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Volume 4
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Cells, Volume 4, Issue 3 (September 2015) – 17 articles , Pages 234-568

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3878 KiB  
Review
Structural Basis of Targeting the Exportin CRM1 in Cancer
by Achim Dickmanns, Thomas Monecke and Ralf Ficner
Cells 2015, 4(3), 538-568; https://doi.org/10.3390/cells4030538 - 21 Sep 2015
Cited by 50 | Viewed by 11075
Abstract
Recent studies have demonstrated the interference of nucleocytoplasmic trafficking with the establishment and maintenance of various cancers. Nucleocytoplasmic transport is highly regulated and coordinated, involving different nuclear transport factors or receptors, importins and exportins, that mediate cargo transport from the cytoplasm into the [...] Read more.
Recent studies have demonstrated the interference of nucleocytoplasmic trafficking with the establishment and maintenance of various cancers. Nucleocytoplasmic transport is highly regulated and coordinated, involving different nuclear transport factors or receptors, importins and exportins, that mediate cargo transport from the cytoplasm into the nucleus or the other way round, respectively. The exportin CRM1 (Chromosome region maintenance 1) exports a plethora of different protein cargoes and ribonucleoprotein complexes. Structural and biochemical analyses have enabled the deduction of individual steps of the CRM1 transport cycle. In addition, CRM1 turned out to be a valid target for anticancer drugs as it exports numerous proto-oncoproteins and tumor suppressors. Clearly, detailed understanding of the flexibility, regulatory features and cooperative binding properties of CRM1 for Ran and cargo is a prerequisite for the design of highly effective drugs. The first compound found to inhibit CRM1-dependent nuclear export was the natural drug Leptomycin B (LMB), which blocks export by competitively interacting with a highly conserved cleft on CRM1 required for nuclear export signal recognition. Clinical studies revealed serious side effects of LMB, leading to a search for alternative natural and synthetic drugs and hence a multitude of novel therapeutics. The present review examines recent progress in understanding the binding mode of natural and synthetic compounds and their inhibitory effects. Full article
(This article belongs to the Special Issue Nucleocytoplasmic Transport)
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1576 KiB  
Review
NAD+-Metabolizing Ectoenzymes in Remodeling Tumor–Host Interactions: The Human Myeloma Model
by Alberto L. Horenstein, Antonella Chillemi, Valeria Quarona, Andrea Zito, Ilaria Roato, Fabio Morandi, Danilo Marimpietri, Marina Bolzoni, Denise Toscani, Robert J. Oldham, Massimiliano Cuccioloni, A. Kate Sasser, Vito Pistoia, Nicola Giuliani and Fabio Malavasi
Cells 2015, 4(3), 520-537; https://doi.org/10.3390/cells4030520 - 17 Sep 2015
Cited by 83 | Viewed by 10633
Abstract
Nicotinamide adenine dinucleotide (NAD+) is an essential co-enzyme reported to operate both intra- and extracellularly. In the extracellular space, NAD+ can elicit signals by binding purinergic P2 receptors or it can serve as the substrate for a chain of ectoenzymes. [...] Read more.
Nicotinamide adenine dinucleotide (NAD+) is an essential co-enzyme reported to operate both intra- and extracellularly. In the extracellular space, NAD+ can elicit signals by binding purinergic P2 receptors or it can serve as the substrate for a chain of ectoenzymes. As a substrate, it is converted to adenosine (ADO) and then taken up by the cells, where it is transformed and reincorporated into the intracellular nucleotide pool. Nucleotide-nucleoside conversion is regulated by membrane-bound ectoenzymes. CD38, the main mammalian enzyme that hydrolyzes NAD+, belongs to the ectoenzymatic network generating intracellular Ca2+-active metabolites. Within this general framework, the extracellular conversion of NAD+ can vary significantly according to the tissue environment or pathological conditions. Accumulating evidence suggests that tumor cells exploit such a network for migrating and homing to protected areas and, even more importantly, for evading the immune response. We report on the experience of this lab to exploit human multiple myeloma (MM), a neoplastic expansion of plasma cells, as a model to investigate these issues. MM cells express high levels of surface CD38 and grow in an environment prevalently represented by closed niches hosted in the bone marrow (BM). An original approach of this study derives from the recent use of the clinical availability of therapeutic anti-CD38 monoclonal antibodies (mAbs) in perturbing tumor viability and enzymatic functions in conditions mimicking what happens in vivo. Full article
(This article belongs to the Special Issue NAD+ Metabolism and Signaling)
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3816 KiB  
Review
Specialized Cilia in Mammalian Sensory Systems
by Nathalie Falk, Marlene Lösl, Nadja Schröder and Andreas Gießl
Cells 2015, 4(3), 500-519; https://doi.org/10.3390/cells4030500 - 11 Sep 2015
Cited by 79 | Viewed by 15314
Abstract
Cilia and flagella are highly conserved and important microtubule-based organelles that project from the surface of eukaryotic cells and act as antennae to sense extracellular signals. Moreover, cilia have emerged as key players in numerous physiological, developmental, and sensory processes such as hearing, [...] Read more.
Cilia and flagella are highly conserved and important microtubule-based organelles that project from the surface of eukaryotic cells and act as antennae to sense extracellular signals. Moreover, cilia have emerged as key players in numerous physiological, developmental, and sensory processes such as hearing, olfaction, and photoreception. Genetic defects in ciliary proteins responsible for cilia formation, maintenance, or function underlie a wide array of human diseases like deafness, anosmia, and retinal degeneration in sensory systems. Impairment of more than one sensory organ results in numerous syndromic ciliary disorders like the autosomal recessive genetic diseases Bardet-Biedl and Usher syndrome. Here we describe the structure and distinct functional roles of cilia in sensory organs like the inner ear, the olfactory epithelium, and the retina of the mouse. The spectrum of ciliary function in fundamental cellular processes highlights the importance of elucidating ciliopathy-related proteins in order to find novel potential therapies. Full article
(This article belongs to the Special Issue Cilia and Flagella: Biogenesis and Function)
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3575 KiB  
Review
Nephron Patterning: Lessons from Xenopus, Zebrafish, and Mouse Studies
by Audrey Desgrange and Silvia Cereghini
Cells 2015, 4(3), 483-499; https://doi.org/10.3390/cells4030483 - 11 Sep 2015
Cited by 64 | Viewed by 11072
Abstract
The nephron is the basic structural and functional unit of the vertebrate kidney. To ensure kidney functions, the nephrons possess a highly segmental organization where each segment is specialized for the secretion and reabsorption of particular solutes. During embryogenesis, nephron progenitors undergo a [...] Read more.
The nephron is the basic structural and functional unit of the vertebrate kidney. To ensure kidney functions, the nephrons possess a highly segmental organization where each segment is specialized for the secretion and reabsorption of particular solutes. During embryogenesis, nephron progenitors undergo a mesenchymal-to-epithelial transition (MET) and acquire different segment-specific cell fates along the proximo-distal axis of the nephron. Even if the morphological changes occurring during nephrogenesis are characterized, the regulatory networks driving nephron segmentation are still poorly understood. Interestingly, several studies have shown that the pronephric nephrons in Xenopus and zebrafish are segmented in a similar fashion as the mouse metanephric nephrons. Here we review functional and molecular aspects of nephron segmentation with a particular interest on the signaling molecules and transcription factors recently implicated in kidney development in these three different vertebrate model organisms. A complete understanding of the mechanisms underlying nephrogenesis in different model organisms will provide novel insights on the etiology of several human renal diseases. Full article
(This article belongs to the Special Issue The Kidney: Development, Disease and Regeneration)
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1107 KiB  
Review
Ciliary/Flagellar Protein Ubiquitination
by Huan Long, Qiyu Wang and Kaiyao Huang
Cells 2015, 4(3), 474-482; https://doi.org/10.3390/cells4030474 - 02 Sep 2015
Cited by 12 | Viewed by 8158
Abstract
Cilia/flagella are conserved eukaryotic organelles that play an important role in the control of cell motility and detection of environmental cues. However, the molecular mechanisms underlying ciliary/flagellar assembly, maintenance, disassembly, and signal transduction are not yet completely understood. Recent studies demonstrated that post-translational [...] Read more.
Cilia/flagella are conserved eukaryotic organelles that play an important role in the control of cell motility and detection of environmental cues. However, the molecular mechanisms underlying ciliary/flagellar assembly, maintenance, disassembly, and signal transduction are not yet completely understood. Recent studies demonstrated that post-translational modifications (PTMs) such as phosphorylation, methylation, glutamylation, and ubiquitination are involved in these processes. In this mini review, we present a summary of research progress in ciliary/flagellar protein ubiquitination, including the ubiquitin conjugation system identified by proteomics as well as the role of ciliary/flagellar protein ubiquitination in flagellar disassembly, motility, and signal transduction. Moreover, we described putative further research directions in the study of ciliary/flagellar protein ubiquitination. Full article
(This article belongs to the Special Issue Cilia and Flagella: Biogenesis and Function)
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2715 KiB  
Review
Multiple Export Mechanisms for mRNAs
by Mildred Delaleau and Katherine L. B. Borden
Cells 2015, 4(3), 452-473; https://doi.org/10.3390/cells4030452 - 28 Aug 2015
Cited by 59 | Viewed by 10898
Abstract
Nuclear mRNA export plays an important role in gene expression. We describe the mechanisms of mRNA export including the importance of mRNP assembly, docking with the nuclear basket of the nuclear pore complex (NPC), transit through the central channel of the NPC and [...] Read more.
Nuclear mRNA export plays an important role in gene expression. We describe the mechanisms of mRNA export including the importance of mRNP assembly, docking with the nuclear basket of the nuclear pore complex (NPC), transit through the central channel of the NPC and cytoplasmic release. We describe multiple mechanisms of mRNA export including NXF1 and CRM1 mediated pathways. Selective groups of mRNAs can be preferentially transported in order to respond to cellular stimuli. RNAs can be selected based on the presence of specific cis-acting RNA elements and binding of specific adaptor proteins. The role that dysregulation of this process plays in human disease is also discussed. Full article
(This article belongs to the Special Issue Nucleocytoplasmic Transport)
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2613 KiB  
Article
Mitochondrial Impairment May Increase Cellular NAD(P)H: Resazurin Oxidoreductase Activity, Perturbing the NAD(P)H-Based Viability Assays
by Vasily A. Aleshin, Artem V. Artiukhov, Henry Oppermann, Alexey V. Kazantsev, Nikolay V. Lukashev and Victoria I. Bunik
Cells 2015, 4(3), 427-451; https://doi.org/10.3390/cells4030427 - 21 Aug 2015
Cited by 31 | Viewed by 7760
Abstract
Cellular NAD(P)H-dependent oxidoreductase activity with artificial dyes (NAD(P)H-OR) is an indicator of viability, as the cellular redox state is important for biosynthesis and antioxidant defense. However, high NAD(P)H due to impaired mitochondrial oxidation, known as reductive stress, should increase NAD(P)H-OR yet perturb viability. [...] Read more.
Cellular NAD(P)H-dependent oxidoreductase activity with artificial dyes (NAD(P)H-OR) is an indicator of viability, as the cellular redox state is important for biosynthesis and antioxidant defense. However, high NAD(P)H due to impaired mitochondrial oxidation, known as reductive stress, should increase NAD(P)H-OR yet perturb viability. To better understand this complex behavior, we assayed NAD(P)H-OR with resazurin (Alamar Blue) in glioblastoma cell lines U87 and T98G, treated with inhibitors of central metabolism, oxythiamin, and phosphonate analogs of 2-oxo acids. Targeting the thiamin diphosphate (ThDP)-dependent enzymes, the inhibitors are known to decrease the NAD(P)H production in the pentose phosphate shuttle and/or upon mitochondrial oxidation of 2-oxo acids. Nevertheless, the inhibitors elevated NAD(P)H-OR with resazurin in a time- and concentration-dependent manner, suggesting impaired NAD(P)H oxidation rather than increased viability. In particular, inhibition of the ThDP-dependent enzymes affects metabolism of malate, which mediates mitochondrial oxidation of cytosolic NAD(P)H. We showed that oxythiamin not only inhibited mitochondrial 2-oxo acid dehydrogenases, but also induced cell-specific changes in glutamate and malate dehydrogenases and/or malic enzyme. As a result, inhibition of the 2-oxo acid dehydrogenases compromises mitochondrial metabolism, with the dysregulated electron fluxes leading to increases in cellular NAD(P)H-OR. Perturbed mitochondrial oxidation of NAD(P)H may thus complicate the NAD(P)H-based viability assay. Full article
(This article belongs to the Special Issue NAD+ Metabolism and Signaling)
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1408 KiB  
Review
Spatiotemporal Regulation of Nuclear Transport Machinery and Microtubule Organization
by Naoyuki Okada and Masamitsu Sato
Cells 2015, 4(3), 406-426; https://doi.org/10.3390/cells4030406 - 21 Aug 2015
Cited by 20 | Viewed by 9229
Abstract
Spindle microtubules capture and segregate chromosomes and, therefore, their assembly is an essential event in mitosis. To carry out their mission, many key players for microtubule formation need to be strictly orchestrated. Particularly, proteins that assemble the spindle need to be translocated at [...] Read more.
Spindle microtubules capture and segregate chromosomes and, therefore, their assembly is an essential event in mitosis. To carry out their mission, many key players for microtubule formation need to be strictly orchestrated. Particularly, proteins that assemble the spindle need to be translocated at appropriate sites during mitosis. A small GTPase (hydrolase enzyme of guanosine triphosphate), Ran, controls this translocation. Ran plays many roles in many cellular events: nucleocytoplasmic shuttling through the nuclear envelope, assembly of the mitotic spindle, and reorganization of the nuclear envelope at the mitotic exit. Although these events are seemingly distinct, recent studies demonstrate that the mechanisms underlying these phenomena are substantially the same as explained by molecular interplay of the master regulator Ran, the transport factor importin, and its cargo proteins. Our review focuses on how the transport machinery regulates mitotic progression of cells. We summarize translocation mechanisms governed by Ran and its regulatory proteins, and particularly focus on Ran-GTP targets in fission yeast that promote spindle formation. We also discuss the coordination of the spatial and temporal regulation of proteins from the viewpoint of transport machinery. We propose that the transport machinery is an essential key that couples the spatial and temporal events in cells. Full article
(This article belongs to the Special Issue Nucleocytoplasmic Transport)
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1084 KiB  
Review
Nuclear Import of Yeast Proteasomes
by Julianne Burcoglu, Liang Zhao and Cordula Enenkel
Cells 2015, 4(3), 387-405; https://doi.org/10.3390/cells4030387 - 07 Aug 2015
Cited by 10 | Viewed by 7787
Abstract
Proteasomes are highly conserved protease complexes responsible for the degradation of aberrant and short-lived proteins. In highly proliferating yeast and mammalian cells, proteasomes are predominantly nuclear. During quiescence and cell cycle arrest, proteasomes accumulate in granules in close proximity to the nuclear envelope/ER. [...] Read more.
Proteasomes are highly conserved protease complexes responsible for the degradation of aberrant and short-lived proteins. In highly proliferating yeast and mammalian cells, proteasomes are predominantly nuclear. During quiescence and cell cycle arrest, proteasomes accumulate in granules in close proximity to the nuclear envelope/ER. With prolonged quiescence in yeast, these proteasome granules pinch off as membraneless organelles, and migrate as stable entities through the cytoplasm. Upon exit from quiescence, the proteasome granules clear and the proteasomes are rapidly transported into the nucleus, a process reflecting the dynamic nature of these multisubunit complexes. Due to the scarcity of studies on the nuclear transport of mammalian proteasomes, we summarised the current knowledge on the nuclear import of yeast proteasomes. This pathway uses canonical nuclear localisation signals within proteasomal subunits and Srp1/Kap95, and the canonical import receptor, named importin/karyopherin αβ. Blm10, a conserved 240 kDa protein, which is structurally related to Kap95, provides an alternative import pathway. Two models exist upon which either inactive precursor complexes or active holo-enzymes serve as the import cargo. Here, we reconcile both models and suggest that the import of inactive precursor complexes predominates in dividing cells, while the import of mature enzymes mainly occurs upon exit from quiescence. Full article
(This article belongs to the Special Issue Nucleocytoplasmic Transport)
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3360 KiB  
Review
Autophagy and Neurodegeneration: Insights from a Cultured Cell Model of ALS
by Francesca Navone, Paola Genevini and Nica Borgese
Cells 2015, 4(3), 354-386; https://doi.org/10.3390/cells4030354 - 06 Aug 2015
Cited by 64 | Viewed by 10802
Abstract
Autophagy plays a major role in the elimination of cellular waste components, the renewal of intracellular proteins and the prevention of the build-up of redundant or defective material. It is fundamental for the maintenance of homeostasis and especially important in post-mitotic neuronal cells, [...] Read more.
Autophagy plays a major role in the elimination of cellular waste components, the renewal of intracellular proteins and the prevention of the build-up of redundant or defective material. It is fundamental for the maintenance of homeostasis and especially important in post-mitotic neuronal cells, which, without competent autophagy, accumulate protein aggregates and degenerate. Many neurodegenerative diseases are associated with defective autophagy; however, whether altered protein turnover or accumulation of misfolded, aggregate-prone proteins is the primary insult in neurodegeneration has long been a matter of debate. Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by selective degeneration of motor neurons. Most of the ALS cases occur in sporadic forms (SALS), while 10%–15% of the cases have a positive familial history (FALS). The accumulation in the cell of misfolded/abnormal proteins is a hallmark of both SALS and FALS, and altered protein degradation due to autophagy dysregulation has been proposed to contribute to ALS pathogenesis. In this review, we focus on the main molecular features of autophagy to provide a framework for discussion of our recent findings about the role in disease pathogenesis of the ALS-linked form of the VAPB gene product, a mutant protein that drives the generation of unusual cytoplasmic inclusions. Full article
(This article belongs to the Special Issue Autophagy)
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11895 KiB  
Article
Non-Overlapping Distributions and Functions of the VDAC Family in Ciliogenesis
by Shubhra Majumder, Ayla Cash and Harold A. Fisk
Cells 2015, 4(3), 331-353; https://doi.org/10.3390/cells4030331 - 31 Jul 2015
Cited by 13 | Viewed by 7466
Abstract
Centrosomes are major microtubule-organizing centers of animal cells that consist of two centrioles. In mitotic cells, centrosomes are duplicated to serve as the poles of the mitotic spindle, while in quiescent cells, centrosomes move to the apical membrane where the oldest centriole is [...] Read more.
Centrosomes are major microtubule-organizing centers of animal cells that consist of two centrioles. In mitotic cells, centrosomes are duplicated to serve as the poles of the mitotic spindle, while in quiescent cells, centrosomes move to the apical membrane where the oldest centriole is transformed into a basal body to assemble a primary cilium. We recently showed that mitochondrial outer membrane porin VDAC3 localizes to centrosomes where it negatively regulates ciliogenesis. We show here that the other two family members, VDAC1 and VDAC2, best known for their function in mitochondrial bioenergetics, are also found at centrosomes. Like VDAC3, centrosomal VDAC1 is predominantly localized to the mother centriole, while VDAC2 localizes to centriolar satellites in a microtubule-dependent manner. Down-regulation of VDAC1 leads to inappropriate ciliogenesis, while its overexpression suppresses cilia formation, suggesting that VDAC1 and VDAC3 both negatively regulate ciliogenesis. However, this negative effect on ciliogenesis is not shared by VDAC2, which instead appears to promote maturation of primary cilia. Moreover, because overexpression of VDAC3 cannot compensate for depletion of VDAC1, our data suggest that while the entire VDAC family localizes to centrosomes, they have non-redundant functions in cilogenesis. Full article
(This article belongs to the Special Issue Cilia and Flagella: Biogenesis and Function)
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1331 KiB  
Review
Cyclic GMP and Cilia Motility
by Todd A. Wyatt
Cells 2015, 4(3), 315-330; https://doi.org/10.3390/cells4030315 - 31 Jul 2015
Cited by 14 | Viewed by 7498
Abstract
Motile cilia of the lungs respond to environmental challenges by increasing their ciliary beat frequency in order to enhance mucociliary clearance as a fundamental tenant of innate defense. One important second messenger in transducing the regulable nature of motile cilia is cyclic guanosine [...] Read more.
Motile cilia of the lungs respond to environmental challenges by increasing their ciliary beat frequency in order to enhance mucociliary clearance as a fundamental tenant of innate defense. One important second messenger in transducing the regulable nature of motile cilia is cyclic guanosine 3′,5′-monophosphate (cGMP). In this review, the history of cGMP action is presented and a survey of the existing data addressing cGMP action in ciliary motility is presented. Nitric oxide (NO)-mediated regulation of cGMP in ciliated cells is presented in the context of alcohol-induced cilia function and dysfunction. Full article
(This article belongs to the Special Issue Cilia and Flagella: Biogenesis and Function)
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3054 KiB  
Review
Novel Insights into the Development and Function of Cilia Using the Advantages of the Paramecium Cell and Its Many Cilia
by Junji Yano, Megan S. Valentine and Judith L. Van Houten
Cells 2015, 4(3), 297-314; https://doi.org/10.3390/cells4030297 - 29 Jul 2015
Cited by 12 | Viewed by 10389
Abstract
Paramecium species, especially P. tetraurelia and caudatum, are model organisms for modern research into the form and function of cilia. In this review, we focus on the ciliary ion channels and other transmembrane proteins that control the beat frequency and wave form [...] Read more.
Paramecium species, especially P. tetraurelia and caudatum, are model organisms for modern research into the form and function of cilia. In this review, we focus on the ciliary ion channels and other transmembrane proteins that control the beat frequency and wave form of the cilium by controlling the signaling within the cilium. We put these discussions in the context of the advantages that Paramecium brings to the understanding of ciliary motility: mutants for genetic dissections of swimming behavior, electrophysiology, structural analysis, abundant cilia for biochemistry and modern proteomics, genomics and molecular biology. We review the connection between behavior and physiology, which allows the cells to broadcast the function of their ciliary channels in real time. We build a case for the important insights and advantages that this model organism continues to bring to the study of cilia. Full article
(This article belongs to the Special Issue Cilia and Flagella: Biogenesis and Function)
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1169 KiB  
Review
Misdelivery at the Nuclear Pore Complex—Stopping a Virus Dead in Its Tracks
by Justin W. Flatt and Urs F. Greber
Cells 2015, 4(3), 277-296; https://doi.org/10.3390/cells4030277 - 28 Jul 2015
Cited by 36 | Viewed by 12350
Abstract
Many viruses deliver their genomes into the host cell’s nucleus before they replicate. While onco-retroviruses and papillomaviruses tether their genomes to host chromatin upon mitotic breakdown of the nuclear envelope, lentiviruses, such as human immunodeficiency virus, adenoviruses, herpesviruses, parvoviruses, influenza viruses, hepatitis B [...] Read more.
Many viruses deliver their genomes into the host cell’s nucleus before they replicate. While onco-retroviruses and papillomaviruses tether their genomes to host chromatin upon mitotic breakdown of the nuclear envelope, lentiviruses, such as human immunodeficiency virus, adenoviruses, herpesviruses, parvoviruses, influenza viruses, hepatitis B virus, polyomaviruses, and baculoviruses deliver their genomes into the nucleus of post-mitotic cells. This poses the significant challenge of slipping a DNA or RNA genome past the nuclear pore complex (NPC) embedded in the nuclear envelope. Quantitative fluorescence imaging is shedding new light on this process, with recent data implicating misdelivery of viral genomes at nuclear pores as a bottleneck to virus replication. Here, we infer NPC functions for nuclear import of viral genomes from cell biology experiments and explore potential causes of misdelivery, including improper virus docking at NPCs, incomplete translocation, virus-induced stress and innate immunity reactions. We conclude by discussing consequences of viral genome misdelivery for viruses and host cells, and lay out future questions to enhance our understanding of this phenomenon. Further studies into viral genome misdelivery may reveal unexpected aspects about NPC structure and function, as well as aid in developing strategies for controlling viral infections to improve human health. Full article
(This article belongs to the Special Issue Nucleocytoplasmic Transport)
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592 KiB  
Editorial
Cells Best Paper Award 2015
by Alexander E. Kalyuzhny
Cells 2015, 4(3), 275-276; https://doi.org/10.3390/cells4030275 - 15 Jul 2015
Viewed by 3394
Abstract
Cells has instituted a “Best Paper” award to recognize the most outstanding papers in the area of cell biology, molecular biology, and biophysics, published in Cells. Full article
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Review
The Possible Roles of the Dentate Granule Cell’s Leptin and Other Ciliary Receptors in Alzheimer’s Neuropathology
by James F. Whitfield, Anna Chiarini, Ilaria Dal Prà, Ubaldo Armato and Balu Chakravarthy
Cells 2015, 4(3), 253-274; https://doi.org/10.3390/cells4030253 - 13 Jul 2015
Cited by 5 | Viewed by 7701
Abstract
Dentate-gyral granule cells in the hippocampus plus dentate gyrus memory-recording/retrieving machine, unlike most other neurons in the brain, are continuously being generated in the adult brain with the important task of separating overlapping patterns of data streaming in from the outside world via [...] Read more.
Dentate-gyral granule cells in the hippocampus plus dentate gyrus memory-recording/retrieving machine, unlike most other neurons in the brain, are continuously being generated in the adult brain with the important task of separating overlapping patterns of data streaming in from the outside world via the entorhinal cortex. This “adult neurogenesis” is driven by tools in the mature granule cell’s cilium. Here we report our discovery of leptin’s LepRb receptor in this cilium. In addition, we discuss how ciliary LepRb signaling might be involved with ciliary p75NTR and SSTR3 receptors in adult neurogenesis and memory formation as well as attenuation of Alzheimer’s neuropathology by reducing the production of its toxic amyloid-β-derived drivers. Full article
(This article belongs to the Special Issue Cilia and Flagella: Biogenesis and Function)
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1543 KiB  
Article
Uremic Toxins Induce ET-1 Release by Human Proximal Tubule Cells, which Regulates Organic Cation Uptake Time-Dependently
by Carolien M. S. Schophuizen, Joost G. J. Hoenderop, Rosalinde Masereeuw and Lambert P. van den Heuvel
Cells 2015, 4(3), 234-252; https://doi.org/10.3390/cells4030234 - 26 Jun 2015
Cited by 5 | Viewed by 5795
Abstract
In renal failure, the systemic accumulation of uremic waste products is strongly associated with the development of a chronic inflammatory state. Here, the effect of cationic uremic toxins on the release of inflammatory cytokines and endothelin-1 (ET-1) was investigated in conditionally immortalized proximal [...] Read more.
In renal failure, the systemic accumulation of uremic waste products is strongly associated with the development of a chronic inflammatory state. Here, the effect of cationic uremic toxins on the release of inflammatory cytokines and endothelin-1 (ET-1) was investigated in conditionally immortalized proximal tubule epithelial cells (ciPTEC). Additionally, we examined the effects of ET-1 on the cellular uptake mediated by organic cation transporters (OCTs). Exposure of ciPTEC to cationic uremic toxins initiated production of the inflammatory cytokines IL-6 (117 ± 3%, p < 0.001), IL-8 (122 ± 3%, p < 0.001), and ET-1 (134 ± 5%, p < 0.001). This was accompanied by a down-regulation of OCT mediated 4-(4-(dimethylamino)styryl)-N-methylpyridinium-iodide (ASP+) uptake in ciPTEC at 30 min (23 ± 4%, p < 0.001), which restored within 60 min of incubation. Exposure to ET-1 for 24 h increased the ASP+ uptake significantly (20 ± 5%, p < 0.001). These effects could be blocked by BQ-788, indicating activation of an ET-B-receptor-mediated signaling pathway. Downstream the receptor, iNOS inhibition by (N(G)‐monomethyl‐l‐arginine) l-NMMA acetate or aminoguanidine, as well as protein kinase C activation, ameliorated the short-term effects. These results indicate that uremia results in the release of cytokines and ET-1 from human proximal tubule cells, in vitro. Furthermore, ET-1 exposure was found to regulate proximal tubular OCT transport activity in a differential, time-dependent, fashion. Full article
(This article belongs to the Special Issue The Kidney: Development, Disease and Regeneration)
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