scholarly journals BRD4 regulates self‐renewal ability and tumorigenicity of glioma‐initiating cells by enrichment in the Notch1 promoter region

2020 ◽  
Vol 10 (6) ◽  
Author(s):  
Zhennan Tao ◽  
Xuetao Li ◽  
Hao Wang ◽  
Guangliang Chen ◽  
Zibin Feng ◽  
...  
Keyword(s):  
Promoter Region ◽  
Self Renewal ◽  
Glioma Initiating Cells

The Regulation of β-arrestin1 in Leukemia Initiating Cells of Children B-Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3538-3538
Author(s):  
Lin Zou ◽  
Shan Liu ◽  
Yi Shu ◽  
Ru Qin ◽  
Kang Li ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Mrna Expression ◽  
Promoter Region ◽  
Lymphoblastic Leukemia ◽  
The Self ◽  
Mrna Expression Level ◽  
Self Renewal ◽  
Nsg Mice

Abstract Background Leukemia is the most common malignant tumor in children under 15 years old. The main subtype of children leukemia is acute lymphoblastic leukemia (ALL), and B-lineage ALL (B-ALL) accounts for approximately 70%. The leukemia-initiating cells (LICs) are cancer stem cells with long-term repopulating potential and propagation ability, to maintain the leukemia cell phenotype, and possess leukemia-initiating activity. However, the regulation of LICs for the leukemia progression is poorly understood. The multifunctional scaffold proteins β-arrestins are proven to mediate H4 acetylation and gene expression. And β-arrestin2 is found to regulate the initiation and progression of chronic myeloid leukemia (CML). However, the role of β-arrestin1 in B-ALL is still unknown. Our preliminary data showed that both the high expression of β-arrestin1 and high proportion of CD34+CD38- cells are positively correlated with risk stratification and poor prognosis of childhood B-ALL. And β-arrestin1 binds with EZH2 to increase BCR/ABL H4 acetylation and thus promotes CML cell progression in vitro and in vivo. The aim of study is to investigate the essential function of β-arrestin1 in LICs from B-ALL. Materials and Methods The bone marrow (BM) and periphery blood (PB) of children B-ALL patients were collected, isolated and identified LICs by Magnetic-activated cell sorting (MACS) and flow cytometry. The total RNA and protein were purified for gene and protein expression by real-time RT-PCR and Western blot. The leukemia cells (LICs, Raji, and Reh) of β-arrestin1 depletion were constructed by transient or stable screening si-β-arrestin1 (siβ1) lentivirus vector. The serial cell colony formation and NSG mice survival analysis was measured the LICs self-renewal ability. The CCK8 and MTS assays were used to detect the cell proliferation, and annexin V-FITC and PI staining for cell apoptosis. The DNA methylation of gene promoter region was detected by methylation-specific PCR and the methltransferase activity by ELISA. The telomere length was indicated by Southern blot and FISH, and telomerase activity by TRAP. Electrophoretic mobility shift assay (EMSA) and dual-luciferase reporter assay were applied to explain gene transcription. Student’s t test and Log-Rank test were used in the corresponding statistical significance and P<0.05 were considered significant. All the statistical analysis was performed using the GraphPad Prism (Version 5.0) software packages and SPSS 17.0. Results The expression of β-arrestin1 was elevated in LICs from B-ALL patients, and the high level of β-arrestin1 was negatively correlated with the survival of these patients. Further study showed that the loss of β-arrestin1 in B-ALL LICs attenuates their self-renewal capacity and promotes their senescence in vitro and in vivo. The mRNA expression level of β-arrestin1 is negatively correlated with that of PTEN in LICs. Moreover, the DNA methylation of the PTEN promoter region, the activity and the expression of DNMTs were enhanced in the LICs. The inhibition of DNMT1 activity impaired the self-renewal and increased the expression of PTEN of LICs. In addition, depletion of β-arrestin1 significantly decreased DNMT1 activity and PTEN methylation, and consistently increased PTEN expression in LICs. For B-ALL cell senescence, the mRNA expression level of β-arrestin1 is negatively related with the length of telomere, positively related with the activity of telomerase and the mRNA expression of hTERT in B-ALL LICs and engrafted NSG mice. Moreover, the weakened effect of β-arrestin1 on telomere, telomerase and the gene of hTERT were observed by injected the inhibitor of telomerase in leukemic mice. In addition, depletion of β-arrestin1 significantly decreased the binding of SP1 to the promoter of hTERT and thus reduced the transcription of hTERT in B-ALL Raji and Reh cells. Furthermore, β-arrestin1 interacted with P300 to bind with SP1 in the -104bp to -113bp of hTERT core promoter region in B-ALL cells. Conclusions β-arrestin1 could regulate the self-renewal and senescence of LICs from B-ALL, by partially mediating DNMT1 activity and hTERT transcription respectively, indicating that β-arrestin1 is a potential therapeutic target for B-ALL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Cathepsin B and uPAR regulate self-renewal of glioma-initiating cells through GLI-regulated Sox2 and Bmi1 expression

2012 ◽  
Vol 34 (3) ◽  
pp. 550-559 ◽  
Author(s):  
Sreelatha Gopinath ◽  
RamaRao Malla ◽  
Kiranmai Alapati ◽  
Bharathi Gorantla ◽  
Meena Gujrati ◽  
...  
Keyword(s):  
Cathepsin B ◽  
Self Renewal ◽  
Glioma Initiating Cells ◽  
Bmi1 Expression

scholarly journals Repression of kit Expression by Plzf in Germ Cells

2007 ◽  
Vol 27 (19) ◽  
pp. 6770-6781 ◽  
Author(s):  
Doria Filipponi ◽  
Robin M. Hobbs ◽  
Sergio Ottolenghi ◽  
Pellegrino Rossi ◽  
Emmanuele A. Jannini ◽  
...  
Keyword(s):  
Germ Cells ◽  
Transcriptional Repression ◽  
Promoter Region ◽  
Spermatogonial Stem Cell ◽  
Stem Cell Population ◽  
Male Mice ◽  
Self Renewal ◽  
Expression Of Genes

ABSTRACT Male mice lacking expression of Plzf, a DNA sequence-specific transcriptional repressor, show progressive germ cell depletion due to exhaustion of the spermatogonial stem cell population. This is likely due to the deregulated expression of genes controlling the switch between spermatogonial self-renewal and differentiation. Here we show that Plzf directly represses the transcription of kit, a hallmark of spermatogonial differentiation. Plzf represses both endogenous kit expression and expression of a reporter gene under the control of the kit promoter region. A discrete sequence of the kit promoter, required for Plzf-mediated kit transcriptional repression, is bound by Plzf both in vivo and in vitro. A 3-bp mutation in this Plzf binding site abolishes the responsiveness of the kit promoter to Plzf repression. A significant increase in kit expression is also found in the undifferentiated spermatogonia isolated from Plzf −/− mice. Thus, we suggest that one mechanism by which Plzf maintains the pool of spermatogonial stem cells is through a direct repression of kit expression.

scholarly journals AURKA Governs Self-Renewal Capacity in Glioma-Initiating Cells via Stabilization/Activation of β-catenin/Wnt Signaling

2013 ◽  
Vol 11 (9) ◽  
pp. 1101-1111 ◽  
Author(s):  
Zhibo Xia ◽  
Ping Wei ◽  
Heng Zhang ◽  
Zhiming Ding ◽  
Lixuan Yang ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Self Renewal ◽  
Glioma Initiating Cells

PTEN status is related to cell proliferation and self-renewal independent of CD133 phenotype in the glioma-initiating cells

2010 ◽  
Vol 349 (1-2) ◽  
pp. 149-157 ◽  
Author(s):  
Ru-Bin Cheng ◽  
Rui-Juan Ma ◽  
Zhao-Kai Wang ◽  
Shan-Jun Yang ◽  
Xiang-Zhi Lin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Self Renewal ◽  
Glioma Initiating Cells

scholarly journals BOT-02 2-METHYLTHIO MODIFICATION OF N6-ISOPENTENYLADENOSINE IN MITOCHONDRIAL TRNAS BY CDK5RAP1 PROMOTES THE MAINTENANCE OF GLIOMA-INITIATING CELLS

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii12-ii12
Author(s):  
Takahiro Yamamoto ◽  
Atsushi Fujimura ◽  
Wei Fan-Yan ◽  
Keitarou Kai ◽  
Tatsuya Takezaki ◽  
...  
Keyword(s):  
Translational Control ◽  
Cytotoxic Effect ◽  
Regulatory Subunit ◽  
Mitochondrial Translation ◽  
Mt Dna ◽  
Self Renewal ◽  
Glioma Initiating Cells ◽  
Undifferentiated State ◽  
Tumorigenic Potential ◽  
Elevated Activity

Abstract 2-Methylthio-N6-isopentenyl modification of adenosine (ms2i6A) is an evolutionally conserved modification that is found in mitochondrial (mt)-tRNAs. Cdk5 regulatory subunit-associated protein 1 (CDK5RAP1) specifically converts N6-isopentenyladenosine (i6A) to ms2i6A at position A37 of four mt-DNA-encoded tRNAs, and the modification regulates efficient mitochondrial translation and energy metabolism in mammals. Here, we report that the ms2 conversion mediated by CDK5RAP1 in mt-tRNAs is required to sustain glioma-initiating cell (GIC)-related traits. CDK5RAP1 maintained the self-renewal capacity, undifferentiated state, and tumorigenic potential of GICs. This regulation was not related to the translational control of mt-proteins. CDK5RAP1 abrogated the antitumor effect of i6A by converting i6A to ms2i6A and protected GICs from excessive autophagy triggered by i6A. The elevated activity of CDK5RAP1 contributed to the amelioration of the cytotoxic effect of i6A and promoted GIC maintenance. The hypoxic microenvironment in the tumor core activated CDK5RAP1, whose activity was inversely correlated with the oxygen concentration because of two [4Fe-4S] clusters in the enzyme. This work demonstrates that CDK5RAP1 is crucial for the detoxification of endogenous i6A and that GICs readily utilize this mechanism for survival.

scholarly journals FSMP-01. ID1 MEDIATES ONE-CARBON MEDIATED PURINE SYNTHESIS IN GLIOBLASTOMA

2021 ◽  
Vol 3 (Supplement_1) ◽  
pp. i16-i16
Author(s):  
Kimia Ghannad-Zadeh ◽  
Megan Wu ◽  
Taylor Wilson ◽  
Robert Flick ◽  
Sunit Das
Keyword(s):  
De Novo ◽  
Regulatory Protein ◽  
Metabolic Reprogramming ◽  
Glioblastoma Cells ◽  
Self Renewal ◽  
Purine Synthesis ◽  
Glioma Initiating Cells ◽  
Effective Combination ◽  
Transcriptional Regulatory ◽  
One Carbon Metabolism

Abstract Inhibitor of DNA-binding-1 (ID1) is a transcriptional regulatory protein involved in maintenance of self-renewal and inhibition of differentiation, and acts as a key regulator of tumorigenesis in glioblastoma. Studies suggest that de novo purine synthesis is essential for the maintenance of rapid proliferation rates in glioma initiating cells. We hypothesise that ID1 plays a role in reprogramming one-carbon mediated de novo purine synthesis, thereby metabolically contributing to the tumorigenic advantage seen in ID1-high glioblastoma cells. The effect of ID1 regulation on metabolic reprogramming of glioblastoma was studied using ID1-knockout U251 glioblastoma cell lines. Protein expression analysis and liquid chromatography mass-spectrometry were respectively used to assess expression and concentration of metabolic enzymes and intermediates of one-carbon and de novo purine synthesis pathways. CD44 expression was analyzed as a marker of cancer stem cells. The expression of DHFR and MTHFD2 was significantly decreased after ID1 knockout. Furthermore, PAICS expression, and overall concentration of IMP, AMP, GMP, and ATP were reduced after ID1 knockout. ID1 expression in glioblastoma tumor xenografts was associated with positive expression of one-carbon metabolism and purine synthesis enzymes, while ID1-/- cells within the same xenograft had significantly reduced expression of these enzymes. The expression of CD44 was reduced after ID1 knockout. This data suggests that ID1 mediates an increase in one-carbon mediated de novo purine synthesis, thereby regulating metabolic reprogramming in glioblastoma cells. The correlation between CD44 and ID1 expression provides further support that ID1 maintains a less differentiated phenotype in a subset of glioblastoma cells, and metabolic reprogramming is one of the mechanisms through which this phenotype, and the capacity for self-renewal are maintained. Further elucidation of the mechanisms through which ID1 mediates metabolic reprograming of glioblastoma cells can lead to developing effective combination therapies coupling chemotherapeutic strategies with targeting of metabolic programs used by cancer initiating cells.

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