Polycomb group protein BMI1 prevents neuroblastoma cells from DNA-damage-induced apoptotic cell death
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ABSTRACT:
PROVIDER: PRJNA783041 | ENA |
REPOSITORIES: ENA
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Project description:BMI1 is a polycomb protein and its overexpression has been correlated with cancer development and aggressiveness. We previously reported that v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN)-induced BMI1 positively regulated neuroblastoma (NB) cell proliferation via the transcriptional suppression of tumor suppressors in NB cells. In order to evaluate the potential of BMI1 as a new target for NB therapy, we herein examined the effects of BMI1 reductions on NB cell differentiation and apoptotic NB cell death. BMI1 knockdown (KD) up to 7 days in NB cells significantly induced their differentiation. BMI1 depletion up to 14 days significantly induced apoptotic NB cell death along with the activation of p53, increases in p73, and induction of p53 family downstream molecules. BMI1 depletion in vivo markedly suppressed NB xenograft tumor growth. A pathological analysis using the TUNEL assay indicated the induction of apoptotic cell death. BMI1 reductions activated ATM and increased γ-H2AX in NB cells. Importantly, these DNA damage signals and apoptotic cell death were not canceled by transduction of polycomb group molecules EZH2 and RING1B. Further, EZH2 or RING1B knockdown could not induce apoptotic NB cell death at the same level of BMI1 KD. Together, BMI1 appears to be a promising target of molecular therapy for NB tumors and our report clarified, for the first time, the shared role of PcG proteins in DNA damage response of NB cells.
2022-11-08 | GSE189449 | GEO
Project description:Bmi1 is a component of the Polycomb-repressive complexes (PRC) and essential for maintaining the pool of adult stem cells. PRC are key regulators for embryonic development by modifying chromatin architecture and maintaining gene repression. To assess the role of Bmi1 in pluripotent stem cells and upon exit from pluripotency during differentiation, we studied forced Bmi1 expression in mouse embryonic stem cells (ESC). We found that ESC do not express detectable levels of Bmi1 RNA and protein and that forced Bmi1 expression had no obvious influence on ESC self-renewal. However, upon ESC differentiation Bmi1 effectively enhanced development of hematopoietic cells. Global transcriptional profiling identified a large array of genes that were differentially regulated during ESC differentiation by Bmi1. Importantly, we found that Bmi1 induced a prominent up-regulation of Gata2, a zinc finger transcription factor, which is essential for primitive hematopoietic cell generation from mesoderm. In addition, Bmi1 caused sustained growth and a more than 100-fold expansion of ESC-derived hematopoietic stem/progenitor cells within 2-3 weeks of culture. The enhanced proliferative capacity was associated with reduced Ink4a/Arf expression in Bmi1-transduced cells. Taken together, our experiments demonstrate distinct activities of Bmi1 in ESC and ESC-derived hematopoietic progenitor cells. In addition, Bmi1 enhances the propensity of ESC in differentiating towards the hematopoietic lineage. Thus, Bmi1 could be a candidate gene for engineered adult stem cell derivation from ESC. 8 samples in total. Bmi1 embryonic stem cells sample_1 (Bmi1_ESC_1) Bmi1 embryonic stem cells sample_2 (Bmi1_ESC_2) Untreated CCE embryonic stem cells (CCE_ESC_Control) Empty vector CCE embryonic stem cells (CCE_ESC_Vector) Bmi1 embryoid body sample_1 (Bmi1_EB_1) Bmi1 embryoid body sample_2 (Bmi1_EB_2) Empty vector control embryoid body sample_1 (Vector_EB_1) Empty vector control embryoid body sample_2 (Vector_EB_2)
2011-04-29 | E-GEOD-20958 | biostudies-arrayexpress
Project description:Bmi1 is a component of the Polycomb-repressive complexes (PRC) and essential for maintaining the pool of adult stem cells. PRC are key regulators for embryonic development by modifying chromatin architecture and maintaining gene repression. To assess the role of Bmi1 in pluripotent stem cells and upon exit from pluripotency during differentiation, we studied forced Bmi1 expression in mouse embryonic stem cells (ESC). We found that ESC do not express detectable levels of Bmi1 RNA and protein and that forced Bmi1 expression had no obvious influence on ESC self-renewal. However, upon ESC differentiation Bmi1 effectively enhanced development of hematopoietic cells. Global transcriptional profiling identified a large array of genes that were differentially regulated during ESC differentiation by Bmi1. Importantly, we found that Bmi1 induced a prominent up-regulation of Gata2, a zinc finger transcription factor, which is essential for primitive hematopoietic cell generation from mesoderm. In addition, Bmi1 caused sustained growth and a more than 100-fold expansion of ESC-derived hematopoietic stem/progenitor cells within 2-3 weeks of culture. The enhanced proliferative capacity was associated with reduced Ink4a/Arf expression in Bmi1-transduced cells. Taken together, our experiments demonstrate distinct activities of Bmi1 in ESC and ESC-derived hematopoietic progenitor cells. In addition, Bmi1 enhances the propensity of ESC in differentiating towards the hematopoietic lineage. Thus, Bmi1 could be a candidate gene for engineered adult stem cell derivation from ESC.
2011-04-29 | GSE20958 | GEO
Project description:Glioblastoma (GBM) is the most common and aggressive primary brain tumor with limited therapeutic options, possibly because of the highly tumorigenic subpopulations of stem cell-like cells. Mechanisms that sustain cancer stem cells are crucial to tumor progression. The polycomb group protein BMI1 (BMI1 proto-oncogene, polycomb ring finger) maintains cancer hallmarks including the glioblastoma stem-like cell (GSC) state. Ubiquitin-specific protease 22 (USP22) is highly expressed in and required for the maintenance of cancer stem cells (CSCs). Previously, we observed that forced expressed microRNA-218 in glioblastoma cells led to suppressed BMI1 expression. However, the pathways engaged by USP22 or driving BMI1 accumulation in GSCs remained elusive. Here, we found USP22 to be a novel deubiquitylase of BMI1. USP22 directly deubiquitylates and stabilizes BMI1. USP22 protein levels are elevated in tumor neurosphere. USP22 depletion induces BMI1 destabilization, and results in the inhibition of GSCs self-renewal by regulating a broad range of genes involved in glioma stemness and progression. Xenograft analyses using U87MG cells showed that both USP22 and BMI1 depletion attenuated tumor growth. Clinically, the expression levels of USP22 and BMI1 were positively correlated with those common targets like POSTN, HEY2, or PDGFRA and inversely correlated with ATF3 in human glioblastoma specimens. Taken together, our data reveals that USP22 functions as a novel deubiquitylase of BMI1 and inhibits self-renewal of GSCs by stabilizing BMI1. These findings also indicate that the USP22-BMI1 axis has a critical role in glioma tumorigenesis and that targeting the axis may provide a new therapeutic approach for human glioblastoma.
2017-01-01 | GSE89239 | GEO
Project description:Nano gold simulated autophagy prevents cell death
| PRJNA542349 | ENA
Project description:NguyenLK2011 - Ubiquitination dynamics in
Ring1B-Bmi1 system
This theoretical model investigates the
dynamics of Ring1B/Bmi1 ubiquitination to identify bistable
switch-like and oscillatory behaviour in the
system. Michaelis-Menten (MM) equations are used to formulate
the model. However, the authors show that the dynamics persist even
for Mass-Action kinetics. This SBML file is the MM version of the
model.
This model is described in the article:
Switches,
excitable responses and oscillations in the Ring1B/Bmi1
ubiquitination system.
Nguyen LK, Muñoz-García J,
Maccario H, Ciechanover A, Kolch W, Kholodenko BN.
PLoS Comput. Biol. 2011 Dec; 7(12):
e1002317
Abstract:
In an active, self-ubiquitinated state, the Ring1B ligase
monoubiquitinates histone H2A playing a critical role in
Polycomb-mediated gene silencing. Following ubiquitination by
external ligases, Ring1B is targeted for proteosomal
degradation. Using biochemical data and computational modeling,
we show that the Ring1B ligase can exhibit abrupt switches,
overshoot transitions and self-perpetuating oscillations
between its distinct ubiquitination and activity states. These
different Ring1B states display canonical or multiply branched,
atypical polyubiquitin chains and involve association with the
Polycomb-group protein Bmi1. Bistable switches and oscillations
may lead to all-or-none histone H2A monoubiquitination rates
and result in discrete periods of gene (in)activity. Switches,
overshoots and oscillations in Ring1B catalytic activity and
proteosomal degradation are controlled by the abundances of
Bmi1 and Ring1B, and the activities and abundances of external
ligases and deubiquitinases, such as E6-AP and USP7.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000622.
To cite BioModels Database, please use:
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An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000622 | BioModels
Project description:The Bmi1 Polycomb protein is involved in the epigenetic repressive control of self renewal and survival of cancer initiating cells. In Chronic Myeloid Leukemia (CML), bmi1 expression increases gradually as the disease progresses from a chronic latent phase to a deadly blast crisis. We developped an inducible shRNA system to silence Bmi1 in the human K562 chronic myeloid leukemia (CML) cell line in order to identify new Bmi1-target genes.
2015-05-12 | GSE54262 | GEO
Project description:Identification of BMI1, RYBP and H2AK119UB interactome in Glioblastoma (GBM) to elucidate BMI1 roles independent of the PRC1-complex in GBM.
2021-09-09 | PXD022057 | Pride
Project description:The Bmi1 Polycomb protein is involved in the epigenetic repressive control of self renewal and survival of cancer initiating cells. In Chronic Myeloid Leukemia (CML), bmi1 expression increases gradually as the disease progresses from a chronic latent phase to a deadly blast crisis. We developped an inducible shRNA system to silence Bmi1 in the human K562 chronic myeloid leukemia (CML) cell line in order to identify new Bmi1-target genes. Gene profiling was performed on inducible shBmi1-K562 cells incubated without (P3-K562+shBMI1) or with doxycycline for 96h (P4-K562+shBMI1+doxycycline) using HG-U133 Plus2 Affymetrix Arrays.
2015-05-12 | E-GEOD-54262 | biostudies-arrayexpress
Project description:Bmi1 is a component of polycomb repressive complex 1 and its role in the inheritance of the stemness of adult somatic stem cells has been well characterized. Bmi1 maintains the self-renewal capacity of adult stem cells, at least partially, by repressing the Ink4a/Arf locus that encodes a cyclin-dependent kinase inhibitor, p16Ink4a, and a tumor suppressor, p19Arf 14. Deletion of both Ink4a and Arf in Bmi1-deficient mice substantially restored the defective self-renewal capacity of HSCs and neural stem cells.
2012-02-08 | GSE31086 | GEO