* bone marrow stromal cells
* cleidocranial dysplasia
* microRNA-31
* osteogenesis
* senescence
* stemness
|full-text-url=https://sci-hub.do/10.1002/jcb.28223
}}
{{medline-entry
|title=Timosaponin A-III inhibits oncogenic phenotype via regulation of PcG protein [[BMI1]] in breast cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29528145
|abstract=Polycomb group (PcG) protein [[BMI1]] is an important regulator of oncogenic phenotype and is often overexpressed in several human malignancies including breast cancer. Aberrant expression of [[BMI1]] is associated with metastasis and poor prognosis in cancer patients. At present, therapy reagents that can efficiently inhibit the expression of [[BMI1]] are not very well known. Here, we report that Timosaponin A-III (TA-III), a steroidal saponin obtained from the rhizomes of an herb, Anemarrhena asphodeloides, strongly inhibits expression of [[BMI1]] in breast cancer cells. Treatment of breast cancer cells with TA-III resulted in inhibition of oncogenic phenotypes such as proliferation, migration and invasion, and induction of cellular senescence. Inhibition of these oncogenic phenotypes was accompanied by downregulation of [[BMI1]] expression and histone posttranslational modification activity of [[PRC1]]. The mechanistic analysis of TA-III-induced inhibition of oncogenic activity and [[BMI1]] expression suggests that downregulation of c-Myc mediates TA-III effect on [[BMI1]]. We further show that exogenous [[BMI1]] overexpression can overcome TA-III-induced inhibition of oncogenic phenotypes. We also show that TA-III induces expression of tumor suppressive miR-200c and miR-141, which are negatively regulated by [[BMI1]]. In summary, our data suggest that TA-III is a potent inhibitor of [[BMI1]] and that it can be successfully used to inhibit the growth of tumors where PcG protein [[BMI1]] and PcG activities are upregulated.
|mesh-terms=* Breast Neoplasms
* Carcinogenesis
* Cell Line, Tumor
* Cell Movement
* Cell Proliferation
* Cellular Senescence
* Down-Regulation
* Female
* Gene Expression Regulation, Neoplastic
* Humans
* MCF-7 Cells
* MicroRNAs
* Oncogenes
* Phenotype
* Polycomb Repressive Complex 1
* Polycomb-Group Proteins
* Protein Processing, Post-Translational
* Saponins
* Steroids
|keywords=* BMI1
* Timosaponin A-III
* breast cancer
* cellular senescence
* miR-141
* miR-200c
* polycomb group proteins
* tumor suppressors
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986597
}}
{{medline-entry
|title=Suppressing P16  and P14  pathways overcomes apoptosis in individualized human embryonic stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27965321
|abstract=Dissociation-induced apoptosis is a striking phenomenon in human embryonic stem cells (hESCs), but not in naive mouse ESCs. Rho-associated kinase-dependent actin-myosin hyperactivation is an underlying mechanism that triggers apoptosis in dissociated hESCs; however, in this study, we show that the [i]Ink4A-ARF[/i]-mediated senescence pathway is another mechanism to cause apoptosis in individualized hESCs. We show that P16  and P14  are immediately induced in hESCs upon dissociation, but not in mouse ESCs. Overexpression of [[BMI1]], a suppressor for [i]Ink4A-ARF[/i], greatly promotes survival and cloning efficiency of individualized hESCs mechanistically [i]via[/i] direct binding the H3K27me3-marked [i]Ink4A-ARF[/i] locus. Forced expression of [[BMI1]] in hESCs does not reduce the actin-myosin activation that is triggered by dissociation, which indicates it is an independent pathway for hESC survival. Furthermore, dual inhibition of both [i]Ink4A-ARF[/i] and actin-myosin hyperactivation enables successful passaging of hESCs [i]via[/i] gelatin, a nonbioactive matrix. In sum, we provide an additional mechanism that underlies cell death in individualized hESCs that might help to fully understand the differential cell characteristics between naive and primed ESCs.-Wang, W., Zhu, Y., Huang, K., Shan, Y., Du, J., Dong, X., Ma, P., Wu, P., Zhang, J., Huang, W., Zhang, T., Liao, B., Yao, D., Pan, G., Liu, J. Suppressing P16  and P14  pathways overcomes apoptosis in individualized human embryonic stem cells.
|mesh-terms=* Actins
* Animals
* Apoptosis
* Cell Line
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* Embryonic Stem Cells
* Humans
* Mice
* Myosins
* Polycomb Repressive Complex 1
* Tumor Suppressor Protein p14ARF
|keywords=* BMI1
* hESCs
* mESCs
* senescence
|full-text-url=https://sci-hub.do/10.1096/fj.201600782R
}}
{{medline-entry
|title=[[BMI1]] inhibits senescence and enhances the immunomodulatory properties of human mesenchymal stem cells via the direct suppression of MKP-1/DUSP1.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27454161
|abstract=For the application of mesenchymal stem cells (MSCs) as clinical therapeutics, the regulation of cellular aging is important to protect hMSCs from an age-associated decline in their function. In this study, we evaluated the effects of hypoxia on cellular senescence and the immunomodulatory abilities of hUCB-MSCs. Hypoxic-cultured hUCB-MSCs showed enhanced proliferation and had increased immunosuppressive effects on mitogen-induced mononuclear cell proliferation. We found that [[BMI1]], a member of the polycomb repressive complex protein group, showed increased expression in hypoxic-cultured hUCB-MSCs, and the further knock-down of [[BMI1]] in hypoxic cells induced decreased proliferative and immunomodulatory abilities in hUCB-MSCs, along with COX-2/PGE2 down-regulation. Furthermore, the expression of phosphorylated p38 MAP kinase increased in response to the over-expression of [[BMI1]] in normoxic conditions, suggesting that [[BMI1]] regulates the immunomodulatory properties of hUCB-MSCs via p38 MAP kinase-mediated COX-2 expression. More importantly, we identified [[BMI1]] as a direct repressor of MAP kinase phosphatase-1 (MKP-1)/DUSP1, which suppresses p38 MAP kinase activity. In conclusion, our results demonstrate that [[BMI1]] plays a key role in the regulation of the immunomodulatory properties of hUCB-MSCs, and we suggest that these findings might provide a strategy to enhance the functionality of hUCB-MSCs for use in therapeutic applications.
|mesh-terms=* Cell Hypoxia
* Cell Proliferation
* Cellular Senescence
* Down-Regulation
* Dual Specificity Phosphatase 1
* Humans
* Interferon-alpha
* Mesenchymal Stem Cells
* Phosphorylation
* Polycomb Repressive Complex 1
* Signal Transduction
* Tumor Necrosis Factor-alpha
* p38 Mitogen-Activated Protein Kinases
|keywords=* BMI1
* Hypoxia
* MKP-1
* aging
* hMSCs
* immunomodulation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5032689
}}
{{medline-entry
|title=Adipose-derived stem cells from lean and obese humans show depot specific differences in their stem cell markers, exosome contents and senescence: role of protein kinase C delta (PKCδ) in adipose stem cell niche.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27358894
|abstract=Adipose-derived stem cells (ASC) and its exosomes are gaining utmost importance in the field of regenerative medicine. The ASCs tested for their potential in wound healing are predominantly derived from the subcutaneous depot of lean donors. However, it is important to characterize the ASC derived from different adipose depots as these depots have clinically distinct roles. We characterized the ASC derived from subcutaneous and omental depots from a lean donor (sc-ASCn and om-ASCn) and compared it to the ASC derived from an obese donor (sc-ASCo and om-ASCo) using flow cytometry and real time qPCR. We show that stem cell markers Oct4, Sal4, Sox15, [[KLF4]] and [[BMI1]] have distinct expression patterns in each ASC. We evaluated the secretome of the ASC and characterized their secreted exosomes. We show long noncoding RNAs (lncRNAs) are secreted by ASC and their expression varied between the ASC's derived from different depots. Protein kinase C delta (PKCδ) regulates the mitogenic signals in stem cells. We evaluated the effect of silencing PKCδ in sc-ASCn, om-ASCn, sc-ASCo and om-ASCo. Using β-galactosidase staining, we evaluated the percentage of senescent cells in sc-ASCn, om-ASCn, sc-ASCo and om-ASCo. Our results also indicated that silencing PKCδ increases the percentage of senescent cells. Our case-specific study demonstrates a role of PKCδ in maintaining the adipose stem cell niche and importantly demonstrates depot-specific differences in adipose stem cells and their exosome content.

|keywords=* Adipose-derived stem cells (ASCs)
* Protein kinase C delta (PKCδ)
* adipose stem cell markers
* exosome
* long noncoding RNAs (lncRNA)
* obesity
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923648
}}
{{medline-entry
|title=A miR-200c/141-[[BMI1]] autoregulatory loop regulates oncogenic activity of [[BMI1]] in cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27105531
|abstract=MicroRNAs (miRNAs) are known to function as oncomiRs or tumor suppressors and are important noncoding RNA regulators of oncogenesis. The miR-200c/141 locus on chromosome 12 encodes miR-200c and miR-141, two members of the miR-200 family, which have been shown to function as tumor suppressive miRNAs by targeting multiple oncogenic factors such as polycomb group protein [[BMI1]]. Here, we show that [[BMI1]] reciprocally functions as a transcriptional repressor of the miR-200c/141 cluster and that [[BMI1]] inhibitors upregulate expression of miR-200c and miR-141. Our data suggest that [[BMI1]] binds to the miR-200c/141 promoter and regulates it through transcription factor binding motifs E-box 2 and Z-box 1 to repress expression of miR-200c/141 cluster. We also show that PTC-209, a small molecule inhibitor of [[BMI1]] gene expression induces cellular senescence and transcriptionally upregulates expression of miR-200c/141 cluster in breast cancer cells. Furthermore, inhibition of expression of miR-200c or miR-141 overcomes tumor suppressive effects of PTC-209 including induction of cellular senescence and downregulation of breast cancer stem cell phenotype. Therefore, our studies suggest a reciprocal regulation between [[BMI1]] and miR-200c/141 cluster, and that [[BMI1]] inhibitory drugs can further amplify their inhibitory effects on [[BMI1]] via multiple mechanisms including posttranscriptional regulation by upregulating [[BMI1]] targeting miRNAs.
|mesh-terms=* Cell Line
* Cell Line, Tumor
* Cellular Senescence
* Gene Expression Regulation, Neoplastic
* HEK293 Cells
* Heterocyclic Compounds, 2-Ring
* Humans
* MCF-7 Cells
* MicroRNAs
* Neoplasms
* Neoplastic Stem Cells
* Polycomb Repressive Complex 1
* Promoter Regions, Genetic
* Protein Binding
* Thiazoles
|keywords=* BMI1
* breast cancer
* miR-141
* microRNA
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094995
}}
{{medline-entry
|title=MicroRNA-31 is a transcriptional target of histone deacetylase inhibitors and a regulator of cellular senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25737447
|abstract=MicroRNAs (miRNAs) have emerged as important regulators of tumorigenesis. Several miRNAs, which can function either as oncomiRs or tumor suppressive miRs are deregulated in cancer cells. The microRNA-31 (miR-31) has been shown to be overexpressed in metastatic breast cancer. It promotes multiple oncogenic phenotypes, including proliferation, motility, and invasion of cancer cells. Using a breast cancer-related miRNA array analysis, we identified miR-31 as a novel target of histone deacetylase inhibitors (HDACi) in breast cancer cells. Specifically, we show that sodium butyrate (NaB) and panobinostat (LBH589), two broad-spectrum HDAC inhibitors up-regulate hsa-miR-31 (miR-31). The up-regulation of miR-31 was accompanied by repression of the polycomb group (PcG) protein [[BMI1]] and induction of cellular senescence. We further show that inhibition of miR-31 overcomes the senescence-inducing effect of HDACi, and restores expression of the PcG protein [[BMI1]]. Interestingly, [[BMI1]] also acts as a repressor of miR-31 transcription, suggesting a cross-negative feedback loop between the expression of miR-31 and [[BMI1]]. Our data suggest that miR-31 is an important physiological target of HDACi, and that it is an important regulator of senescence relevant to cancer. These studies further suggest that manipulation of miR-31 expression can be used to modulate senescence-related pathological conditions such as cancer, and the aging process. 
|mesh-terms=* Apoptosis
* Butyric Acid
* Cell Line, Tumor
* Cellular Senescence
* Feedback, Physiological
* Female
* Gene Expression Regulation, Neoplastic
* Histone Deacetylase Inhibitors
* Humans
* Hydroxamic Acids
* Indoles
* MCF-7 Cells
* MicroRNAs
* Microarray Analysis
* Oligonucleotide Array Sequence Analysis
* Panobinostat
* Polycomb Repressive Complex 1
* Signal Transduction
* Transcription, Genetic
|keywords=* Breast Cancer
* Histone Deacetylase Inhibitor (HDAC Inhibitor) (HDI)
* MicroRNA (miRNA)
* Polycomb
* Senescence
* bmi1
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400362
}}
{{medline-entry
|title=PLK1 inhibition down-regulates polycomb group protein [[BMI1]] via modulation of the miR-200c/141 cluster.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25505268
|abstract=The polycomb group protein [[BMI1]] is an important regulator of cancer stem cell (CSC) phenotype and is often overexpressed in cancer cells. Its overexpression leads to increase in CSC fraction and therapy resistance in tumors. [[BMI1]] functions via polycomb repressive complex 1 (PRC1)-mediated gene silencing and also via PRC1-independent transcriptional activities. At present, very little is known about the therapy reagents that can efficiently inhibit [[BMI1]] expression, and the CSC phenotype. Here, we report that the polo-like kinase 1 (PLK1) regulates [[BMI1]] expression, and that its inhibition can efficiently down-regulate [[BMI1]] expression and PRC1 activity, and induce premature senescence in breast cancer cells. We also show that the exogenous [[BMI1]] overexpression mitigates anti-oncogenic effects of PLK1 inhibition and overcomes senescence induction by PLK1 inhibitors. We further show that PLK1 inhibition down-regulates [[BMI1]] by upregulating the miRNA-200c/141 cluster, which encodes miR-200c and miR-141, both of which are known to post-transcriptionally downregulate [[BMI1]] expression. Thus, our data suggest that PLK1 inhibitors can be successfully used to inhibit growth of tumors in which PcG protein [[BMI1]] is overexpressed or the PRC1 activity is deregulated. 
|mesh-terms=* Blotting, Western
* Cell Cycle Proteins
* Cell Line, Tumor
* Female
* Humans
* MicroRNAs
* Polycomb Repressive Complex 1
* Protein Binding
* Protein-Serine-Threonine Kinases
* Proto-Oncogene Proteins
* Reverse Transcriptase Polymerase Chain Reaction
|keywords=* Breast Cancer
* Cancer Biology
* Cell Growth
* Cellular Regulation
* Cellular Senescence
* Gene Regulation
* Polycomb
* microRNA (miRNA)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317019
}}
{{medline-entry
|title=microRNA-141 regulates [[BMI1]] expression and induces senescence in human diploid fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24091627
|abstract=Polycomb group protein [[BMI1]] is an important regulator of senescence, aging, and cancer. On one hand, it is overexpressed in cancer cells and is required for self-renewal of stem cells. On the other hand, it is downregulated during senescence and aging. MicroRNAs have emerged as major regulators of almost every gene associated with cancer, aging, and related pathologies. At present, very little is known about the miRNAs that regulate the expression of [[BMI1]]. Here, we report that miR-141 posttranscriptionally downregulates [[BMI1]] expression in human diploid fibroblasts (HDFs) via a miR-141 targeting sequence in the 3' untranslated region of [[BMI1]] mRNA. We also show that overexpression of miR-141 induces premature senescence in HDFs via targeting of [[BMI1]] in normal but not in exogenous [[BMI1]]-overexpressing HDFs. Induction of premature senescence in HDFs was accompanied by upregulation of p16INK4a, an important downstream target of [[BMI1]] and a major regulator of senescence. Our results suggest that miR-141-based therapies could be developed to treat pathologies where [[BMI1]] is deregulated. 
|mesh-terms=* Cell Line
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* Diploidy
* Down-Regulation
* Fibroblasts
* Humans
* MicroRNAs
* Polycomb Repressive Complex 1
* Retinoblastoma Protein
* Signal Transduction
* Up-Regulation
|keywords=* BMI1
* aging
* miR-141
* microRNA
* polycomb group proteins
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906339
}}