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Transcriptomic analysis unveils correlations between regulative apoptotic caspases and genes of cholesterol homeostasis in human brain

ABSTRACT: Caspases are cysteine-proteases with key roles in the execution phase of apoptosis. Additional cellular activities, unrelated to cell death seem to be influenced by these enzymes. Identification of genes co-regulated with caspases could help to ascertain new biological roles for these proteases.To identify genes and pathways under the influence of caspase-2 we silenced its expression in U87MG glioblastoma cell line. Transcriptional expression profiles of cells transfected with caspase-2 siRNA or control siRNA were compared. Gene expression profiling was evaluated from 2 replicates of U87MG cells transfected with CASP2-siRNA, or with Control-siRNA.

ORGANISM(S): Homo sapiens

SUBMITTER: raffaella picco

PROVIDER: E-GEOD-61388 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcriptomic analysis unveils correlations between regulative apoptotic caspases and genes of cholesterol homeostasis in human brain

Project description:Caspases are cysteine-proteases with key roles in the execution phase of apoptosis. Additional cellular activities, unrelated to cell death seem to be influenced by these enzymes. Identification of genes co-regulated with caspases could help to ascertain new biological roles for these proteases.To identify genes and pathways under the influence of caspase-2 we silenced its expression in U87MG glioblastoma cell line. Transcriptional expression profiles of cells transfected with caspase-2 siRNA or control siRNA were compared.

2014-09-13 | GSE61388 | GEO

Stucki2005 - caspase-3 metabolism

Project description:Jörg W. Stucki & Hans-Uwe Simon. Mathematical modeling of the regulation of caspase-3 activation and degradation. Journal of Theoretical Biology 234, 1 (2005). Caspases are thought to be important players in the execution process of apoptosis. Inhibitors of apoptosis (IAPs) are able to block caspases and therefore apoptosis. The fact that a subgroup of the IAP family inhibits active caspases implies that not each caspase activation necessarily leads to apoptosis. In such a scenario, however, processed and enzymically active caspases should somehow be removed. Indeed, IAP–caspase complexes covalently bind ubiquitin, resulting in degradation by the 26S proteasome. Following release from mitochondria, IAP antagonists (e.g. second mitochondrial activator of caspases (Smac)) inactivate IAPs. Moreover, although pro-apoptotic factors such as irradiation or anti-cancer drugs may release Smac from mitochondria in tumor cells, high cytoplasmic survivin and ML-IAP levels might be able to neutralize it and, consequently, IAPs would further be able to bind activated caspases. Here, we propose a simple mathematical model, describing the molecular interactions between Smac deactivators, Smac, IAPs, and caspase-3, including the requirements for both induction and prevention of apoptosis, respectively. In addition, we predict a novel mechanism of caspase-3 degradation that might be particularly relevant in long-living cells.

2024-09-02 | BIOMD0000001059 | BioModels

Established glioma cell lines prove valuable models for tumour heterogeneity - mediated cellular response studies in vitro

Project description:Both established glioma cells lines U87MG and U373 were used for studying their interactions in the indirect co-cultures. Eventhough both being derived from the glioma tissue, those two cell lines prove morphologically and physiologically disctinct. Therefore their intre-cellular interactions were examined on gene exprexssion level in vitro to observe whether those co-cultures could make for a suitable in vitro cell model mimicking the in vivo glioma tumour heterogeneity. Three biological replicates of four cell set-ups were performed: U87MG monoculture, U373 monoculture, U87MG co-cultured with U373 (in Boyden chambers) and U373 co-cultured with U87MG (in Boyden chambers).

2015-04-08 | E-GEOD-59634 | biostudies-arrayexpress

Systematic Mapping of ADAR1 Binding Reveals its Regulatory Roles in Multiple RNA Processing Pathways [small RNA-seq]

Project description:ADARs are the primary factors underlying A-to-I editing in metazoans. We conducted the first global study of ADAR1-RNA interaction in human cells using CLIP-Seq. In contrast to the expected predominant binding of ADAR1 to Alu repeats, thousands of CLIP sites were located in non-Alu regions. This unexpectedly frequent non-Alu binding enabled discovery of transcriptome-wide functional and biophysical targets of ADAR1 in the regulation of mRNA processing including alternative 3' UTR usage and alternative splicing. In addition, a global analysis of ADAR1 binding to non-Alu regions also revealed its primary interaction with microRNA (miRNA) transcripts in the nucleus, which subsequently affected expression levels of mature miRNAs. A complex global picture was revealed regarding the dependence of this function on the double-stranded RNA binding domains or deaminase activity. Our study unfolded a broad landscape of the diverse functional roles of ADAR1. To identify ADAR binding dependent miRNA defferential expression profiles, U87MG cells were transfected with ADAR1 overexpression vector, RNA binding mutant (EAA and E912A), siRNA of ADAR1 or controls.

2015-03-11 | E-GEOD-55362 | biostudies-arrayexpress

A proteomic platform unveils the brain glycogen phosphorylase as a potential metabolic target for glioblastoma multiforme

Project description:In the last few years, several efforts have been ended to identify original strategies against gli-oblastoma multiforme (GBM): this requires a more detailed investigation of the molecular mechanism of GBM so that novel targets can be identiﬁed for new possible therapeutic agents. Here, using a combined proteomic approach, we evaluated the ability of a blood brain barrier permeable 2,3-benzodiazepin-4-one, called 1g, to interfere with the activity and the expression of brain glycogen phosphorylase (PYGB) on U87MG cell line in parallel with the capability of this compound to inhibit the cell growth and cycle. Thus, our results highlighted PYGB as a potential metabolic target in GBM prompting 1g as a capable anticancer drug thanks to its ability to nega-tively modulate the uptake and metabolism of glucose, the so called “Warburg effect”, whose increase is considered a common feature of cancer cells in respect of their normal counterparts.

2022-08-11 | PXD034933 | Pride

Phosphoproteomic Analysis Defines BABAM1 as mTORC2 Downstream Effector Promoting DNA Damage Response in Glioblastoma Cells

Project description:Glioblastoma (GBM) is a devastating primary brain cancer with a poor prognosis. GBM is associated with an abnormal mechanistic target of rapamycin (mTOR) signaling pathway, consisting of two distinct kinase complexes: mTORC1 and mTORC2. The complexes play critical roles in cell proliferation, survival, migration, metabolism, and DNA damage response. This study investigated the aberrant mTORC2 signaling pathway in GBM cells by performing quantitative phosphoproteomic analysis of U87MG cells under different drug treatment conditions. Interestingly, a functional analysis of phosphoproteome revealed that mTORC2 inhibition might be involved in double-strand break (DSB) repair. We further characterized the relationship between mTORC2 and BRISC and BRCA1-A Complex Member 1 (BABAM1). We demonstrated that pBABAM1 at Ser29 is regulated by mTORC2 to initiate DNA damage response, contributing to DNA repair and cancer cell survival. Accordingly, the inactivation of mTORC2 significantly ablated pBABAM1 (Ser29), reduced DNA repair activities in the nucleus, and promoted apoptosis of the cancer cells. Furthermore, we also recognized that histone H2AX phosphorylation at Ser139 (γH2AX) could be controlled by mTORC2 to repair the DNA. These results provided a better understanding of mTORC2 function in oncogenic DNA damage response and might lead to specific mTORC2 treatments for brain cancer patients in the future.

2022-11-08 | PXD033325 | Pride

Transcription profiling of human glioma cells treated with TGF-beta or an inhibitor of the TGF-beta Receptor I LY2109761

Project description:In order to identify the genes that are regulated by TGF-beta in glioma, we serum starved two glioma cell lines, U373MG and U87MG, for 16h and we treated them with vehicle,100pM TGF-beta, 2uM inhibitor of the TGF-beta Receptor I(TbRI)(LY2109761), or both 100pM TGF-beta plus 2uM TbRI for 3h. Then, cell were collected and total RNA was extracted.

2007-05-16 | E-MEXP-903 | biostudies-arrayexpress

Caspase-9 is a positive regulator of osteoblastic cell migration identified by diaPASEF proteomics

Project description:Caspase-9 is traditionally considered as the initiator caspase of the intrinsic apoptotic pathway. In the last decade, however, other functions beyond initiation/execution of cell death have been described including cell type-dependent regulation of proliferation, differentiation/maturation, mitochondrial and endosomal/lysosomal homeostasis. As previous studies revealed non-apoptotic functions of caspases in osteogenesis and bone homeostasis, this study was performed to identify proteins and pathways deregulated by knockout of caspase-9 in mouse MC3T3-E1 osteoblasts. Data-independent acquisition – parallel accumulation serial fragmentation (diaPASEF) proteomics was used to compare protein profiles of control and caspase-9 knockout cells. A total of 7669 protein groups were quantified and 283 upregulated/141 downregulated protein groups were associated with the caspase-9 knockout phenotype. The deregulated proteins were mainly enriched for those associated with cell migration/motility and DNA replication/repair. Altered migration was confirmed in MC3T3-E1 cells with genetic and pharmacological inhibition of caspase-9. ABHD2, an established regulator of cell migration, was identified as a possible substrate of caspase-9. We conclude that caspase-9 acts as a modulator of osteoblastic MC3T3-E1 cell migration and therefore may be involved in bone remodeling and fracture repair.

2024-04-17 | PXD045703 | Pride

Transcription profiling of human glioblastoma cell lines after treatment with two ubiquitin-proteasome system inhibitors to characterize the molecular signals of cell death by necrosis

Project description:The regulation of necrotic death and its relevance in anti-cancer therapy are largely unknown. Here we have investigated the pro-apoptotic and pro-necrotic activities of two ubiquitin-proteasome system inhibitors (UPSIs): bortezomib and G5. The present study points out that the glioblastoma cell lines U87MG and T98G are useful models to study the susceptibility to apoptosis and necrosis in response to UPSIs. U87MG cells are resistant to apoptosis induced by bortezomib and G5 but susceptible to necrosis induced by G5. On the opposite T98G cells are susceptible to apoptosis induced by both inhibitors but show some resistance to G5-induced necrosis. By comparing the transcriptional profiles of the two cell lines, we have found that the resistance to G5-induced necrosis could arise from differences in glutathione synthesis/utilization and in the microenvironment. In particular collagen IV, which is highly expressed in T98G cells, and fibronectin, whose adhesive function is counteracted by tenascin-C in U87MG cells, can restrain the necrotic response to G5. Collectively, our results provide an initial characterization of the molecular signals governing cell death by necrosis in glioblastoma cell lines. Experiment Overall Design: Gene expression profiling was evaluated from 3 replicates each of T98G and U87MG cells.

2009-10-16 | E-GEOD-14889 | biostudies-arrayexpress

Identification of allele-specific alternative mRNA processing via transcriptome sequencing

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2012-03-29 | E-GEOD-29738 | biostudies-arrayexpress

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