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The Role of Aquaporins in Ocular Lens Homeostasis.
Schey KL, Petrova RS, Gletten RB, Donaldson PJ
(2017) Int J Mol Sci 18:
MeSH Terms: Animals, Aquaporins, Biological Transport, Active, Eye Proteins, Homeostasis, Humans, Lens, Crystalline, Permeability, Protein Isoforms, Water
Show Abstract · Added April 3, 2018
Aquaporins (AQPs), by playing essential roles in the maintenance of ocular lens homeostasis, contribute to the establishment and maintenance of the overall optical properties of the lens over many decades of life. Three aquaporins, AQP0, AQP1 and AQP5, each with distinctly different functional properties, are abundantly and differentially expressed in the different regions of the ocular lens. Furthermore, the diversity of AQP functionality is increased in the absence of protein turnover by age-related modifications to lens AQPs that are proposed to alter AQP function in the different regions of the lens. These regional differences in AQP functionality are proposed to contribute to the generation and directionality of the lens internal microcirculation; a system of circulating ionic and fluid fluxes that delivers nutrients to and removes wastes from the lens faster than could be achieved by passive diffusion alone. In this review, we present how regional differences in lens AQP isoforms potentially contribute to this microcirculation system by highlighting current areas of investigation and emphasizing areas where future work is required.
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10 MeSH Terms
UNC-45a promotes myosin folding and stress fiber assembly.
Lehtimäki JI, Fenix AM, Kotila TM, Balistreri G, Paavolainen L, Varjosalo M, Burnette DT, Lappalainen P
(2017) J Cell Biol 216: 4053-4072
MeSH Terms: Actomyosin, Cell Adhesion, Cell Line, Tumor, Cell Movement, Cell Polarity, Gene Expression, Humans, Intracellular Signaling Peptides and Proteins, Myosin Type II, Osteoblasts, Proteasome Endopeptidase Complex, Protein Folding, Protein Isoforms, Stress Fibers, Tetratricopeptide Repeat
Show Abstract · Added March 14, 2018
Contractile actomyosin bundles, stress fibers, are crucial for adhesion, morphogenesis, and mechanosensing in nonmuscle cells. However, the mechanisms by which nonmuscle myosin II (NM-II) is recruited to those structures and assembled into functional bipolar filaments have remained elusive. We report that UNC-45a is a dynamic component of actin stress fibers and functions as a myosin chaperone in vivo. UNC-45a knockout cells display severe defects in stress fiber assembly and consequent abnormalities in cell morphogenesis, polarity, and migration. Experiments combining structured-illumination microscopy, gradient centrifugation, and proteasome inhibition approaches revealed that a large fraction of NM-II and myosin-1c molecules fail to fold in the absence of UNC-45a. The remaining properly folded NM-II molecules display defects in forming functional bipolar filaments. The C-terminal UNC-45/Cro1/She4p domain of UNC-45a is critical for NM-II folding, whereas the N-terminal tetratricopeptide repeat domain contributes to the assembly of functional stress fibers. Thus, UNC-45a promotes generation of contractile actomyosin bundles through synchronized NM-II folding and filament-assembly activities.
© 2017 Lehtimäki et al.
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15 MeSH Terms
Implications of the N-terminal heterogeneity for the neuronal K-Cl cotransporter KCC2 function.
Markkanen M, Ludwig A, Khirug S, Pryazhnikov E, Soni S, Khiroug L, Delpire E, Rivera C, Airaksinen MS, Uvarov P
(2017) Brain Res 1675: 87-101
MeSH Terms: Amino Acid Sequence, Animals, Female, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons, Protein Isoforms, Rats, Symporters
Show Abstract · Added April 3, 2018
The neuron-specific K-Cl cotransporter KCC2 maintains the low intracellular chloride concentration required for the fast hyperpolarizing responses of the inhibitory neurotransmitters γ-aminobutyric acid (GABA) and glycine. The two KCC2 isoforms, KCC2a and KCC2b differ by their N-termini as a result of alternative promoter usage. Whereas the role of KCC2b in mediating the chloride transport is unequivocal, the physiological role of KCC2a in neurons has remained obscure. We show that KCC2a isoform can decrease the intracellular chloride concentration in cultured neurons and attenuate calcium responses evoked by application of the GABA receptor agonist muscimol. While the biotinylation assay detected both KCC2 isoforms at the cell surface of cultured neurons, KCC2a was not detected at the plasma membrane in immunostainings, suggesting that the N-terminal KCC2a epitope is masked. Confirming this hypothesis, KCC2a surface expression was detected by the C-terminal KCC2 pan antibody but not by the N-terminal KCC2a antibody in KCC2b-deficient neurons. One possible cause for the epitope masking is the binding site of Ste20-related proline-alanine-rich kinase (SPAK) in the KCC2a N-terminus. SPAK, a known regulator of K-Cl cotransporters, was co-immunoprecipitated in a complex with KCC2a but not KCC2b isoform. Moreover, SPAK overexpression decreased the transport activity of KCC2a but not that of KCC2b, as revealed by rubidium flux assay in HEK293 cells. Thus, our data indicate that both KCC2 isoforms perform as chloride cotransporters in neuronal cells, while their N-terminal heterogeneity could play an important role in fine-tuning of the K-Cl transport activity.
Copyright © 2017 Elsevier B.V. All rights reserved.
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13 MeSH Terms
Associations of Vitamin D-Binding Globulin and Bioavailable Vitamin D Concentrations With Coronary Heart Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA).
Robinson-Cohen C, Zelnick LR, Hoofnagle AN, Lutsey PL, Burke G, Michos ED, Shea SJC, Tracy R, Siscovick DS, Psaty B, Kestenbaum B, de Boer IH
(2017) J Clin Endocrinol Metab 102: 3075-3084
MeSH Terms: African Americans, Aged, Aged, 80 and over, Asian Continental Ancestry Group, Biological Availability, Case-Control Studies, Coronary Disease, European Continental Ancestry Group, Female, Hispanic Americans, Humans, Male, Mass Spectrometry, Middle Aged, Proportional Hazards Models, Protein Isoforms, Risk Factors, United States, Vitamin D, Vitamin D-Binding Protein
Show Abstract · Added September 19, 2017
Context - Low 25-hydroxyvitamin D [25(OH)D] is associated with coronary heart disease (CHD) in people who are white and Chinese but not black or Hispanic. Vitamin D binding globulin (VDBG) avidly binds 25(OH)D, reducing its bioavailability, and differs in isoform and concentration by race.
Objective - Evaluate associations of VDBG with CHD and whether accounting for VDBG or estimating bioavailable 25(OH)D explains the heterogeneity of the association of 25(OH)D with CHD.
Design and Setting - We conducted a case-cohort study within the Multi-Ethnic Study of Atherosclerosis. Participants with an incident CHD event over 12 years of follow-up (n = 538) and a randomly assigned subcohort (n = 999) were included. We measured baseline 25(OH)D, VDBG, and isoforms using mass spectrometry and estimated bioavailable 25(OH)D from published equations.
Results - VDBG was associated with an increased risk of CHD [hazard ratio, 1.77 (95% confidence interval, 1.46 to 2.14) per standard deviation increment, P < 0.0001], without evidence of heterogeneity by race or isoform (each P for interaction > 0.1). Low total 25(OH)D was differentially associated with CHD events, by race, with or without adjustment for VDBG (P for interaction = 0.04 or 0.05, respectively). Associations of 25(OH)D with CHD were strengthened with adjustment for VDBG among participants who were white or Chinese, and bioavailable 25(OH)D was associated with CHD events only among white participants.
Conclusions - High VDBG concentration was associated with CHD events in all racial and ethnic groups. Incorporation of VDBG strengthened existing associations of 25(OH)D with CHD but did not explain racial heterogeneity in associations of 25(OH)D with CHD.
Copyright © 2017 Endocrine Society
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20 MeSH Terms
The nature and biology of basement membranes.
Pozzi A, Yurchenco PD, Iozzo RV
(2017) Matrix Biol 57-58: 1-11
MeSH Terms: Agrin, Animals, Basement Membrane, Bone Diseases, Developmental, Collagen Type IV, Diabetic Nephropathies, Extracellular Matrix, Gene Expression Regulation, Heparan Sulfate Proteoglycans, Humans, Laminin, Lupus Nephritis, Mechanotransduction, Cellular, Membrane Glycoproteins, Mutation, Protein Isoforms
Show Abstract · Added March 26, 2017
Basement membranes are delicate, nanoscale and pliable sheets of extracellular matrices that often act as linings or partitions in organisms. Previously considered as passive scaffolds segregating polarized cells, such as epithelial or endothelial cells, from the underlying mesenchyme, basement membranes have now reached the center stage of biology. They play a multitude of roles from blood filtration to muscle homeostasis, from storing growth factors and cytokines to controlling angiogenesis and tumor growth, from maintaining skin integrity and neuromuscular structure to affecting adipogenesis and fibrosis. Here, we will address developmental, structural and biochemical aspects of basement membranes and discuss some of the pathogenetic mechanisms causing diseases linked to abnormal basement membranes.
Copyright © 2017 Elsevier B.V. All rights reserved.
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16 MeSH Terms
Regulation of KCNQ/Kv7 family voltage-gated K channels by lipids.
Taylor KC, Sanders CR
(2017) Biochim Biophys Acta Biomembr 1859: 586-597
MeSH Terms: Amino Acid Sequence, Binding Sites, Cell Membrane, Epilepsy, Benign Neonatal, Fatty Acids, Unsaturated, Hearing Loss, Bilateral, Humans, Hydrophobic and Hydrophilic Interactions, KCNQ1 Potassium Channel, Long QT Syndrome, Membrane Lipids, Models, Molecular, Phosphatidylinositol 4,5-Diphosphate, Protein Binding, Protein Isoforms, Protein Structure, Secondary
Show Abstract · Added November 21, 2018
Many years of studies have established that lipids can impact membrane protein structure and function through bulk membrane effects, by direct but transient annular interactions with the bilayer-exposed surface of protein transmembrane domains, and by specific binding to protein sites. Here, we focus on how phosphatidylinositol 4,5-bisphosphate (PIP) and polyunsaturated fatty acids (PUFAs) impact ion channel function and how the structural details of the interactions of these lipids with ion channels are beginning to emerge. We focus on the Kv7 (KCNQ) subfamily of voltage-gated K channels, which are regulated by both PIP and PUFAs and play a variety of important roles in human health and disease. This article is part of a Special Issue entitled: Lipid order/lipid defects and lipid-control of protein activity edited by Dirk Schneider.
Copyright © 2016 Elsevier B.V. All rights reserved.
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MeSH Terms
High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML.
Zhao Y, Liu Q, Acharya P, Stengel KR, Sheng Q, Zhou X, Kwak H, Fischer MA, Bradner JE, Strickland SA, Mohan SR, Savona MR, Venters BJ, Zhou MM, Lis JT, Hiebert SW
(2016) Cell Rep 16: 2003-16
MeSH Terms: Antineoplastic Agents, Azepines, Cell Line, Tumor, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Clustered Regularly Interspaced Short Palindromic Repeats, DNA-Directed RNA Polymerases, Drug Resistance, Neoplasm, Enhancer Elements, Genetic, Gene Expression Regulation, Leukemic, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Myeloid, Acute, MicroRNAs, Multigene Family, Myeloid Cell Leukemia Sequence 1 Protein, Promoter Regions, Genetic, Protein Isoforms, Proteins, Proto-Oncogene Proteins c-kit, Transcription, Genetic, Translocation, Genetic, Triazoles
Show Abstract · Added April 6, 2017
Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML. PRO-seq also identified an enhancer 3' to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRNAs, including MIR29C and MIR29B2, that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was upregulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET-inhibitor-induced cell death.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
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23 MeSH Terms
Prostaglandin E2 receptor EP3 regulates both adipogenesis and lipolysis in mouse white adipose tissue.
Xu H, Fu JL, Miao YF, Wang CJ, Han QF, Li S, Huang SZ, Du SN, Qiu YX, Yang JC, Gustafsson JÅ, Breyer RM, Zheng F, Wang NP, Zhang XY, Guan YF
(2016) J Mol Cell Biol 8: 518-529
MeSH Terms: Adipocytes, Adipogenesis, Adipose Tissue, White, Animals, Cell Differentiation, Gene Deletion, Inflammation, Insulin Resistance, Lipolysis, Lipoproteins, VLDL, Mice, Mice, Obese, Obesity, Phenotype, Protein Isoforms, Rats, Sprague-Dawley, Receptors, Prostaglandin E, EP3 Subtype, Signal Transduction, Triglycerides
Show Abstract · Added February 7, 2019
Among the four prostaglandin E2 receptors, EP3 receptor is the one most abundantly expressed in white adipose tissue (WAT). The mouse EP3 gene gives rise to three isoforms, namely EP3α, EP3β, and EP3γ, which differ only at their C-terminal tails. To date, functions of EP3 receptor and its isoforms in WAT remain incompletely characterized. In this study, we found that the expression of all EP3 isoforms were downregulated in WAT of both db/db and high-fat diet-induced obese mice. Genetic ablation of three EP3 receptor isoforms (EP3 mice) or EP3α and EP3γ isoforms with EP3β intact (EP3β mice) led to an obese phenotype with increased food intake, decreased motor activity, reduced insulin sensitivity, and elevated serum triglycerides. Since the differentiation of preadipocytes and mouse embryonic fibroblasts to adipocytes was markedly facilitated by either pharmacological blockade or genetic deletion/inhibition of EP3 receptor via the cAMP/PKA/PPARγ pathway, increased adipogenesis may contribute to obesity in EP3 and EP3β mice. Moreover, both EP3 and EP3β mice had increased lipolysis in WAT mainly due to the activated cAMP/PKA/hormone-sensitive lipase pathway. Taken together, our findings suggest that EP3 receptor and its α and γ isoforms are involved in both adipogenesis and lipolysis and influence food intake, serum lipid levels, and insulin sensitivity.
© The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.
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MeSH Terms
An amyotrophic lateral sclerosis-linked mutation in GLE1 alters the cellular pool of human Gle1 functional isoforms.
Aditi , Glass L, Dawson TR, Wente SR
(2016) Adv Biol Regul 62: 25-36
MeSH Terms: Amyotrophic Lateral Sclerosis, Animals, Cytoplasm, Cytoplasmic Granules, Gene Expression, HeLa Cells, Humans, Mutagenesis, Insertional, Nuclear Envelope, Nucleocytoplasmic Transport Proteins, Phytic Acid, Point Mutation, Protein Aggregates, Protein Isoforms, RNA, Small Interfering
Show Abstract · Added February 15, 2016
Amyotrophic lateral sclerosis (ALS) is a lethal late onset motor neuron disease with underlying cellular defects in RNA metabolism. In prior studies, two deleterious heterozygous mutations in the gene encoding human (h)Gle1 were identified in ALS patients. hGle1 is an mRNA processing modulator that requires inositol hexakisphosphate (IP) binding for function. Interestingly, one hGLE1 mutation (c.1965-2A>C) results in a novel 88 amino acid C-terminal insertion, generating an altered protein. Like hGle1A, at steady state, the altered protein termed hGle1-IVS14-2A>C is absent from the nuclear envelope rim and localizes to the cytoplasm. hGle1A performs essential cytoplasmic functions in translation and stress granule regulation. Therefore, we speculated that the ALS disease pathology results from altered cellular pools of hGle1 and increased cytoplasmic hGle1 activity. GFP-hGle1-IVS14-2A>C localized to stress granules comparably to GFP-hGle1A, and rescued stress granule defects following siRNA-mediated hGle1 depletion. As described for hGle1A, overexpression of the hGle1-IVS14-2A>C protein also induced formation of larger SGs. Interestingly, hGle1A and the disease associated hGle1-IVS14-2A>C overexpression induced the formation of distinct cytoplasmic protein aggregates that appear similar to those found in neurodegenerative diseases. Strikingly, the ALS-linked hGle1-IVS14-2A>C protein also rescued mRNA export defects upon depletion of endogenous hGle1, acting in a potentially novel bi-functional manner. We conclude that the ALS-linked hGle1-c.1965-2A>C mutation generates a protein isoform capable of both hGle1A- and hGle1B-ascribed functions, and thereby uncoupled from normal mechanisms of hGle1 regulation.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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15 MeSH Terms
Identification of a Novel Transcript and Regulatory Mechanism for Microsomal Triglyceride Transfer Protein.
Suzuki T, Brown JJ, Swift LL
(2016) PLoS One 11: e0147252
MeSH Terms: Alternative Splicing, Animals, CHO Cells, Carrier Proteins, Cricetulus, Electrophoresis, Polyacrylamide Gel, Female, HEK293 Cells, Humans, Mice, Protein Isoforms, RNA, Messenger, Rabbits, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added February 22, 2016
Microsomal triglyceride transfer protein (MTP) is essential for the assembly of triglyceride-rich apolipoprotein B-containing lipoproteins. Previous studies in our laboratory identified a novel splice variant of MTP in mice that we named MTP-B. MTP-B has a unique first exon (1B) located 2.7 kB upstream of the first exon (1A) for canonical MTP (MTP-A). The two mature isoforms, though nearly identical in sequence and function, have different tissue expression patterns. In this study we report the identification of a second MTP splice variant (MTP-C), which contains both exons 1B and 1A. MTP-C is expressed in all the tissues we tested. In cells transfected with MTP-C, protein expression was less than 15% of that found when the cells were transfected with MTP-A or MTP-B. In silico analysis of the 5'-UTR of MTP-C revealed seven ATGs upstream of the start site for MTP-A, which is the only viable start site in frame with the main coding sequence. One of those ATGs was located in the 5'-UTR for MTP-A. We generated reporter constructs in which the 5'-UTRs of MTP-A or MTP-C were inserted between an SV40 promoter and the coding sequence of the luciferase gene and transfected these constructs into HEK 293 cells. Luciferase activity was significantly reduced by the MTP-C 5'-UTR, but not by the MTP-A 5'-UTR. We conclude that alternative splicing plays a key role in regulating MTP expression by introducing unique 5'-UTRs, which contain elements that alter translation efficiency, enabling the cell to optimize MTP levels and activity.
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14 MeSH Terms