Phosphoinositides in the nucleus and myogenic differentiation: how a nuclear turtle with a PHD builds muscle

Divecha, Nullin

doi:10.1042/bst20150238

Cited by 3 publications

(2 citation statements)

References 57 publications

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“…They interact with a wide range of proteins like: Star-PAP poly(A) polymerase, histone 1, TAF3, UBF, etc. ( Osborne et al, 2001 ; Yildirim et al, 2013 ; Divecha, 2016 ). The interaction of phospholipids with such proteins can result in the activation of the protein (like Start-PAP) or affect the stability with other proteins to form particular complexes like TAF3 with H3K4me3 ( Stijf-Bultsma et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Novel Ribonuclease Activity Differs between Fibrillarins from Arabidopsis thaliana

et al. 2017

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Fibrillarin is one of the most important nucleolar proteins that have been shown as essential for life. Fibrillarin localizes primarily at the periphery between fibrillar center and dense fibrillar component as well as in Cajal bodies. In most plants there are at least two different genes for fibrillarin. In Arabidopsis thaliana both genes show high level of expression in transcriptionally active cells. Here, we focus on two important differences between A. thaliana fibrillarins. First and most relevant is the enzymatic activity by AtFib2. The AtFib2 shows a novel ribonuclease activity that is not seen with AtFib1. Second is a difference in the ability to interact with phosphoinositides and phosphatidic acid between both proteins. We also show that the novel ribonuclease activity as well as the phospholipid binding region of fibrillarin is confine to the GAR domain. The ribonuclease activity of fibrillarin reveals in this study represents a new role for this protein in rRNA processing.

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Section: Discussionmentioning

confidence: 99%

Novel Ribonuclease Activity Differs between Fibrillarins from Arabidopsis thaliana

et al. 2017

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“…PPIns and in particular PtdIns, PtdIns4P, PtdIns5P, PtdIns(4,5)P 2 and PtdIns(3,4,5)P 3 are localized in the nucleus ( 53 ), in the nuclear envelope and in the nucleoplasm. Within the nucleoplasm PtdIns(4,5)P 2 and PtdIns4P have been localised by immunostaining to splicing speckles, nucleoli and to nuclear lipid islets ( 54 ). In the nucleus, the levels of PPIns respond to specific stimuli, such as cell stress, DNA damage, cell cycle progression or cell differentiation ( 55 ).…”

Section: The Potential For Targeting Nuclear Phosphoinositides As Epigenetic Regulators In Amlmentioning

confidence: 99%

“Modulating Phosphoinositide Profiles as a Roadmap for Treatment in Acute Myeloid Leukemia”

et al. 2021

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Polyphosphoinositides (PPIns) and their modulating enzymes are involved in regulating many important cellular functions including proliferation, differentiation or gene expression, and their deregulation is involved in human diseases such as metabolic syndromes, neurodegenerative disorders and cancer, including Acute Myeloid Leukemia (AML). Given that PPIns regulating enzymes are highly druggable targets, several studies have recently highlighted the potential of targeting them in AML. For instance many inhibitors targeting the PI3K pathway are in various stages of clinical development and more recently other novel enzymes such as PIP4K2A have been implicated as AML targets. PPIns have distinct subcellular organelle profiles, in part driven by the specific localisation of enzymes that metabolise them. In particular, in the nucleus, PPIns are regulated in response to various extracellular and intracellular pathways and interact with specific nuclear proteins to control epigenetic cell state. While AML does not normally manifest with as many mutations as other cancers, it does appear in large part to be a disease of dysregulation of epigenetic signalling and many novel therapeutics are aimed at reprogramming AML cells toward a differentiated cell state or to one that is responsive to alternative successful but limited AML therapies such as ATRA. Here, we propose that by combining bioinformatic analysis with inhibition of PPIns pathways, especially within the nucleus, we might discover new combination therapies aimed at reprogramming transcriptional output to attenuate uncontrolled AML cell growth. Furthermore, we outline how different part of a PPIns signalling unit might be targeted to control selective outputs that might engender more specific and therefore less toxic inhibitory outcomes.

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Quantitative profiling of the endonuclear glycerophospholipidome of murine embryonic fibroblasts

Tribble

Ivanova

Grabon

et al. 2016

Journal of Lipid Research

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The mammalian nuclear matrix is now recognized as a site of lipid biosynthesis and signaling in both normal and pathological states (reviewed in 1-8). Radioisotope and stable isotope tracer studies consistently identify glycerophospholipids (GPLs), and the enzymatic activities that metabolize them, within purified nuclear fractions purportedly devoid of nuclear envelope and other cellular membrane contaminants (9-15). These findings suggest the existence of an independently-regulated GPL pool within the nuclear matrix, one distinct from the nuclear envelope and from bulk cellular membranes. In support of this interpretation, nuclear isoforms of a number of GPL metabolic enzymes have been described (10,11,(16)(17)(18)(19)(20)(21)(22). The STAR-PAP RNA poly-A polymerase, the direct modification of a phosphoinositide headgroup presented to an inositide kinase by a nuclear receptor, and nuclear phosphoinositide control of the basal transcription machinery all provide compelling examples of GPL-regulated activities that discharge their functions within the nuclear matrix (23-27). At issue, however, is the scale of nuclear GPL metabolism and nuclear GPL load.This difficult question can now be addressed using quantitative mass spectrometric methods. The single major study on this topic estimates that phosphatidylcholine (PtdCho) alone occupies 10-16% of the nuclear matrix of IRB-32 cells by volume (14). This is a startling conclusion Abstract A reliable method for purifying envelope-stripped nuclei from immortalized murine embryonic fibroblasts (iMEFs) was established. Quantitative profiling of the glycerophospholipids (GPLs) in envelope-free iMEF nuclei yields several conclusions. First, we find the endonuclear glycerophospholipidome differs from that of bulk membranes, and phosphatidylcholine (PtdCho) and phosphatidylethanolamine species are the most abundant endonuclear GPLs by mass. By contrast, phosphatidylinositol (PtdIns) represents a minor species. We also find only a slight enrichment of saturated versus unsaturated GPL species in iMEF endonuclear fractions. Moreover, much lower values for GPL mass were measured in the iMEF nuclear matrix than those reported for envelope-stripped IMF-32 nuclei. The collective results indicate that the nuclear matrix in these cells is a GPL-poor environment where GPL occupies only approximately 0.1% of the total nuclear matrix volume. This value suggests GPL accommodation in this compartment can be satisfied by binding to resident proteins. Finally, we find no significant role for the PtdIns/PtdChotransfer protein, PITP, in shuttling PtdIns into the iMEF nuclear

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Phosphoinositides in the nucleus and myogenic differentiation: how a nuclear turtle with a PHD builds muscle

Cited by 3 publications

References 57 publications

Novel Ribonuclease Activity Differs between Fibrillarins from Arabidopsis thaliana

Novel Ribonuclease Activity Differs between Fibrillarins from Arabidopsis thaliana

“Modulating Phosphoinositide Profiles as a Roadmap for Treatment in Acute Myeloid Leukemia”

Quantitative profiling of the endonuclear glycerophospholipidome of murine embryonic fibroblasts

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