Nuclear Inositides and Inositide-Dependent Signaling Pathways in Myelodysplastic Syndromes

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Abstract

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by peripheral blood cytopenia and abnormal myeloproliferation, as well as a variable risk of evolution into acute myeloid leukemia (AML). The nucleus is a highly organized organelle with several distinct domains where nuclear inositides localize to mediate essential cellular events. Nuclear inositides play a critical role in the modulation of erythropoiesis or myelopoiesis. Here, we briefly review the nuclear structure, the localization of inositides and their metabolic enzymes in subnuclear compartments, and the molecular aspects of nuclear inositides in MDS.

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Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling.

Keji Zhao, Weidong Wang, Oliver J. Rando … (1998)

Lymphocyte activation is accompanied by visible changes in chromatin structure. We find that antigen receptor signaling induces the rapid association of the BAF complex with chromatin. PIP2, which is regulated by activation stimuli, is sufficient in vitro to target the BAF complex to chromatin, but it has no effect on related chromatin remodeling complexes containing SNF2L or hISWI. Purification and peptide sequencing of the subunits of the complex revealed beta-actin as well as a novel actin-related protein, BAF53. beta-actin and BAF53 are required for maximal ATPase activity of BRG1 and are also required with BRG1 for association of the complex with chromatin/matrix. This work indicates that membrane signals control the activity of the mammalian SWI/SNF or BAF complex and demonstrates a direct interface between signaling and chromatin regulation.

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Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A

Pui-Mun Wong, Yan Feng, Junru Wang … (2015)

Autophagy is a cellular catabolic process critical for cell viability and homoeostasis. Inhibition of mammalian target of rapamycin (mTOR) complex-1 (mTORC1) activates autophagy. A puzzling observation is that amino acid starvation triggers more rapid autophagy than pharmacological inhibition of mTORC1, although they both block mTORC1 activity with similar kinetics. Here we find that in addition to mTORC1 inactivation, starvation also causes an increase in phosphatase activity towards ULK1, an mTORC1 substrate whose dephosphorylation is required for autophagy induction. We identify the starvation-stimulated phosphatase for ULK1 as the PP2A–B55α complex. Treatment of cells with starvation but not mTORC1 inhibitors triggers dissociation of PP2A from its inhibitor Alpha4. Furthermore, pancreatic ductal adenocarcinoma cells, whose growth depends on high basal autophagy, possess stronger basal phosphatase activity towards ULK1 and require ULK1 for sustained anchorage-independent growth. Taken together, concurrent mTORC1 inactivation and PP2A–B55α stimulation fuel ULK1-dependent autophagy.

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A PtdIns4,5P2-regulated nuclear poly(A) polymerase controls expression of select mRNAs.

Shayne C. Barlow, Ping Wang, Chunhua Song … (2008)

Phosphoinositides are a family of lipid signalling molecules that regulate many cellular functions in eukaryotes. Phosphatidylinositol-4,5-bisphosphate (PtdIns4,5P2), the central component in the phosphoinositide signalling circuitry, is generated primarily by type I phosphatidylinositol 4-phosphate 5-kinases (PIPKIalpha, PIPKIbeta and PIPKIgamma). In addition to functions in the cytosol, phosphoinositides are present in the nucleus, where they modulate several functions; however, the mechanism by which they directly regulate nuclear functions remains unknown. PIPKIs regulate cellular functions through interactions with protein partners, often PtdIns4,5P2 effectors, that target PIPKIs to discrete subcellular compartments, resulting in the spatial and temporal generation of PtdIns4,5P2 required for the regulation of specific signalling pathways. Therefore, to determine roles for nuclear PtdIns4,5P2 we set out to identify proteins that interacted with the nuclear PIPK, PIPKIalpha. Here we show that PIPKIalpha co-localizes at nuclear speckles and interacts with a newly identified non-canonical poly(A) polymerase, which we have termed Star-PAP (nuclear speckle targeted PIPKIalpha regulated-poly(A) polymerase) and that the activity of Star-PAP can be specifically regulated by PtdIns4,5P2. Star-PAP and PIPKIalpha function together in a complex to control the expression of select mRNAs, including the transcript encoding the key cytoprotective enzyme haem oxygenase-1 (refs 8, 9) and other oxidative stress response genes by regulating the 3'-end formation of their mRNAs. Taken together, the data demonstrate a model by which phosphoinositide signalling works in tandem with complement pathways to regulate the activity of Star-PAP and the subsequent biosynthesis of its target mRNA. The results reveal a mechanism for the integration of nuclear phosphoinositide signals and a method for regulating gene expression.

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Journal

Journal ID (nlm-ta): Cells

Journal ID (iso-abbrev): Cells

Journal ID (publisher-id): cells

Title: Cells

Publisher: MDPI

ISSN (Electronic): 2073-4409

Publication date (Electronic): 12 March 2020

Publication date Collection: March 2020

Volume: 9

Issue: 3

Electronic Location Identifier: 697

Affiliations

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, 40126 Bologna, Italy; jie.xian2@ 123456unibo.it (J.X.); eric.owusuobeng2@ 123456unibo.it (E.O.O.); stefano.ratti@ 123456unibo.it (S.R.); isabella.rusciano3@ 123456unibo.it (I.R.); mariavittoria.marvi2@ 123456unibo.it (M.V.M.); antonietta.fazio2@ 123456unibo.it (A.F.); alessia.destefano@ 123456studio.unibo.it (A.D.S.); s.mongiorgi@ 123456unibo.it (S.M.); alessandra.cappellini@ 123456unibo.it (A.C.); giulia.ramazzotti@ 123456unibo.it (G.R.); lucia.manzoli@ 123456unibo.it (L.M.); matilde.follo@ 123456unibo.it (M.Y.F.)

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[* ]Correspondence: lucio.cocco@ 123456unibo.it ; Tel.: +39-051-209-1639

[†]

These authors contributed equally to this paper.

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Stefano Ratti https://orcid.org/0000-0002-6258-5345

Giulia Ramazzotti https://orcid.org/0000-0001-9684-714X

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Publisher ID: cells-09-00697

DOI: 10.3390/cells9030697

PMC ID: 7140618

PubMed ID: 32178280

SO-VID: e8477e86-d08f-4f20-ac71-8ac6dc98fff0

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Nuclear Inositides and Inositide-Dependent Signaling Pathways in Myelodysplastic Syndromes

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Neuronal Signaling

Most cited references 114

Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling.

Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A

A PtdIns4,5P2-regulated nuclear poly(A) polymerase controls expression of select mRNAs.

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