Glioblastoma stem cells after RNF8 overexpression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE190638 | GEO | 2022/12/10
REPOSITORIES: GEO
Similar Datasets
Project description:Glioblastoma (GBM) is a lethal brain tumor with remarkable intra-tumoral heterogeneity and therapeutic resistance which is linked to glioma stem cell (GSC). GSC contains unstable genome and elevated genomic instability could impair GSC self-renewal and tumorigenicity. In addition, GSC displays great dependency on BubR1, which is a key regulator of spindle assembly checkpoint (SAC) for proper chromosomal segregation. SAC prevents precocious anaphase progression in the presence of unattached kinetochores to ensure genomic integrity. To date, the regulation of SAC in GBM is still poorly understood and whether SAC could be exploited as a therapeutic target for GBM remains unknown. In our study, we revealed a previously unrecognized role of RNF8 in promoting SAC activation in GBM. GBM preferentially downregulates RNF8 in part by promoter methylation and low RNF8 expression correlates with inferior patient prognosis. Overexpression (OE) of wild-type RNF8 but not FHA and RING mutants significantly reduces GSC self-renewal, proliferation and tumorigenicity, and increases genomic instability. Mechanistically, the RING domain associates with the closed conformer of Mad2 (c-Mad2) and c-Mad2 exists as a complex with p31comet. CAMK2D binds transiently to the FHA domain via threonine 287 and this leads to RNF8 phosphorylation at serine 157. Furthermore, CAMK2D functions to recruit RNF8 to RNA splicing proteins to promote SAC activation independently of its enzymatic activity. To indirectly target RNF8-associated SAC in GBM, we exploited Connectivity Map (CMAP) and found that PLK1 inhibitor (PLK1i) could mimic RNF8-OE gene signature. Combination of PLK1i and proteostatic stressor leads to synergistic killing in GSCs. Collectively, our study unveiled an unconventional role of RNF8 in SAC regulation, dissected its molecular mechanisms and highlights the biological complexity of E3 ubiqtuitin ligases.
2023-07-21 | PXD038123 | JPOST Repository
Project description:During metaphase, in response to improper kinetochore-microtubule attachments, the spindle assembly checkpoint (SAC) activates the mitotic checkpoint complex (MCC) to inhibit the anaphase-promoting complex/cyclosome (APC/C). The Mad1-Mad2 complex provides a catalytic platform for MCC assembly. Mad1-bound Mad2 recruits open-Mad2 through asymmetric dimerization and Mad1 phosphorylation by Mps1 promotes conversion of Mad2 from an open (O-Mad2) to closed (C-Mad2) state, which binds Cdc20 to form the MCC. How Mad1 phosphorylation catalytically activates MCC formation is poorly understood. This study characterises Mad1 phosphorylation by Mps1 and provides structural and biochemical insights into a phosphorylation-specific Mad1-Cdc20 interaction, which allows for a tripartite assembly of Bub1-Mad1-Cdc20 on the C-terminal domain of Mad1. We also identify a folded state of Mad1-Mad2 complex, suggesting a model by which the Cdc20-Mad1 interaction brings the Cdc20 MIM motif near Mad2. The Cdc20 MIM motif is then entrapped by the Mad2 safety belt to form a stable complex, allowing spontaneous MCC assembly.
2023-03-11 | PXD031872 | Pride
Project description:Analysis of the transcriptional response to aneuploidy in mouse epidermis. In this study we measured the transcriptional response to aneuploidy by aboragting the spindle checkpoint in mouse epidermis. We found that, whereas spindle checkpoint inactivation in the epidermis is tolerated, but results in metabolic deranged cells, SAC abrogation kills bulge stem cells Mad2; K14-Cre mice were sacrificed at indicated timepoints and epidermis was separated from dermis using overnight trypsin. RNA was isolated and expression patterns were compared between K14-Cre; Mad2f/f and Cfre negative animals for all timepoints.
2013-01-22 | E-GEOD-42698 | biostudies-arrayexpress
Project description:Transcriptome analysis to map transcriptomes of Mad2 p53null-driven aneuploid liver cancers and T-ALLs, to determine correlation between copy number changes and expression changes and to map the transcriptional response to CIN Chromosome instability (CIN) leads to aneuploidy and copy number variations (CNVs). Even though both are hallmarks of cancer cells, aneuploidy inhibits proliferation of untransformed cells, suggesting that cancer cells have adapted to cope with CIN. The spindle assembly checkpoint (SAC) prevents CIN by monitoring chromosome attachment and sister chromatid tension in mitosis. By conditionally inactivating Mad2, an essential SAC gene, we find that SAC inactivation in T-cells or hepatocytes is remarkably well tolerated and becomes tumorigenic when placed in a p53null or p53+/- predisposed background. The resulting T-ALLs and HCCs are highly aneuploid, exhibit clonal copy number changes that are tumor specific despite ongoing CIN, indicating that CIN is a powerful driver of tumor evolution.
2017-03-20 | GSE63687 | GEO
Project description:Ibrahim2008 - Mitotic Spindle Assembly Checkpoint - Convey variant
The Mitotic Spindle Assembly Checkpoint ((M)SAC) is an evolutionary conserved mechanism. This model incorporates the perspectives of three central control pathways, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. MCC:APC dissociation is described by two alternatives models, namely the "Dissociation" and the "Convey" model variants. Both these model are available in BioModels Database. This model corresponds to the "Convey" variant.
This model is described in the article:
In-silico modeling of the mitotic spindle assembly checkpoint.
Ibrahim B, Diekmann S, Schmitt E, Dittrich P
PLoS One. 2008 Feb 6;3(2):e1555.
Abstract:
BACKGROUND: The Mitotic Spindle Assembly Checkpoint ((M)SAC) is an evolutionary conserved mechanism that ensures the correct segregation of chromosomes by restraining cell cycle progression from entering anaphase until all chromosomes have made proper bipolar attachments to the mitotic spindle. Its malfunction can lead to cancer.
PRINCIPLE FINDINGS: We have constructed and validated for the human (M)SAC mechanism an in silico dynamical model, integrating 11 proteins and complexes. The model incorporates the perspectives of three central control pathways, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. Originating from the biochemical reactions for the underlying molecular processes, non-linear ordinary differential equations for the concentrations of 11 proteins and complexes of the (M)SAC are derived. Most of the kinetic constants are taken from literature, the remaining four unknown parameters are derived by an evolutionary optimization procedure for an objective function describing the dynamics of the APC:Cdc20 complex. MCC:APC dissociation is described by two alternatives, namely the "Dissociation" and the "Convey" model variants. The attachment of the kinetochore to microtubuli is simulated by a switching parameter silencing those reactions which are stopped by the attachment. For both, the Dissociation and the Convey variants, we compare two different scenarios concerning the microtubule attachment dependent control of the dissociation reaction. Our model is validated by simulation of ten perturbation experiments.
CONCLUSION: Only in the controlled case, our models show (M)SAC behaviour at meta- to anaphase transition in agreement with experimental observations. Our simulations revealed that for (M)SAC activation, Cdc20 is not fully sequestered; instead APC is inhibited by MCC binding.
This model describes the controlled dissociation variant of the mitotic spindle assembly checkpoint. If the tool you use has problems with events, you can uncomment the assignment rules for u and u_prime and comment out the list of events.
In accordance with the authors due to typos in the original publication some initial conditions and parameters were slightly changed in the model:
article
model
[O-Mad2]
1.5e-7 M
1.3e-7 M
[BubR1:Bub3]
1.30e-7 M
1.27e-7 M
k -4
0.01 M -1
s -1
0.02 M -1
s -1
k -5
0.1 M -1
s -1
0.2 M -1
s -1
This model is hosted on BioModels Database
and identified by: MODEL6655578762
.
To cite BioModels Database, please use: BioModels Database: 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.
2008-09-01 | BIOMD0000000187 | BioModels
Project description:Ibrahim2008 - Mitotic Spindle Assembly Checkpoint - Dissociation variant
The Mitotic Spindle Assembly Checkpoint ((M)SAC) is an evolutionary conserved mechanism. This model incorporates the perspectives of three central control pathways, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. MCC:APC dissociation is described by two alternatives models, namely the "Dissociation" and the "Convey" model variants. Both these model are available in BioModels Database. This model corresponds to the "Dissociation" variant.
This model is described in the article:
In-silico modeling of the mitotic spindle assembly checkpoint.
Ibrahim B, Diekmann S, Schmitt E, Dittrich P
PLoS One. 2008 Feb 6;3(2):e1555.
Abstract:
BACKGROUND: The Mitotic Spindle Assembly Checkpoint ((M)SAC) is an evolutionary conserved mechanism that ensures the correct segregation of chromosomes by restraining cell cycle progression from entering anaphase until all chromosomes have made proper bipolar attachments to the mitotic spindle. Its malfunction can lead to cancer.
PRINCIPLE FINDINGS: We have constructed and validated for the human (M)SAC mechanism an in silico dynamical model, integrating 11 proteins and complexes. The model incorporates the perspectives of three central control pathways, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. Originating from the biochemical reactions for the underlying molecular processes, non-linear ordinary differential equations for the concentrations of 11 proteins and complexes of the (M)SAC are derived. Most of the kinetic constants are taken from literature, the remaining four unknown parameters are derived by an evolutionary optimization procedure for an objective function describing the dynamics of the APC:Cdc20 complex. MCC:APC dissociation is described by two alternatives, namely the "Dissociation" and the "Convey" model variants. The attachment of the kinetochore to microtubuli is simulated by a switching parameter silencing those reactions which are stopped by the attachment. For both, the Dissociation and the Convey variants, we compare two different scenarios concerning the microtubule attachment dependent control of the dissociation reaction. Our model is validated by simulation of ten perturbation experiments.
CONCLUSION: Only in the controlled case, our models show (M)SAC behaviour at meta- to anaphase transition in agreement with experimental observations. Our simulations revealed that for (M)SAC activation, Cdc20 is not fully sequestered; instead APC is inhibited by MCC binding.
This model describes the controlled dissociation variant of the mitotic spindle assembly checkpoint. If the tool you use has problems with events, you can uncomment the assignment rules for u and u_prime and comment out the list of events.
In accordance with the authors due to typos in the original publication some initial conditions and parameters were slightly changed in the model:
article
model
[O-Mad2]
1.5e-7 M
1.3e-7 M
[BubR1:Bub3]
1.30e-7 M
1.27e-7 M
k -4
0.01 M -1
s -1
0.02 M -1
s -1
k -5
0.1 M -1
s -1
0.2 M -1
s -1
This model is hosted on BioModels Database
and identified by: MODEL6655615431
.
To cite BioModels Database, please use: BioModels Database: 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.
2008-09-02 | BIOMD0000000186 | BioModels
Project description:Mad2 and p53 loss were combined in liver or T-cells specificely leading to early onset and highly aggressive aneuploid HCC and T-ALL. Tumours were characterized for (recurrrent) copy number changes with a focus on whole chromosome abnormalities. DNA content was compared to the DNA content of sex-matched uninfiltrated control liver samples from litter mates Chromosome instability (CIN) leads to aneuploidy and copy number variations (CNVs). Even though both are hallmarks of cancer cells, aneuploidy inhibits proliferation of untransformed cells, suggesting that cancer cells have adapted to cope with CIN. The spindle assembly checkpoint (SAC) prevents CIN by monitoring chromosome attachment and sister chromatid tension in mitosis. By conditionally inactivating Mad2, an essential SAC gene, we find that SAC inactivation in T-cells or hepatocytes is remarkably well tolerated and becomes tumorigenic when placed in a p53null or p53+/- predisposed background. The resulting T-ALLs and HCCs are highly aneuploid, exhibit clonal copy number changes that are tumor specific despite ongoing CIN, indicating that CIN is a powerful driver of tumor evolution.
2017-03-20 | GSE63686 | GEO
Project description:Chromosome instability (CIN) leads to aneuploidy and copy number variations (CNVs). Even though both are hallmarks of cancer cells, aneuploidy inhibits proliferation of untransformed cells, suggesting that cancer cells have adapted to cope with CIN. The spindle assembly checkpoint (SAC) prevents CIN by monitoring chromosome attachment and sister chromatid tension in mitosis. By conditionally inactivating Mad2, an essential SAC gene, we find that SAC inactivation in T-cells or hepatocytes is remarkably well tolerated and becomes tumorigenic when placed in a p53null or p53+/- predisposed background. The resulting T-ALLs and HCCs are highly aneuploid, exhibit clonal copy number changes that are tumor specific despite ongoing CIN, indicating that CIN is a powerful driver of tumor evolution.
2017-03-20 | GSE63688 | GEO
Project description:The pluripotency transcription factor SOX2 is essential for the maintenance of glioblastoma stem cells (GSC), which drive tumor growth and treatment resistance.To understand how SOX2 is regulated in GSCs, we utilized a proteomic approach and identified the E3 ubiquitin ligase TRIM26 as a direct SOX2-interacting protein. Unexpectedly, we found TRIM26 depletion decreased SOX2 protein levels and increased SOX2 polyubiquitination in patient-derived GSCs, suggesting TRIM26 promotes SOX2 protein stability. Accordingly, TRIM26 knockdown reduced SOX2 transcriptional activity, self-renewal capacity, and in vivo tumorigenicity in multiple GSC lines. Mechanistically, we found TRIM26, via its C-terminal PRYSPRY domain, but independent of its RING domain, stabilizes SOX2 protein by directly inhibiting the interaction of SOX2 with WWP2, which we identify as a bona fide SOX2 E3 ligase in GSCs. Our work identifies E3 ligase competition as a critical mechanism of SOX2 regulation, with functional consequences for GSC identity and maintenance.
2021-11-04 | PXD028933 | Pride
Project description:Inhibition of an initiating oncogene often leads to extensive tumor cell death, a phenomenon known as oncogene addiction. This has led to the search for compounds that specifically target and inhibit oncogenes as anti-cancer agents. Whether chromosomal instability (CIN) generated as a result of deregulation of the mitotic checkpoint pathway, a frequent characteristic of solid tumors, has any effect on oncogene addiction, however, has not been explored systematically. We show here that induction of chromosome instability by overexpression of the mitotic checkpoint gene Mad2 does not affect the regression of Kras driven lung tumors upon Kras inhibition. However, tumors that experience transient Mad2 overexpression and consequent chromosome instability recur at dramatically elevated rates. The recurrent tumors are highly aneuploid and have varied activation of pro-proliferative pathways. Thus, early CIN may be responsible for tumor relapse after seemingly effective anti-cancer treatments. Experiment Overall Design: Lung tumor tissue from TI-K (CCSP-rtTA;TRE-KrasV12), TI-KM (CCSP-rtTA; TRE-KrasV12; TRE-Mad2), recurrence (TI-KM) or normal lung tissue (CCSP-rtTA) was subjected to RNA extraction and individual samples hybridized to array platform MOE430A 2.0 Affymetrix.
2010-01-22 | E-GEOD-19753 | biostudies-arrayexpress