Investigation of the Mechanism of Action by Comprehensive Transcriptome Analysis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE241312 | GEO | 2024/05/14
REPOSITORIES: GEO
Similar Datasets
Project description:Velcrin compounds kill cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12) by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A–SLFN12 complex is not fully understood. Here, we report that the physiological substrate of SLFN12 RNase is tRNALeu(TAA). SLFN12 selectively digests tRNALeu(TAA), and velcrin treatment promotes the cleavage of tRNALeu(TAA) by inducing PDE3A–SLFN12 complex formation in vitro. We found that distinct sequences in the variable loop and acceptor stem of tRNALeu(TAA) are required for substrate digestion. Velcrin treatment of sensitive cells results in downregulation of tRNALeu(TAA), ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. Velcrin-induced cleavage of tRNALeu(TAA) by SLFN12 and the concomitant global inhibition of protein synthesis thus define a new mechanism of apoptosis initiation.
2022-09-01 | GSE185827 | GEO
Project description:Velcrin compounds kill cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12) by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A–SLFN12 complex is not fully understood. Here, we report that the physiological substrate of SLFN12 RNase is tRNALeu(TAA). SLFN12 selectively digests tRNALeu(TAA), and velcrin treatment promotes the cleavage of tRNALeu(TAA) by inducing PDE3A–SLFN12 complex formation in vitro. We found that distinct sequences in the variable loop and acceptor stem of tRNALeu(TAA) are required for substrate digestion. Velcrin treatment of sensitive cells results in downregulation of tRNALeu(TAA), ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. Velcrin-induced cleavage of tRNALeu(TAA) by SLFN12 and the concomitant global inhibition of protein synthesis thus define a new mechanism of apoptosis initiation.
2022-09-01 | GSE185826 | GEO
Project description:Velcrin compounds kill cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12) by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A–SLFN12 complex is not fully understood. Here, we report that the physiological substrate of SLFN12 RNase is tRNALeu(TAA). SLFN12 selectively digests tRNALeu(TAA), and velcrin treatment promotes the cleavage of tRNALeu(TAA) by inducing PDE3A–SLFN12 complex formation in vitro. We found that distinct sequences in the variable loop and acceptor stem of tRNALeu(TAA) are required for substrate digestion. Velcrin treatment of sensitive cells results in downregulation of tRNALeu(TAA), ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. Velcrin-induced cleavage of tRNALeu(TAA) by SLFN12 and the concomitant global inhibition of protein synthesis thus define a new mechanism of apoptosis initiation.
2022-09-01 | GSE185822 | GEO
Project description:Garvie CW, Wu X, Papanastasiou M, Lee S, Fuller J, Schnitzler GR, Horner SW, Baker A, Zhang T, Mullahoo JP, Westlake L, Hoyt SH, Toetzl M, Ranaghan M, de Waal L, McGaunn J, Kaplan B, Piccioni F, Yang X, Lange M, Tersteegen A, Raymond D, Lewis TA, Carr SA, Cherniack AD, Lemke C, Meyerson M, Greulich H. 2021. DNMDP and related compounds, or "velcrins", induce complex formation between the phosphodiesterase PDE3A and the SLFN12 protein, leading to a cytotoxic response in cancer cells that express elevated levels of both proteins. The mechanisms by which velcrins induce complex formation, and how the PDE3A-SLFN12 complex causes cancer cell death, are not fully understood. Here, we show that PDE3A and SLFN12 form a heterotetramer stabilized by binding of DNMDP. Interactions between the C-terminal alpha helix of SLFN12 and residues near the active site of PDE3A are required for complex formation, and are further stabilized by interactions between SLFN12 and DNMDP. Moreover, we demonstrate that SLFN12 is an RNase, that PDE3A binding increases SLFN12 RNase activity, and that SLFN12 RNase activity is required for DNMDP response. This new mechanistic understanding will facilitate development of velcrin compounds into new cancer therapies.
2021-06-14 | MSV000087620 | MassIVE
Project description:Improving gene set enrichment analysis (GSEA) by using regulation directionality
| PRJNA860153 | ENA
Project description:Background: The intestinal lining renews itself in a programmed fashion that can be affected by adaptation to surgical procedures such as gastric bypass. Results: RNA sequencing suggested significant decreases of gene expression associated with G2/M DNA damage checkpoint regulation of the cell cycle pathway, and significant increases in gene expression associated with CDP-diacylglycerol biosynthesis pathway TCA cycle II pathway, and pyrimidine ribonucleotide salvage pathway after RYGB. Since SLFN12 is reported to influence enterocytic differentiation, we stained mucosa for SLFN12 and observed increased SLFN12 immunoreactivity. We investigated SLFN12 overexpression in HIEC-6 and FHs 74 Int intestinal epithelial cells and observed similar increased expression of the following genes that were also increased after RYGB: HES2, CARD9, SLC19A2, FBXW7, STXBP4, SPARCL1, and UTS. Conclusions: Our data suggests that RYGB promotes SLFN12 protein expression, cellular mechanism and replication pathways, and genes associated with differentiation and restitution (HES2, CARD9, SLC19A2) and obesity-related genes (FBXW7, STXBP4, SPARCL1, UTS).
2022-11-01 | GSE214758 | GEO
Project description:Neural stem cells (NSCs) are considered to be the cell-of-origin of brain tumor stem cells. To identify the genetic pathways responsible for the transformation of normal NSCs to brain-tumor-initiating cells, we used Sleeping Beauty (SB) transposons, to mutagenize NSCs. Mobilized SB transposons induced the immortalization of NSCs. Immortalized NSCs induced tumors upon subcutaneous transplantation in immunocompromized mice. To further classify the immortalized cells and mouse tumors, we performed Gene Set Enrichment Analysis (GSEA) using DNA microarray data. Ten immortalized NSC lines (four WT and six p53 mutant lines) and two normal NSCs were used for RNA extraction and hybridization on Affymetrix microarrays. CEL files were processed using the RMA algorithm to normalize the data. Unsupervised hierarchical clustering was applied to the normalized gene expression data across samples using the R module pvclust (Suzuki and Shimodaira, Bioinformatics 22, 1540-1542, 2006). Hierarchical clustering showed a close similarity in gene expression between all ten immortalized lines, compared with two normal NSCs. We then compared their gene expression profiles to those present in the brain transcriptome database (Cahoy et al., J Neurosci 28, 264-278, 2008). Using five gene sets that are associated with neurons, oligodendrocytes, OPCs, astrocytes and cultured astroglial cells, GSEA enrichment scores were calculated for the ten immortalized NSCs lines against two control normal NSCs. GSEA enrichment analysis was performed using GSEA software v. 2.07 (http://www.broadinstitute.org/gsea). We found a strong enrichment for genes that are differentially expressed in the cultured astroglial cells. Twelve tumors (six WT and six p53 mutant tumors) and three control subcutaneous tissues were used for RNA extraction and hybridization on Affymetrix microarrays. CEL files were processed using the RMA algorithm to normalize the data. Unsupervised hierarchical clustering was applied to the normalized gene expression data across samples using the R module pvclust (Suzuki and Shimodaira, Bioinformatics 22, 1540-1542, 2006). Hierarchical clustering of 12 tumors showed a close similarity between the tumors, compared with three control subcutaneous tissues. We next performed GSEA analysis on the tumors. Using gene sets specific to the four defined GBM subtypes (Verhaak et al., Cancer Cell 17, 98-110, 2010), a GSEA enrichment score was then calculated for the twelve tumor samples against three control subcutaneous tissue samples. GSEA enrichment analysis was performed using GSEA software v. 2.07 (http://www.broadinstitute.org/gsea). This analysis showed that the mouse tumors were significantly enriched for genes specific for the mesenchymal GBM. Immortalized cell lines and tumors were used for RNA extraction and hybridization on Affymetrix microarrays. Ten immortalized lines (Line 3, 28, 31, 59, 95, 116, 119, 120, 123, 331) were compared with two normal NSCs. Twelve tumors were generated from four lines (1, 31, 59, 123) and compared with three subcutaneous tissues (SubQ).
2012-03-30 | E-GEOD-36897 | biostudies-arrayexpress
Project description:Investigation of the Mechanism of Action by Comprehensive Transcriptome Analysis
| PRJNA1007669 | ENA
Project description:Here, we report that macrophage-derived itaconate exerts a significant suppressive effect on dendritic cell (DC) function. To delve deeper into the impact of itaconate on DCs, we treated bone marrow-derived dendritic cells with 4-OI, a derivative of itaconate, and conducted RNA-seq analysis. Gene-set enrichment analysis (GSEA) of 4-OI-treated DCs showed a general downregulation of innate immunity and immune-response pathways.
2024-06-30 | GSE268402 | GEO
Project description:Expression of insulin in terminally differentiated non-beta pancreatic cell types could be important for treating type-1 diabetes. We observed that the kinase inhibitor GW8510 up-regulated insulin expression in mouse pancreatic alpha cells. Gene-expression profiling and gene-set enrichment analysis of GW8510-treated alpha cells suggested coordinate up-regulation of the p53 pathway, which was further implicated in induction of insulin transcript. In order to determine a potential mechanism of insulin induction by GW8510, we treated mouse alpha cells (aTC1) and beta cells (bTC3) with 3.3 µM GW8510 or 0.1% DMSO for five days, and performed gene-expression profiling followed by gene-set enrichment analysis (GSEA). Three biological replicates were included per condition. GW8510 treatment in each cell line was compared to DMSO-treated control.
2011-08-01 | E-GEOD-31102 | biostudies-arrayexpress