Polyamine homoeostasis

2009 ◽  
Vol 46 ◽  
pp. 11-24 ◽  
Author(s):  
Lo Persson
Keyword(s):  
Mammalian Cells ◽  
Cell Function ◽  
Protein S ◽  
26S Proteasome ◽  
Adenosylmethionine Decarboxylase ◽  
Specific Effects ◽  
Polyamine Transport ◽  
Polyamine Transporter ◽  
Reading Frames ◽  
Synthesis And Degradation

The polyamines are essential for a variety of functions in the mammalian cell. Although their specific effects have not been fully elucidated, it is clear that the cellular polyamines have to be kept within certain levels for normal cell function. Polyamine homoeostasis in mammalian cells is achieved by a complex network of regulatory mechanisms affecting synthesis and degradation, as well as membrane transport of polyamines. The two key enzymes in the polyamine biosynthetic pathway, ODC (ornithine decarboxylase) and AdoMetDC (S-adenosylmethionine decarboxylase), are strongly regulated by feedback mechanisms at several levels, including transcriptional, translational and post-translational. Some of these mechanisms have been shown to be truly unique and include upstream reading frames and ribosomal frameshifting, as well as ubiquitin-independent proteasomal degradation. SSAT (spermidine/spermine N1-acetyltransferase), which is a crucial enzyme for degradation and efflux of polyamines, is also highly regulated by polyamines. A cellular excess of polyamines rapidly induces SSAT, resulting in increased degradation/efflux of the polyamines. The polyamines appear to induce both transcription and translation of the SSAT mRNA. However, the major part of the polyamine-induced increase in SSAT is caused by a marked stabilization of the enzyme against degradation by the 26S proteasome. In addition, active transport of extracellular polyamines into the cell contributes to cellular polyamine homoeostasis. Depletion of cellular polyamines rapidly induces an increased uptake of exogenous polyamines, whereas an excess of polyamines down-regulates the polyamine transporter(s). However, the protein(s) involved in polyamine transport and the exact mechanisms by which the polyamines regulate the transporter(s) are not yet known.

Polyamine transport system mediates agmatine transport in mammalian cells

2001 ◽  
Vol 281 (1) ◽  
pp. C329-C334 ◽  
Author(s):  
Joseph Satriano ◽  
Masato Isome ◽  
Robert A. Casero ◽  
Scott C. Thomson ◽  
Roland C. Blantz
Keyword(s):  
Transport System ◽  
Mammalian Cells ◽  
Maximal Velocity ◽  
Human Carcinoma ◽  
Mammalian Cell Lines ◽  
Carrier Mediated Transport ◽  
Polyamine Transport ◽  
Polyamine Content ◽  
Polyamine Transporter ◽  
Nih 3T3

Agmatine is a biogenic amine with the capacity to regulate a number of nonreceptor-mediated functions in mammalian cells, including intracellular polyamine content and nitric oxide generation. We observed avid incorporation of agmatine into several mammalian cell lines and herein characterize agmatine transport in mammalian cells. In transformed NIH/3T3 cells, agmatine uptake is energy dependent with a saturable component indicative of carrier-mediated transport. Transport displays an apparent Michaelis-Menten constant of 2.5 μM and a maximal velocity of 280 pmol · min−1 · mg−1 protein and requires a membrane potential across the plasma membrane for uptake. Competition with polyamines, but not cationic molecules that utilize the y+ system transporter, suppresses agmatine uptake. Altering polyamine transporter activity results in parallel changes in polyamine and agmatine uptake. Furthermore, agmatine uptake is abrogated in a polyamine transport-deficient human carcinoma cell line. These lines of evidence demonstrate that agmatine utilizes, and is dependent on, the polyamine transporter for cellular uptake. The fact that this transport system is associated with proliferation could be of consequence to the antiproliferative effects of agmatine.

scholarly journals Selective labelling of cell-surface polyamine-binding proteins on leukaemic and solid-tumour cell types using a new polyamine photoprobe

1997 ◽  
Vol 328 (3) ◽  
pp. 889-895 ◽  
Author(s):  
M. Donna FELSCHOW ◽  
Zenghui MI ◽  
J. STANEK ◽  
J. FREI ◽  
W. Carl PORTER
Keyword(s):  
Cell Surface ◽  
Tumour Cell ◽  
Solid Tumour ◽  
Mammalian Cells ◽  
Binding Proteins ◽  
Protein S ◽  
Cell Types ◽  
Biochemical Properties ◽  
Surface Proteins ◽  
Polyamine Transport

Polyamine transport is an active process which contributes to the regulation and maintenance of intracellular polyamine pools. Although the biochemical properties of polyamine transport in mammalian cells have been extensively studied, attempts to isolate and characterize the actual protein(s) have met with limited success. As one approach, photoaffinity labelling of cell surface proteins using a polyamine-conjugated photoprobe may lead to the identification of polyamine-binding proteins (pbps) associated with the transport apparatus and/or other regulatory responses. In a previous study [Felschow, MacDiarmid, Bardos, Wu, Woster and Porter (1995) J. Biol. Chem. 270, 28705-28711], we demonstrated that the photoprobes N4-ASA-spermidine and N1-ASA-norspermine [where the ASA (azidosalicylamidoethyl) group represents the photoreactive moiety] competed effectively with polyamines for transport and selectively labelled two major pbps at 118 and 50 kDa on the surface of murine and human leukaemia cells. In the present study, a new and more potent polyamine-conjugated photoprobe, N1-ASA-spermine, has been synthesized and used to develop a method based on detergent lysis for identifying putative cell-surface pbps on solid-tumour cell types. Transport kinetic assays showed that the new photoprobe competed with spermidine uptake with an apparent Ki of 1 μM, a value 20-50-fold lower than those of earlier probes. In L1210 cells, the new probe identified pbp50 and pbp118 thus reaffirming their identity as pbps. Two new bands were also detected. In A549 human lung adenocarcinoma cells, N1-ASA-spermine identified pbps at 39, 62, 73 and 130 kDa, the latter believed to be a size variant of pbp118. The presence of pbp130/118 in two very different cell types suggests the generality of the protein among mammalian cell types as well as its importance for further study. The high affinity of the photoprobe for the polyamine-transport system strongly suggests that at least some of the identified pbps may be associated with that function.

scholarly journals Lipid disequilibrium disrupts ER proteostasis by impairing ERAD substrate glycan trimming and dislocation

2017 ◽  
Vol 28 (2) ◽  
pp. 270-284 ◽  
Author(s):  
Milton To ◽  
Clark W. H. Peterson ◽  
Melissa A. Roberts ◽  
Jessica L. Counihan ◽  
Tiffany T. Wu ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Mammalian Cells ◽  
26S Proteasome ◽  
Unfolded Protein ◽  
Acid Analogue ◽  
Triacsin C ◽  
Chain Acyl ◽  
Dependent Cell ◽  
Outstanding Question ◽  
The Unfolded Protein Response

The endoplasmic reticulum (ER) mediates the folding, maturation, and deployment of the secretory proteome. Proteins that fail to achieve their native conformation are retained in the ER and targeted for clearance by ER-associated degradation (ERAD), a sophisticated process that mediates the ubiquitin-dependent delivery of substrates to the 26S proteasome for proteolysis. Recent findings indicate that inhibition of long-chain acyl-CoA synthetases with triacsin C, a fatty acid analogue, impairs lipid droplet (LD) biogenesis and ERAD, suggesting a role for LDs in ERAD. However, whether LDs are involved in the ERAD process remains an outstanding question. Using chemical and genetic approaches to disrupt diacylglycerol acyltransferase (DGAT)–dependent LD biogenesis, we provide evidence that LDs are dispensable for ERAD in mammalian cells. Instead, our results suggest that triacsin C causes global alterations in the cellular lipid landscape that disrupt ER proteostasis by interfering with the glycan trimming and dislocation steps of ERAD. Prolonged triacsin C treatment activates both the IRE1 and PERK branches of the unfolded protein response and ultimately leads to IRE1-dependent cell death. These findings identify an intimate relationship between fatty acid metabolism and ER proteostasis that influences cell viability.

scholarly journals Set1 Targets Genes with Essential Identity and Tumor-Suppressing Functions in Planarian Stem Cells

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1182
Author(s):  
Prince Verma ◽  
Court K. M. Waterbury ◽  
Elizabeth M. Duncan
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Mammalian Cells ◽  
Cell Function ◽  
Genotoxic Stress ◽  
Specific Gene ◽  
Cell Identity ◽  
Chromatin Signature ◽  
Lysine Methyltransferase

Tumor suppressor genes (TSGs) are essential for normal cellular function in multicellular organisms, but many TSGs and tumor-suppressing mechanisms remain unknown. Planarian flatworms exhibit particularly robust tumor suppression, yet the specific mechanisms underlying this trait remain unclear. Here, we analyze histone H3 lysine 4 trimethylation (H3K4me3) signal across the planarian genome to determine if the broad H3K4me3 chromatin signature that marks essential cell identity genes and TSGs in mammalian cells is conserved in this valuable model of in vivo stem cell function. We find that this signature is indeed conserved on the planarian genome and that the lysine methyltransferase Set1 is largely responsible for creating it at both cell identity and putative TSG loci. In addition, we show that depletion of set1 in planarians induces stem cell phenotypes that suggest loss of TSG function, including hyperproliferation and an abnormal DNA damage response (DDR). Importantly, this work establishes that Set1 targets specific gene loci in planarian stem cells and marks them with a conserved chromatin signature. Moreover, our data strongly suggest that Set1 activity at these genes has important functional consequences both during normal homeostasis and in response to genotoxic stress.

Species-specific Effects of Nitromethylene Heterocycle Insecticides on Nicotinic Receptors in Locust Neurons and Mouse N1E-115 and BC3H1 Cells

1994 ◽  
Vol 22 (6) ◽  
pp. 454-461
Author(s):  
Marga Oortgiesen ◽  
Ruud Zwart ◽  
Henk P.M. Vijverberg
Keyword(s):  
Mammalian Cells ◽  
Neuroblastoma Cells ◽  
Receptor Subtypes ◽  
Inward Current ◽  
Specific Effects ◽  
Blocking Effects ◽  
Inward Currents ◽  
Species Specific ◽  
Ganglion Neurons

The effects of nitromethylene heterocycle (NMH) insecticides on subtypes of nicotinic acetylcholine (nACh) receptors were investigated in locust thoracic ganglion neurons, mouse N1E-115 neuroblastoma cells, and mouse BC3H1 muscle cells by using electrophysiological techniques. In locust neurons, all of the six NMH insecticides tested induced transient inward currents resembling nicotinic ACh-induced inward currents, while, in the continued presence of the NMH compounds, the ACh-induced inward current was blocked. The amplitude of the inward current and the blocking effects of the NMH insecticides were enhanced by concentrations between 0.1 and 10μM. Cross-desensitisation with the ACh-induced inward current confirmed that the NMH-induced inward current was governed by the activation of nACh receptors. Mammalian endplate type nACh receptors in BC3H1 cells and mammalian neuronal type nACh receptors in N1E-115 cells were much less sensitive to the NMH insecticides than the locust neuronal nACh receptors. At a concentration of 10μM, which blocked 80–100% of the ACh-induced inward current in locust neurons, NMH insecticides only partially blocked the ACh-induced inward currents mediated by the two subtypes of mammalian nACh receptors. NMH insecticides also failed to induce significant agonist effects in the mammalian cells at this concentration. The results provide a possible explanation for the selectively greater toxicity of NMH insecticides to insects than to vertebrates, at the level of nACh receptor subtypes and, hence, demonstrate that this in vitro approach is valuable for the investigation of species-specific interactions of compounds at their target site.

scholarly journals Phosphorylation of 20S proteasome alpha subunit C8 (alpha7) stabilizes the 26S proteasome and plays a role in the regulation of proteasome complexes by gamma-interferon

2004 ◽  
Vol 378 (1) ◽  
pp. 177-184 ◽  
Author(s):  
Suchira BOSE ◽  
Fiona L. L. STRATFORD ◽  
Kerry I. BROADFOOT ◽  
Grant G. F. MASON ◽  
A. Jennifer RIVETT
Keyword(s):  
Mammalian Cells ◽  
Substantial Effect ◽  
26S Proteasome ◽  
20S Proteasome ◽  
Phosphorylation Sites ◽  
Animal Cells ◽  
Catalytic Subunits ◽  
Kinase Ck2 ◽  
Γ Interferon

In animal cells there are several regulatory complexes which interact with 20S proteasomes and give rise to functionally distinct proteasome complexes. γ-Interferon upregulates three immuno beta catalytic subunits of the 20S proteasome and the PA28 regulator, and decreases the level of 26S proteasomes. It also decreases the level of phosphorylation of two proteasome alpha subunits, C8 (α7) and C9 (α3). In the present study we have investigated the role of phosphorylation of C8 by protein kinase CK2 in the formation and stability of 26S proteasomes. An epitope-tagged C8 subunit expressed in mammalian cells was efficiently incorporated into both 20S proteasomes and 26S proteasomes. Investigation of mutants of C8 at the two known CK2 phosphorylation sites demonstrated that these are the two phosphorylation sites of C8 in animal cells. Although phosphorylation of C8 was not absolutely essential for the formation of 26S proteasomes, it did have a substantial effect on their stability. Also, when cells were treated with γ-interferon, there was a marked decrease in phosphorylation of C8, a decrease in the level of 26S proteasomes, and an increase in immunoproteasomes and PA28 complexes. These results suggest that the down-regulation of 26S proteasomes after γ-interferon treatment results from the destabilization that occurs after dephosphorylation of the C8 subunit.

Phosphatidylinositol 3-Kinase Isoform-Specific Effects in Airway Mesenchymal Cell Function

2011 ◽  
Vol 337 (2) ◽  
pp. 557-566 ◽  
Author(s):  
Lyn M. Moir ◽  
Thomas Trian ◽  
Qi Ge ◽  
Peter R. Shepherd ◽  
Janette K. Burgess ◽  
...  
Keyword(s):  
Cell Function ◽  
Mesenchymal Cell ◽  
Phosphatidylinositol 3 Kinase ◽  
Specific Effects ◽  
Phosphatidylinositol 3

scholarly journals Hydrogen, Bicarbonate, and Their Associated Exchangers in Cell Volume Regulation

2021 ◽  
Vol 9 ◽  
Author(s):  
Yizeng Li ◽  
Xiaohan Zhou ◽  
Sean X. Sun
Keyword(s):  
Ion Channels ◽  
Cell Volume ◽  
Volume Regulation ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Water Flux ◽  
Cell Volume Regulation ◽  
Sodium Potassium ◽  
Before And After

Cells lacking a stiff cell wall, e.g., mammalian cells, must actively regulate their volume to maintain proper cell function. On the time scale that protein production is negligible, water flow in and out of the cell determines the cell volume variation. Water flux follows hydraulic and osmotic gradients; the latter is generated by various ion channels, transporters, and pumps in the cell membrane. Compared to the widely studied roles of sodium, potassium, and chloride in cell volume regulation, the effects of proton and bicarbonate are less understood. In this work, we use mathematical models to analyze how proton and bicarbonate, combined with sodium, potassium, chloride, and buffer species, regulate cell volume upon inhibition of ion channels, transporters, and pumps. The model includes several common, widely expressed ion transporters and focuses on obtaining generic outcomes. Results show that the intracellular osmolarity remains almost constant before and after cell volume change. The steady-state cell volume does not depend on water permeability. In addition, to ensure the stability of cell volume and ion concentrations, cells need to develop redundant mechanisms to maintain homeostasis, i.e., multiple ion channels or transporters are involved in the flux of the same ion species. These results provide insights for molecular mechanisms of cell volume regulation with additional implications for water-driven cell migration.

scholarly journals Microplastics - an emerging silent menace to public health

2021 ◽  
Vol 5 (10) ◽  
Author(s):  
Li-Yin Pang ◽  
Shola Sonagara ◽  
Oreoluwatomide Oduwole ◽  
Christopher Gibbins ◽  
Ting Kang Nee
Keyword(s):  
Public Health ◽  
Health Effects ◽  
Mammalian Cells ◽  
Circulatory System ◽  
Epidemiological Studies ◽  
Specific Effects ◽  
Important Pathway ◽  
Living Organisms ◽  
Respiratory Conditions

Over the past few decades, microplastics have become increasingly ubiquitous in the environment and now contaminate the bodies of many living organisms, including humans. Microplastics, as defined here, are plastics within the size range 0.1 μm and 5 mm and are a worrying form of pollution due to public health concerns. This mini-review aims to summarise the route of entry of microplastics into humans and explore the potential detrimental health effects of microplastics. Trophic transfer is an important pathway for microplastic to be transferred across different groups of organisms, with ingestion is regarded as one of the major routes of exposure for humans. Other pathways include inhalation and dermal contact. The health consequences of microplastics manifest because these materials can translocate into the circulatory system and accumulate in the lungs, liver, kidney, and even brain, regardless of the route of entry. Health effects include gastrointestinal disturbances such as inflammation and gut microbiota disruption, respiratory conditions, neurotoxicity and potential cancers. Overall, while it is apparent that microplastics are causing adverse effects on different biological groups and ecosystems, current research is largely focused on marine organisms and aquaculture. Therefore, more studies are needed to investigate specific effects in mammalian cells and tissues, with more long-term epidemiological studies needed on human population considered to be at high-risk due to socioeconomic or other circumstance. Knowledge of the toxicity and long-term health impacts of microplastics is currently limited and requires urgent attention.

scholarly journals RCAN1 Regulates Mitochondrial Function and Increases Susceptibility to Oxidative Stress in Mammalian Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Heshan Peiris ◽  
Daphne Dubach ◽  
Claire F. Jessup ◽  
Petra Unterweger ◽  
Ravinarayan Raghupathi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Function ◽  
Neurodegenerative Disorders ◽  
Mammalian Cells ◽  
Cell Function ◽  
Cellular Energy ◽  
Mitochondrial Ros ◽  
Ros Accumulation ◽  
The Brain ◽  
Increased Susceptibility

Mitochondria are the primary site of cellular energy generation and reactive oxygen species (ROS) accumulation. Elevated ROS levels are detrimental to normal cell function and have been linked to the pathogenesis of neurodegenerative disorders such as Down's syndrome (DS) and Alzheimer’s disease (AD). RCAN1 is abundantly expressed in the brain and overexpressed in brain of DS and AD patients. Data from nonmammalian species indicates that increased RCAN1 expression results in altered mitochondrial function and that RCAN1 may itself regulate neuronal ROS production. In this study, we have utilized mice overexpressing RCAN1RCAN1oxand demonstrate an increased susceptibility of neurons from these mice to oxidative stress. Mitochondria from these mice are more numerous and smaller, indicative of mitochondrial dysfunction, and mitochondrial membrane potential is altered under conditions of oxidative stress. We also generated a PC12 cell line overexpressing RCAN1PC12RCAN1. Similar toRCAN1oxneurons,PC12RCAN1cells have an increased susceptibility to oxidative stress and produce more mitochondrial ROS. This study demonstrates that increasing RCAN1 expression alters mitochondrial function and increases the susceptibility of neurons to oxidative stress in mammalian cells. These findings further contribute to our understanding of RCAN1 and its potential role in the pathogenesis of neurodegenerative disorders such as AD and DS.

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