Role of inorganic polyphosphate in mammalian cells: from signal transduction and mitochondrial metabolism to cell death

2016 ◽  
Vol 44 (1) ◽  
pp. 40-45 ◽  
Author(s):  
Plamena R. Angelova ◽  
Artyom Y. Baev ◽  
Alexey V. Berezhnov ◽  
Andrey Y. Abramov
Keyword(s):  
Signal Transduction ◽  
Cell Death ◽  
Mammalian Cells ◽  
High Energy ◽  
Mitochondrial Metabolism ◽  
Calcium Handling ◽  
Calcium Signal ◽  
Inorganic Polyphosphate ◽  
Long Chain

Inorganic polyphosphate (polyP) is a polymer compromised of linearly arranged orthophosphate units that are linked through high-energy phosphoanhydride bonds. The chain length of this polymer varies from five to several thousand orthophosphates. PolyP is distributed in the most of the living organisms and plays multiple functions in mammalian cells, it is important for blood coagulation, cancer, calcium precipitation, immune response and many others. Essential role of polyP is shown for mitochondria, from implication into energy metabolism and mitochondrial calcium handling to activation of permeability transition pore (PTP) and cell death. PolyP is a gliotransmitter which transmits the signal in astrocytes via activation of P2Y1 receptors and stimulation of phospholipase C. PolyP-induced calcium signal in astrocytes can be stimulated by different lengths of this polymer but only long chain polyP induces mitochondrial depolarization by inhibition of respiration and opening of the PTP. It leads to induction of astrocytic cell death which can be prevented by inhibition of PTP with cyclosporine A. Thus, medium- and short-length polyP plays role in signal transduction and mitochondrial metabolism of astrocytes and long chain of this polymer can be toxic for the cells.

Cannabis-induced cytotoxicity in leukemic cell lines: the role of the cannabinoid receptors and the MAPK pathway

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1214-1221 ◽  
Author(s):  
Thomas Powles ◽  
Robert te Poele ◽  
Jonathan Shamash ◽  
Tracy Chaplin ◽  
David Propper ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cell Death ◽  
Cell Lines ◽  
Leukemic Cell ◽  
Cytotoxic Agents ◽  
Complex Signal ◽  
Signal Transduction Pathways ◽  
Potent Inducer ◽  
Leukemic Cell Lines

Abstract Δ9-Tetrahydrocannabinol (THC) is the active metabolite of cannabis. THC causes cell death in vitro through the activation of complex signal transduction pathways. However, the role that the cannabinoid 1 and 2 receptors (CB1-R and CB2-R) play in this process is less clear. We therefore investigated the role of the CB-Rs in mediating apoptosis in 3 leukemic cell lines and performed microarray and immunoblot analyses to establish further the mechanism of cell death. We developed a novel flow cytometric technique of measuring the expression of functional receptors and used combinations of selective CB1-R and CB2-R antagonists and agonists to determine their individual roles in this process. We have shown that THC is a potent inducer of apoptosis, even at 1 × IC50 (inhibitory concentration 50%) concentrations and as early as 6 hours after exposure to the drug. These effects were seen in leukemic cell lines (CEM, HEL-92, and HL60) as well as in peripheral blood mononuclear cells. Additionally, THC did not appear to act synergistically with cytotoxic agents such as cisplatin. One of the most intriguing findings was that THC-induced cell death was preceded by significant changes in the expression of genes involved in the mitogen-activated protein kinase (MAPK) signal transduction pathways. Both apoptosis and gene expression changes were altered independent of p53 and the CB-Rs.

Multifaceted role of the Saccharomyces cerevisiae Srs2 helicase in homologous recombination regulation

2005 ◽  
Vol 33 (6) ◽  
pp. 1447-1450 ◽  
Author(s):  
M.A. Macris ◽  
P. Sung
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Death ◽  
Dna Replication ◽  
Homologous Recombination ◽  
High Energy ◽  
Yeast Saccharomyces Cerevisiae ◽  
Major Pathway ◽  
Dna Dsbs ◽  
Srs2 Helicase

Homologous recombination (HR) is a major pathway for the elimination of DNA DSBs (double-strand breaks) induced by high-energy radiation and chemicals, or that arise due to endogenous damage and stalled DNA replication forks. If not processed properly, DSBs can lead to cell death, chromosome aberrations and tumorigenesis. Even though HR is important for genome maintenance, it can also interfere with other DNA repair mechanisms and cause gross chromosome rearrangements. In addition, HR can generate DNA or nucleoprotein intermediates that elicit prolonged cell-cycle arrest and sometimes cell death. Genetic analyses in the yeast Saccharomyces cerevisiae have revealed a central role of the Srs2 helicase in preventing untimely HR events and in inhibiting the formation of potentially deleterious DNA structures or nucleoprotein complexes upon DNA replication stress. Paradoxically, efficient repair of DNA DSBs by HR is dependent on Srs2. In this paper, we review recent molecular studies aimed at deciphering the multifaceted role of Srs2 in HR and other cellular processes. These studies have provided critical insights into how HR is regulated in order to preserve genomic integrity and promote cell survival.

scholarly journals Subunit composition of the mammalian serine-palmitoyltransferase defines the spectrum of straight and methyl-branched long-chain bases

2020 ◽  
Vol 117 (27) ◽  
pp. 15591-15598 ◽  
Author(s):  
Museer A. Lone ◽  
Andreas J. Hülsmeier ◽  
Essa M. Saied ◽  
Gergely Karsai ◽  
Christoph Arenz ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Mammalian Cells ◽  
High Density Lipoproteins ◽  
Serine Palmitoyltransferase ◽  
Product Spectrum ◽  
Long Chain Base ◽  
The Individual ◽  
And Function ◽  
Long Chain

Sphingolipids (SLs) are chemically diverse lipids that have important structural and signaling functions within mammalian cells. SLs are commonly defined by the presence of a long-chain base (LCB) that is normally formed by the conjugation ofl-serine and palmitoyl-CoA. This pyridoxal 5-phosphate (PLP)-dependent reaction is mediated by the enzyme serine-palmitoyltransferase (SPT). However, SPT can also metabolize other acyl-CoAs, in the range of C14to C18, forming a variety of LCBs that differ by structure and function. Mammalian SPT consists of three core subunits: SPTLC1, SPTLC2, and SPTLC3. Whereas SPTLC1 and SPTLC2 are ubiquitously expressed, SPTLC3 expression is restricted to certain tissues only. The influence of the individual subunits on enzyme activity is not clear. Using cell models deficient in SPTLC1, SPTLC2, and SPTLC3, we investigated the role of each subunit on enzyme activity and the LCB product spectrum. We showed that SPTLC1 is essential for activity, whereas SPTLC2 and SPTLC3 are partly redundant but differ in their enzymatic properties. SPTLC1 in combination with SPTLC2 specifically formed C18, C19, and C20 LCBs while the combination of SPTLC1 and SPTLC3 yielded a broader product spectrum. We identifiedanteiso-branched-C18 SO (meC18SO) as the primary product of the SPTLC3 reaction. The meC18SO was synthesized fromanteiso-methyl-palmitate, in turn synthesized from a precursor metabolite generated in the isoleucine catabolic pathway. The meC18SO is metabolized to ceramides and complex SLs and is a constituent of human low- and high-density lipoproteins.

scholarly journals The Role of Long-Chain Fatty Acyl-CoA Esters in β-Cell Signal Transduction

2000 ◽  
Vol 130 (2) ◽  
pp. 299S-304S ◽  
Author(s):  
Barbara E. Corkey ◽  
Jude T. Deeney ◽  
Gordon C. Yaney ◽  
Keith Tornheim ◽  
Marc Prentki
Keyword(s):  
Signal Transduction ◽  
Fatty Acyl ◽  
Β Cell ◽  
Cell Signal ◽  
Cell Signal Transduction ◽  
Long Chain

scholarly journals Role of a Small Molecule in the Modulation of Cell Death Signal Transduction Pathways

2018 ◽  
Vol 4 (12) ◽  
pp. 1746-1754 ◽  
Author(s):  
Stella Hartmann ◽  
David J. Nusbaum ◽  
Kevin Kim ◽  
Saleem Alameh ◽  
Chi-Lee C. Ho ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cell Death ◽  
Small Molecule ◽  
Signal Transduction Pathways

scholarly journals Inhibition of ESCRT-II–CHMP6 interactions impedes cytokinetic abscission and leads to cell death

2014 ◽  
Vol 25 (23) ◽  
pp. 3740-3748 ◽  
Author(s):  
Inna Goliand ◽  
Dikla Nachmias ◽  
Ofir Gershony ◽  
Natalie Elia
Keyword(s):  
Amino Acids ◽  
Cell Death ◽  
Mammalian Cells ◽  
Active Role ◽  
Intercellular Bridge ◽  
Ordered Structures ◽  
Daughter Cells ◽  
Membrane Fission ◽  
Resolution Imaging

Recently the ESCRT-III filamentous complex was designated as the driving force for mammalian cell abscission, that is, fission of the intercellular membrane bridge connecting daughter cells at the end of cytokinesis. However, how ESCRT-III is activated to set on abscission has not been resolved. Here we revisit the role of the upstream canonical ESCRT players ESCRT-II and CHMP6 in abscission. Using high-resolution imaging, we show that these proteins form highly ordered structures at the intercellular bridge during abscission progression. Furthermore, we demonstrate that a truncated version of CHMP6, composed of its first 52 amino acids (CHMP6-N), arrives at the intercellular bridge, blocks abscission, and subsequently leads to cell death. This phenotype is abolished in a mutated version of CHMP6-N designed to prevent CHMP6-N binding to its ESCRT-II partner. Of interest, deleting the first 10 amino acids from CHMP6-N does not interfere with its arrival at the intercellular bridge but almost completely abolishes the abscission failure phenotype. Taken together, these data suggest an active role for ESCRT-II and CHMP6 in ESCRT-mediated abscission. Our work advances the mechanistic understanding of ESCRT-mediated membrane fission in cells and introduces an easily applicable tool for upstream inhibition of the ESCRT pathway in live mammalian cells.

scholarly journals Dual Role of Inorganic Polyphosphate (POLYP) in the Regulation of Mitochondria-Dependent Cell Death

2017 ◽  
Vol 112 (3) ◽  
pp. 439a
Author(s):  
Maria de la Encarnacion Solesio Torregrosa ◽  
Mitchell Marta-Ariza ◽  
Fernando Goni ◽  
Evgeny V. Pavlov
Keyword(s):  
Cell Death ◽  
Dual Role ◽  
Inorganic Polyphosphate ◽  
Dependent Cell

scholarly journals Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries

2021 ◽  
Author(s):  
Xianonan Zhang ◽  
Mihir Shetty ◽  
Valentino Clemente ◽  
Stig Linder ◽  
Martina Bazzaro
Keyword(s):  
Cell Carcinoma ◽  
Mammalian Cells ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Mitochondrial Metabolism ◽  
Mitochondrial Activity ◽  
Preclinical Model ◽  
Mitochondrial Number ◽  
Inactivating Mutations

SummaryOvarian clear cell carcinoma (OCCC) is a rare but chemorefractory tumor. About 50% of all OCCC patients have inactivating mutations of ARID1A a member of the SWI/SNF chromatin remodeling complex. Members of the SWI/SNF remodeling have emerged as regulators of the energetic metabolism of mammalian cells, however the role of ARID1A as a modulator of the mitochondrial metabolism in OCCCs is yet to be defined. Here we show that ARID1A-loss results in increased mitochondrial metabolism and renders ARID1A-mutated cells increasingly and selectively dependent on it. The increase in mitochondrial activity following ARID1A loss is associated to increase of C-myc and to increased mitochondrial number and reduction of their size consistent with a higher mitochondrial cristae/outer membrane ratio. Significantly, preclinical testing of the complex I mitochondrial inhibitor IACS-010759 extends overall survival in a preclinical model of ARID1A-mutated OCCC. These findings provide the for targeting mitochondrial activity in ARID1A-mutanted OCCCs.

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