Phosphodiesterase 3A deficient in breast cancer cell
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE130569 | GEO | 2019/09/21
REPOSITORIES: GEO
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Project description:Phosphodiesterase 3A deficient in breast cancer cell
| PRJNA540659 | ENA
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: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:Purpose: By catalyzing hydrolysis of cyclic guanosine monophosphate, phosphodiesterase (PDE) 5 is a critical regulator of its concentration and biological effects in different (patho)physiological processes, including cancers. Being PDE5 a known druggable target, we investigated the clinical significance of its expression in breast cancers and the underlying molecular mechanisms by which it may contribute to breast cancer progression. Experimental Design: RT-PCR and immunoblotting analyses were used for PDE5 expression in eight breast cancer cell lines. To examine PDE5âs impact on cancer phenotype, MCF-7 cells, expressing the lowest levels of PDE5, were engineered to stably overexpress PDE5. Cell proliferation was assessed by MTT assays, motility and invasion by wound-healing, transmigration, matrigel-based invasion assays. RNA sequencing identified differentially-expressed genes. Clinical relevance of PDE5 was investigated by immunohistochemistry on tissues and retrospective studies from the Metabric cohort. Results: PDE5 was expressed at lower levels in luminal A-type breast cancer cells (MCF-7) compared to luminal B-like, HER2-overexpressing and basal-like cells. MCF-7 cells stably overexpressing PDE5 exhibited an increased cell motility and invasion through activation of Rho family of GTPases. Treatment of PDE5 clones with selective ROCK or PDE5 inhibitors completely restored the less motile and weak invasive behavior of control cells. In patients, PDE5 expression was found in ~85% of tumor entities analyzed, with the highest intensity staining in high-grade tumors. Retrospective analyses showed that higher PDE5 levels correlated with poorer survival. Conclusion: PDE5 expression enhances breast cancer cell invasive potential, highlighting its role as a novel molecular candidate with prognostic significance and a potential target in the treatment of breast cancers.
2016-02-01 | E-MTAB-3801 | biostudies-arrayexpress
Project description:The impact of 2',3'-cyclic nucleotide phosphodiesterase (CNPase) on global gene expression in Salmonella was investigated by heterologous expression of mammalian CNPase in a strain containing a deletion of the 'rna' gene. 'rna' encodes an endoribonuclease capable of hydrolyzing RNA into 2',3'-cyclic nucleotide monophosphates (2',3'-cNMPs) such that deletion of 'rna' drastically reduces 2',3'-cNMPs presence to undetectable levels. Expression of CNPase in this strain allowed any effects of CNPase unrelated to 2',3'-cNMPs to be observed.
2021-11-09 | GSE184190 | GEO
Project description:The impact of 2',3'-cyclic nucleotide phosphodiesterase (CNPase) on global gene expression in E. coli was investigated by heterologous expression of mammalian CNPase in a strain containing a deletion of the 'rna' gene. 'rna' encodes an endoribonuclease capable of hydrolyzing RNA into 2',3'-cyclic nucleotide monophosphates (2',3'-cNMPs) such that deletion of 'rna' drastically reduces 2',3'-cNMPs levels to undetectable levels. Expression of CNPase in this strain allowed any effects of CNPase unrelated to 2',3'-cNMPs to be observed.
2021-11-09 | GSE182184 | GEO
Project description:We want to investigate the transcriptional differences between pBABE D4m.3a melanoma cells (cancer cell control) and caMNK D4m.3a melanoma cells (cancer cells with constitutive activation of MNK) to find the transcriptional changes in melanoma cells upon MNK overexpression. This study allows us to examine the role MNK has in regulating key oncogenic factors involved in melanoma metastasis, proliferation and tumor development.
2020-09-16 | GSE141248 | GEO
Project description:Breast cancer invasive growth, metastasis and therapeutic resistance affects the clinical ourcome. We explored the epigenetic mechanisms that control these process in breast cancer cell line, MDA-MB-231 by knocking down a lysine specific demethylase KDM3A We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process. Human breast cancer cell line MDA-MB-231 was infected with scramble or KDM3A shRNA. After selection, the cells were used for microarray analysis.
2016-06-29 | E-GEOD-83818 | biostudies-arrayexpress
Project description:Targeting the Mdm2 oncoprotein by drugs has the potential of re-establishing p53 function and tumor suppression. However, Mdm2-antagonizing drug candidates, e. g. Nutlin-3a, often fail to abolish cancer cell growth sustainably. To overcome these limitations, we inhibited Mdm2 and simultaneously a second negative regulator of p53, the phosphatase Wip1/PPM1D. When combining Nutlin-3a with the Wip1 inhibitor GSK2830371 in the treatment of p53-proficient but not p53-deficient cells, we observed enhanced phosphorylation (Ser 15) and acetylation (Lys 382) of p53, increased expression of p53 target gene products, and synergistic inhibition of cell proliferation. Surprisingly, when testing the two compounds individually, largely distinct sets of genes were induced, as revealed by deep sequencing analysis of RNA. In contrast, the combination of both drugs led to an expression signature that largely comprised that of Nutlin-3a alone. Moreover, the combination of drugs, or the combination of Nutlin-3a with Wip1-depletion by siRNA, activated p53-responsive genes to a greater extent than either of the compounds alone. Simultaneous inhibition of Mdm2 and Wip1 enhanced cell senescence and G2/M accumulation. Taken together, the inhibition of Wip1 might fortify p53-mediated tumor suppression by Mdm2 antagonists.
2016-05-02 | GSE80716 | GEO