1,721,029 research outputs found
RNA sequencing data associate to "New Insights into the Role and Regulation of Nuclear PtdIns(4,5)P2" thesis
No full textThis submission includes two types of RNA sequencing datasets related to the thesis "New Insights into the Role and Regulation of Nuclear PtdIns(4,5)P2."
Processed Datasets: These are two independent raw RNA sequencing datasets containing the unprocessed data directly obtained from sequencing experiments. These datasets contain extracted and normalized data obtained from RNA sequencing, representing the processed outputs used for detailed transcriptomic analysis in the thesis. They provide insights into the specific gene expression profiles and regulatory pathways explored in the study. They serve as the foundational data for the analyses performed and discussed in the thesis.</span
Unclear or nuclear: another role for the phosphatidylinositol cycle?
No full textNo abstract available
Phospholipid signaling
No full textTen years ago, describing what is new in phospholipid signaling in ten pages of Cell would have been easy; it would have been essentially a summary of the phospho-inositidase C (PIC) story: phosphatidylinositol(4,5)bisphos-phate (Ptdlns(4,5)P2) hydrolysis to inositiol(1,4,5)trisphos-phate (Ins(1",4,5)P3), with the synergistic action of Ca 2÷(mobilized by Ins(1,4,5)P3) and diacylglycerol (DAG) onprotein kinase C (PKC) (Table 1). As will become obvious below, the involvement of phospholipids in cell signaling is now enormously more complicated, and as more potential signaling systems emerge, it becomes even less clear as to which does what. With many of the systems, we are at a stage of ignorance similar to that in the late 1970's with PIC, confused and uncertain and largely lacking the tools and basic knowledge to build up the picture. So, with the limited space available we can make no attempt at comprehensive coverage, but we will try to summarize, mostly by specific examples, what we see as the crucial questions as things stand now. The preceding sentence should be taken as a plea for tolerance from workers whose papers we have not cited and who consequently feel slighted
PtdIns5P and Pin1 in oxidative stress signaling
No full textOxidative signaling is important in cellular health, involved in aging and contributes to the development of several diseases such as cancer, neurodegeneration and diabetes. Correct management of reactive oxygen species (ROS) prevents oxidative stress within cells and is imperative for cellular wellbeing. A key pathway that is regulated by oxidative stress is the activation of proline-directed stress kinases (p38, JNK). Phosphorylation induced by these kinases is often translated into cellular outcome through the recruitment of the prolyl-isomerase Pin1. Pin1 binds to phosphorylated substrates using its WW-domain and can induce conformational changes in the target protein through its prolyl-isomerase activity. We show that exposure of cells to UV irradiation or hydrogen peroxide (H2O2), induces the synthesis of the phosphoinositide second messenger PtdIns5P in part by inducing the interaction between phosphatidylinositol-5-phosphate 4-kinase (PIP4K) enzymes that remove PtdIns5P, with Pin1. In response to H2O2 exposure, Murine Embryonic Fibroblasts (MEFs) derived from Pin1-/- mice showed increased cell viability and an increased abundance of PtdIns5P compared to wild-type MEFs. Decreasing the levels of PtdIns5P in Pin1-/- MEFs decreased both their viability in response to H2O2 exposure and the expression of genes required for cellular ROS management. The decrease in the expression of these genes manifested itself in the increased accumulation of cellular ROS. These data strongly argue that PtdIns5P acts as a stress-induced second messenger that can calibrate how cells manage ROS. © 2013
Phosphatidylinositol 5 phosphate (Pi5p): From behind the scenes to the front (nuclear) stage
No full textPhosphatidylinositol (PI)-related signaling plays a pivotal role in many cellular aspects, including survival, cell proliferation, differentiation, DNA damage, and trafficking. PI is the core of a network of proteins represented by kinases, phosphatases, and lipases which are able to add, remove or hydrolyze PI, leading to different phosphoinositide products. Among the seven known phosphoinositides, phosphatidylinositol 5 phosphate (PI5P) was the last to be discovered. PI5P presence in cells is very low compared to other PIs. However, much evidence collected throughout the years has described the role of this mono-phosphoinositide in cell cycles, stress response, T-cell activation, and chromatin remodeling. Interestingly, PI5P has been found in different cellular compartments, including the nucleus. Here, we will review the nuclear role of PI5P, describing how it is synthesized and regulated, and how changes in the levels of this rare phosphoinositide can lead to different nuclear outputs.</p
PtdIns5P is an oxidative stress-induced second messenger that regulates PKB activation
No full textOxidative stress initiates signaling pathways, which protect from stress-induced cellular damage, initiate apoptosis, or drive cells into senescence or into tumorigenesis. Oxidative stress regulates the activity of the cell survival factor PKB, through the regulation of PtdIns(3,4,5)P? synthesis. Whether oxidative stress regulates other phosphoinositides to control PKB activation is not clear. Here we show that PtdIns5P is a redox-regulated second messenger. In response to hydrogen peroxide (H?O?), we measured an increase in PtdIns5P in cells derived from human osteosarcoma, U2OS (5-fold); breast tumors, MDA-MB-468 (2-fold); and fibrosarcoma, HT1080 (3-fold); and in p53-null murine embryonic fibroblasts (8-fold). In U2OS cells, the increase in H?O?-dependent PtdIns5P did not require mTOR, PDK1, PKB, ERK, and p38 signaling or PIKfyve, a lipid kinase that increases PtdIns5P in response to osmotic and oncogenic signaling. A reduction in H?O?-induced PtdIns5P levels by the overexpression of PIP4K revealed its role in PKB activation. Suppression of H?O?-induced PtdIns5P generation reduced PKB activation and, surprisingly, reduced cell sensitivity to growth inhibition by H?O?. These data suggest that inhibition of PIP4K signaling might be useful as a novel strategy to increase the susceptibility of tumor cells to therapeutics that function through increased oxidative stress
Nuclear phosphoinositides and their impact on nuclear functions
No full textPolyphosphoinositides (PPIn) are important lipid molecules whose levels are de-regulated in human diseases such as cancer, neurodegenerative disorders and metabolic syndromes. PPIn are synthesized and degraded by an array of kinases, phosphatases and lipases which are localized to various subcellular compartments and are subject to regulation in response to both extra- and intracellular cues. Changes in the activities of enzymes that metabolize PPIn lead to changes in the profiles of PPIn in various subcellular compartments. Understanding how subcellular PPIn are regulated and how they affect downstream signaling is critical to understanding their roles in human diseases. PPIn are present in the nucleus, and their levels are changed in response to various stimuli, suggesting that they may serve to regulate specific nuclear functions. However, the lack of nuclear downstream targets has hindered the definition of which pathways nuclear PPIn affect. Over recent years, targeted and global proteomic studies have identified a plethora of potential PPIn-interacting proteins involved in many aspects of transcription, chromatin remodelling and mRNA maturation, suggesting that PPIn signalling within the nucleus represents a largely unexplored novel layer of complexity in the regulation of nuclear functions
A luminescence-based reporter to study tau secretion reveals overlapping mechanisms for the release of healthy and pathological tau
No full textIn Alzheimer’s disease, tau pathology is thought to spread via a prion-like manner along connected neuronal networks. For this to occur, the usually cytosolic tau protein must be secreted via an unconventional mechanism prior to uptake into the connected neuron. While secretion of healthy and pathological tau has been documented, it remains under-investigated whether this occurs via overlapping or distinct processes. Here, we established a sensitive bioluminescence-based assay to assess mechanisms underlying the secretion of pseudohyperphosphorylated and wild-type tau in cultured murine hippocampal neurons. We found that under basal conditions, both wild-type and mutant tau are secreted, with mutant tau being more robustly secreted. Pharmacological stimulation of neuronal activity led to a modest increase of wild-type and mutant tau secretion, whereas inhibition of activity had no effect. Interestingly, inhibition of heparin sulfate proteoglycan (HSPG) biosynthesis drastically decreased secretion of both wild-type and mutant tau without affecting cell viability. This shows that native and pathological tau share release mechanisms; both activity-dependent and non-activity-dependent secretion of tau is facilitated by HSPGs
Methods for the determination of the mass of nuclear PtdIns4P, PtdIns5P, and PtdIns(4,5)P2
No full textPhosphatidylinositol (PtdIns) and its phosphorylated derivatives represent less than 5% of total membrane phospholipids in cells. Despite their low abundance, they form a dynamic signaling system that is regulated in response to a variety of extra- and intracellular cues. Protein domains including PH, FYVE, ENTH, PHOX, PHD fingers, and lysine-/arginine-rich patches can bind to specific phosphoinositide isomers, which, in turn, can induce changes in the subcellular localization, posttranslational modification, protein interaction partners, or activity of the protein containing such a domain. Phosphoinositides and the enzymes that synthesize them are found in many different subcellular compartments including the nuclear matrix, heterochromatin, and sites of active RNA splicing, suggesting that phosphoinositides may regulate specific functions within the nuclear compartment. The existence of distinct subcellular pools has led to the challenging task of the quantitation of temporal and spatial changes in phosphoinositides. We report methods to measure the mass levels of three different phosphoinositides within the nuclear compartment
PIP4K2B: Coupling GTP Sensing to PtdIns5P Levels to Regulate Tumorigenesis
No full textAlthough guanine nucleotides are essential for cell growth, how their levels are sensed in mammalian cells is unknown. Sumita et al. show that PIP4K2B, a phosphoinositide kinase, is a molecular sensor that transduces changes in GTP into changes in the levels of the phosphoinositide PtdIns5P to modulate tumour cell growth
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