Phosphatidylinositol-Specific Phospholipase C can inhibit the proliferation of and suppress the phagocytosis of Müller cells via modulating PI3K/AKT signaling pathway
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE212054 | GEO | 2022/09/01
REPOSITORIES: GEO
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Project description:Phosphatidylinositol-Specific Phospholipase C can inhibit the proliferation of and suppress the phagocytosis of Müller cells via modulating PI3K/AKT signaling pathway
| PRJNA873709 | ENA
Project description:Sprouty (Spry) proteins are negative regulators of receptor tyrosine kinase signaling; however, their exact mechanism of action remains incompletely understood. We identified phosphatidylinositol-specific phospholipase C (PLC)-? as a partner of the Spry1 and Spry2 proteins. Spry-PLC? interaction was dependent on the Src homology 2 domain of PLC? and a conserved N-terminal tyrosine residue in Spry1 and Spry2. Overexpression of Spry1 and Spry2 was associated with decreased PLC? phosphorylation and decreased PLC? activity as measured by production of inositol (1,4,5)-triphosphate (IP(3)) and diacylglycerol, whereas cells deficient for Spry1 or Spry1, -2, and -4 showed increased production of IP(3) at baseline and further increased in response to growth factor signals. Overexpression of Spry 1 or Spry2 or small-interfering RNA-mediated knockdown of PLC?1 or PLC?2 abrogated the activity of a calcium-dependent reporter gene, suggesting that Spry inhibited calcium-mediated signaling downstream of PLC?. Furthermore, Spry overexpression in T-cells, which are highly dependent on PLC? activity and calcium signaling, blocked T-cell receptor-mediated calcium release. Accordingly, cultured T-cells from Spry1 gene knockout mice showed increased proliferation in response to T-cell receptor stimulation. These data highlight an important action of Spry, which may allow these proteins to influence signaling through multiple receptors.
| S-EPMC2947483 | biostudies-literature
Project description:Makorin-2 belongs to the makorin RING zinc finger gene family, which encodes putative ribonucleoproteins. Here we cloned the Xenopus makorin-2 (mkrn2) and characterized its function in Xenopus neurogenesis. Forced overexpression of mkrn2 produced tadpoles with dorso-posterior deficiencies and small-head/short-tail phenotype, whereas knockdown of mkrn2 by morpholino antisense oligonucleotides induced double axis in tadpoles. In Xenopus animal cap explant assay, mkrn2 inhibited activin, and retinoic acid induced animal cap neuralization, as evident from the suppression of a pan neural marker, neural cell adhesion molecule. Surprisingly, the anti-neurogenic activity of mkrn2 is independent of the two major neurogenesis signaling cascades, BMP-4 and Wnt8 pathways. Instead, mkrn2 works specifically through the phosphatidylinositol 3-kinase (PI3K) and Akt-mediated neurogenesis pathway. Overexpression of mkrn2 completely abrogated constitutively active PI3K- and Akt-induced, but not dominant negative glycogen synthase kinase-3beta (GSK-3beta)-induced, neural cell adhesion molecule expression, indicating that mkrn2 acts downstream of PI3K and Akt and upstream of GSK-3beta. Moreover, mkrn2 up-regulated the mRNA and protein levels of GSK-3beta. These results revealed for the first time the important role of mkrn2 as a new player in PI3K/Akt-mediated neurogenesis during Xenopus embryonic development.
| S-EPMC2417189 | biostudies-literature
Project description:Gliomas are primary brain tumors with poor prognosis that exhibit frequent abnormalities in phosphatidylinositol 3-kinase (PI3 kinase) signaling. We investigated the molecular mechanism of action of the isoform-selective class I PI3 kinase and mTOR inhibitor PI-103 in human glioma cells. The potent inhibitory effects of PI-103 on the PI3 kinase pathway were quantified. PI-103 and the mTOR inhibitor rapamycin both inhibited ribosomal protein S6 phosphorylation but there were clear differences in the response of upstream components of the PI3 kinase pathway, such as phosphorylation of Thr308-AKT, that were inhibited by PI-103 but not rapamycin. Gene expression profiling identified altered expression of genes encoding regulators of the cell cycle and cholesterol metabolism, and genes modulated by insulin or IGF1 signaling, rapamycin treatment or nutrient starvation. PI-103 decreased expression of positive regulators of G1/S phase progression and increased expression of the negative cell cycle regulator p27kip1. A reversible PI-103-mediated G1 cell cycle arrest occurred without significant apoptosis, consistent with the altered gene expression detected. PI-103 induced vacuolation and processing of LC-3i to LC-3ii, which are features of an autophagic response. In contrast to PI-103, LY294002 and PI-387 induced apoptosis, indicative of likely off-target effects. PI-103 interacted synergistically or additively with cytotoxic agents used in the treatment of glioma, namely vincristine, BCNU and temozolomide. Compared to individual treatments, the combination of PI-103 with temozolomide significantly improved the response of U87MG human glioma xenografts. Our results support the therapeutic potential for PI3 kinase inhibitors with a PI-103-like profile as therapeutic agents for the treatment of glioma. Keywords: Key words: PI-103, glioma, PI3 kinase, mTOR, cell cycle, cytostasis
2009-04-21 | GSE12175 | GEO
Project description:au13-01_pi-plc What are the genes that are regulated by basal PI-PLC? Arabidopsis thaliana cells in suspension (5-days old). Cultivated in environment (middle) Gamborg+2,4-D. Added inhibitors 4 hr before extraction of the RNAs. We try to determine the role of phospholipases C ( PI-PLC) in the control of the basal expression of the genes of suspension of Arabidopsis thaliana. A first experience in which we used the edelfosine as inhibitor allowed us to identify numerous genes the basal expression of which is altered by this inhibition. We want to confirm these results with another inhibitor.
2013-09-01 | GSE46941 | GEO
Project description:The regulation of phospholipid biosynthesis in Saccharomyces cerevisiae through cis-acting upstream activating sequence inositol (UASino) and trans-acting elements, such as the INO2-INO4 complex and OPI1 by inositol supplementation in growth is thoroughly studied. In this study, we provide evidence for the regulation of lipid biosynthesis by phosphatidylinositol-specific phospholipase C (PLC) through UASino and two trans-acting elements. Gene expression analysis and radiolabelling experiments demonstrated that the overexpression of rice PLC in yeast cells altered phospholipid biosynthesis at the levels of transcriptional and enzyme activity.
2012-09-01 | GSE35745 | GEO
Project description:The regulation of phospholipid biosynthesis in Saccharomyces cerevisiae through cis-acting upstream activating sequence inositol (UASino) and trans-acting elements, such as the INO2-INO4 complex and OPI1 by inositol supplementation in growth is thoroughly studied. In this study, we provide evidence for the regulation of lipid biosynthesis by phosphatidylinositol-specific phospholipase C (PLC) through UASino and two trans-acting elements. Gene expression analysis and radiolabelling experiments demonstrated that the overexpression of rice PLC in yeast cells altered phospholipid biosynthesis at the levels of transcriptional and enzyme activity.
2012-04-24 | GSE35677 | GEO
Project description:Microglia are crucial players in the pathogenesis of late-onset Alzheimer's disease (AD), with evidence for both deleterious and beneficial effects. Identifying interventions to modulate microglial responsiveness, promote amyloid β (Aβ) clearance, disrupt plaque formation, or dampen excessive inflammation has therapeutic potential. Bioavailable flavonoids, such as the flavan 3-ols, are of interest due to their antioxidant, metal chelating, signalling, and anti-inflammatory potential. Primary microglia were treated with a series of structurally related flavanol 3-ols to assess effects on phagocytosis, cytokine release, and transcriptional responses by RNA sequencing. Data indicated that the extent of hydroxylation and the presence of the galloyl moiety were strong determinants of flavan 3-ol activity. Epigallocatechin gallate (EGCG) was the most effective flavan-3-ol tested and strongly inhibited phagocytosis of Aβ independent of any metal chelating properties, suggesting a more direct modulation of microglia responsiveness. EGCG was broadly anti-inflammatory, reducing cytokine release and downregulating transcription, particularly of components of the microglia extracellular matrix such as MMP3 and SerpinB2. Collectively, this brings new insight into the actions of flavonoids on microglial responsiveness with potential implications for the therapeutic use of EGCG and structurally related flavanol-3-ols in AD.
| S-EPMC11236853 | biostudies-literature
Project description:A proteomics strategy was used to identify putative GPI-APs from adult B. malayi. Three different sample types were prepared for analysis. Firstly, intact adult worms were treated with PI-PLC to enzymatically release and solubilize the protein away from the lipid moiety. A mock-treatment with no PI-PLC was performed as a negative control. The samples derived from treatment of the intact worms have been named “Surface” but it should be noted that the proteins could originate from any exposed surface like the mouth, vagina, or rectum of the worm. Secondly, a membrane fraction of B. malayi adult female worms was prepared by ultracentrifugation of a total lysate in a sucrose buffer to separate membrane proteins from soluble proteins. This membrane fraction was also treated with PI-PLC or mock-treated without PI-PLC as a negative control. Lastly, a GPI-AP enriched sample was prepared by performing a series of organic solvent partitions to extract GPI-APs from a membrane fraction. This sample was not treated with PI-PLC. Proteins in all three samples types were digested with trypsin and the resulting peptides analyzed by LC-MS/MS.
2019-11-12 | PXD014949 | Pride
Project description:PI3K-Akt-FoxO-mTOR signaling is the central pathway controlling growth and metabolism in all cells. Ubiquitination of the protein kinase Akt prior to its phosphorylation is required for PI3K-Akt activity. Here, we found that the deubiquitinating (DUB) enzyme USP1 removes K63-linked polyubiquitin chains on Akt to restrict PI3K-Akt-FoxO signaling in the mouse muscle during prolonged starvation. DUB screening platform identified USP1 as a direct DUB for Akt, and USP1 depletion in mouse muscle increased Akt ubiquitination, PI3K-Akt-FoxO signaling, and glucose uptake during fasting. Co-immunoprecipitation and mass spectrometry identified Disabled-homolog-2 (Dab2), the tuberous sclerosis complex TSC1/TSC2, and PHLPP1 as USP1 bound proteins. During starvation, Dab2 is essential for Akt recruitment to USP1-TSC1-PHLPP1 complex, and for PI3K-Akt-FoxO inhibition. Surprisingly, USP1 limits TSC1 levels to sustain mTOR-mediated basal protein synthesis rates and maintain its own protein levels. We propose that Dab2 recruits Akt to USP1-TSC1-PHLPP1 complex to efficiently terminate the transmission of growth signals when cellular energy level is low.
| S-SCDT-EMBOR-2019-48791-T | biostudies-other