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Microtubule motors power plasma membrane tubulation in clathrin-independent endocytosis.
Day CA, Baetz NW, Copeland CA, Kraft LJ, Han B, Tiwari A, Drake KR, De Luca H, Chinnapen DJ, Davidson MW, Holmes RK, Jobling MG, Schroer TA, Lencer WI, Kenworthy AK
(2015) Traffic 16: 572-90
MeSH Terms: Animals, COS Cells, Cell Membrane, Cercopithecus aethiops, Cholera Toxin, Clathrin, Dyneins, Endocytosis, HeLa Cells, Humans, Microtubules, Protein Binding, Receptors, Transferrin
Show Abstract · Added February 12, 2016
How the plasma membrane is bent to accommodate clathrin-independent endocytosis remains uncertain. Recent studies suggest Shiga and cholera toxin induce membrane curvature required for their uptake into clathrin-independent carriers by binding and cross-linking multiple copies of their glycosphingolipid receptors on the plasma membrane. But it remains unclear if toxin-induced sphingolipid crosslinking provides sufficient mechanical force for deforming the plasma membrane, or if host cell factors also contribute to this process. To test this, we imaged the uptake of cholera toxin B-subunit into surface-derived tubular invaginations. We found that cholera toxin mutants that bind to only one glycosphingolipid receptor accumulated in tubules, and that toxin binding was entirely dispensable for membrane tubulations to form. Unexpectedly, the driving force for tubule extension was supplied by the combination of microtubules, dynein and dynactin, thus defining a novel mechanism for generating membrane curvature during clathrin-independent endocytosis.
© 2015 The Authors. Traffic published by John Wiley & Sons Ltd.
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13 MeSH Terms
asunder is required for dynein localization and dorsal fate determination during Drosophila oogenesis.
Sitaram P, Merkle JA, Lee E, Lee LA
(2014) Dev Biol 386: 42-52
MeSH Terms: Alleles, Animals, Body Patterning, Cell Cycle Proteins, Cell Lineage, Cell Nucleus, Centrosome, Drosophila, Drosophila Proteins, Dyneins, Female, Gene Expression Regulation, Developmental, Genotype, Homozygote, In Situ Hybridization, Male, Oocytes, Oogenesis, Ovary, Phenotype, Sex Factors, Testis, Transgenes
Show Abstract · Added March 5, 2014
We previously showed that asunder (asun) is a critical regulator of dynein localization during Drosophila spermatogenesis. Because the expression of asun is much higher in Drosophila ovaries and early embryos than in testes, we herein sought to determine whether ASUN plays roles in oogenesis and/or embryogenesis. We characterized the female germline phenotypes of flies homozygous for a null allele of asun (asun(d93)). We find that asun(d93) females lay very few eggs and contain smaller ovaries with a highly disorganized arrangement of ovarioles in comparison to wild-type females. asun(d93) ovaries also contain a significant number of egg chambers with structural defects. A majority of the eggs laid by asun(d93) females are ventralized to varying degrees, from mild to severe; this ventralization phenotype may be secondary to defective localization of gurken transcripts, a dynein-regulated step, within asun(d93) oocytes. We find that dynein localization is aberrant in asun(d93) oocytes, indicating that ASUN is required for this process in both male and female germ cells. In addition to the loss of gurken mRNA localization, asun(d93) ovaries exhibit defects in other dynein-mediated processes such as migration of nurse cell centrosomes into the oocyte during the early mitotic divisions, maintenance of the oocyte nucleus in the anterior-dorsal region of the oocyte in late-stage egg chambers, and coupling between the oocyte nucleus and centrosomes. Taken together, our data indicate that asun is a critical regulator of dynein localization and dynein-mediated processes during Drosophila oogenesis.
Copyright © 2013 Elsevier Inc. All rights reserved.
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23 MeSH Terms
Nuclear-localized Asunder regulates cytoplasmic dynein localization via its role in the integrator complex.
Jodoin JN, Sitaram P, Albrecht TR, May SB, Shboul M, Lee E, Reversade B, Wagner EJ, Lee LA
(2013) Mol Biol Cell 24: 2954-65
MeSH Terms: Amino Acid Sequence, Animals, Carrier Proteins, Cell Cycle Proteins, Cell Division, Cell Nucleus, Cytoplasmic Dyneins, Drosophila Proteins, Drosophila melanogaster, G2 Phase, HeLa Cells, Humans, Male, Molecular Sequence Data, Multiprotein Complexes, Nuclear Envelope, Nuclear Localization Signals, Protein Subunits, Protein Transport, RNA, Small Interfering, Spermatocytes, Subcellular Fractions
Show Abstract · Added March 5, 2014
We previously reported that Asunder (ASUN) is essential for recruitment of dynein motors to the nuclear envelope (NE) and nucleus-centrosome coupling at the onset of cell division in cultured human cells and Drosophila spermatocytes, although the mechanisms underlying this regulation remain unknown. We also identified ASUN as a functional component of Integrator (INT), a multisubunit complex required for 3'-end processing of small nuclear RNAs. We now provide evidence that ASUN acts in the nucleus in concert with other INT components to mediate recruitment of dynein to the NE. Knockdown of other individual INT subunits in HeLa cells recapitulates the loss of perinuclear dynein in ASUN-small interfering RNA cells. Forced localization of ASUN to the cytoplasm via mutation of its nuclear localization sequence blocks its capacity to restore perinuclear dynein in both cultured human cells lacking ASUN and Drosophila asun spermatocytes. In addition, the levels of several INT subunits are reduced at G2/M when dynein is recruited to the NE, suggesting that INT does not directly mediate this step. Taken together, our data support a model in which a nuclear INT complex promotes recruitment of cytoplasmic dynein to the NE, possibly via a mechanism involving RNA processing.
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22 MeSH Terms
Human Asunder promotes dynein recruitment and centrosomal tethering to the nucleus at mitotic entry.
Jodoin JN, Shboul M, Sitaram P, Zein-Sabatto H, Reversade B, Lee E, Lee LA
(2012) Mol Biol Cell 23: 4713-24
MeSH Terms: 1-Alkyl-2-acetylglycerophosphocholine Esterase, Animals, Carrier Proteins, Cell Cycle Proteins, Cell Line, Tumor, Cell Nucleus, Centrosome, Chromosomal Proteins, Non-Histone, Drosophila melanogaster, Dyneins, Female, G2 Phase, Genetic Complementation Test, HEK293 Cells, HeLa Cells, Humans, Immunoblotting, Male, Mice, Microfilament Proteins, Microscopy, Fluorescence, Microtubule-Associated Proteins, Mitosis, Mutation, Nuclear Pore, Protein Binding, RNA Interference, Spindle Apparatus
Show Abstract · Added March 5, 2014
Recruitment of dynein motors to the nuclear surface is an essential step for nucleus-centrosome coupling in prophase. In cultured human cells, this dynein pool is anchored to nuclear pore complexes through RanBP2-Bicaudal D2 (BICD2) and Nup133- centromere protein F (CENP-F) networks. We previously reported that the asunder (asun) gene is required in Drosophila spermatocytes for perinuclear dynein localization and nucleus-centrosome coupling at G2/M of male meiosis. We show here that male germline expression of mammalian Asunder (ASUN) protein rescues asun flies, demonstrating evolutionary conservation of function. In cultured human cells, we find that ASUN down-regulation causes reduction of perinuclear dynein in prophase of mitosis. Additional defects after loss of ASUN include nucleus-centrosome uncoupling, abnormal spindles, and multinucleation. Coimmunoprecipitation and overlapping localization patterns of ASUN and lissencephaly 1 (LIS1), a dynein adaptor, suggest that ASUN interacts with dynein in the cytoplasm via LIS1. Our data indicate that ASUN controls dynein localization via a mechanism distinct from that of either BICD2 or CENP-F. We present a model in which ASUN promotes perinuclear enrichment of dynein at G2/M that facilitates BICD2- and CENP-F-mediated anchoring of dynein to nuclear pore complexes.
1 Communities
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28 MeSH Terms
Regulation of dynein localization and centrosome positioning by Lis-1 and asunder during Drosophila spermatogenesis.
Sitaram P, Anderson MA, Jodoin JN, Lee E, Lee LA
(2012) Development 139: 2945-54
MeSH Terms: Animals, Animals, Genetically Modified, Cell Cycle Proteins, Centrosome, Drosophila Proteins, Drosophila melanogaster, Dynactin Complex, Dyneins, Humans, Male, Microtubule-Associated Proteins, Models, Biological, Phenotype, Spermatids, Spermatocytes, Spermatogenesis
Show Abstract · Added March 5, 2014
Dynein, a microtubule motor complex, plays crucial roles in cell-cycle progression in many systems. The LIS1 accessory protein directly binds dynein, although its precise role in regulating dynein remains unclear. Mutation of human LIS1 causes lissencephaly, a developmental brain disorder. To gain insight into the in vivo functions of LIS1, we characterized a male-sterile allele of the Drosophila homolog of human LIS1. We found that centrosomes do not properly detach from the cell cortex at the onset of meiosis in most Lis-1 spermatocytes; centrosomes that do break cortical associations fail to attach to the nucleus. In Lis-1 spermatids, we observed loss of attachments between the nucleus, basal body and mitochondria. The localization pattern of LIS-1 protein throughout Drosophila spermatogenesis mirrors that of dynein. We show that dynein recruitment to the nuclear surface and spindle poles is severely reduced in Lis-1 male germ cells. We propose that Lis-1 spermatogenesis phenotypes are due to loss of dynein regulation, as we observed similar phenotypes in flies null for Tctex-1, a dynein light chain. We have previously identified asunder (asun) as another regulator of dynein localization and centrosome positioning during Drosophila spermatogenesis. We now report that Lis-1 is a strong dominant enhancer of asun and that localization of LIS-1 in male germ cells is ASUN dependent. We found that Drosophila LIS-1 and ASUN colocalize and coimmunoprecipitate from transfected cells, suggesting that they function within a common complex. We present a model in which Lis-1 and asun cooperate to regulate dynein localization and centrosome positioning during Drosophila spermatogenesis.
1 Communities
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16 MeSH Terms
Adropin deficiency is associated with increased adiposity and insulin resistance.
Ganesh Kumar K, Zhang J, Gao S, Rossi J, McGuinness OP, Halem HH, Culler MD, Mynatt RL, Butler AA
(2012) Obesity (Silver Spring) 20: 1394-402
MeSH Terms: Adiposity, Animals, Axonemal Dyneins, Blood Glucose, Dietary Carbohydrates, Dietary Fats, Dyslipidemias, Eating, Energy Metabolism, Fasting, Fatty Liver, Female, Glucose Clamp Technique, Insulin Resistance, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Proteins
Show Abstract · Added July 21, 2014
Adropin is a secreted peptide that improves hepatic steatosis and glucose homeostasis when administered to diet-induced obese mice. It is not clear if adropin is a peptide hormone regulated by signals of metabolic state. Moreover, the significance of a decline in adropin expression with obesity with respect to metabolic disease is also not clear. We investigated the regulation of serum adropin by metabolic status and diet. Serum adropin levels were high in chow-fed conditions and were suppressed by fasting and diet-induced obesity (DIO). High adropin levels were observed in mice fed a high-fat low carbohydrate diet, whereas lower levels were observed in mice fed a low-fat high carbohydrate diet. To investigate the role of adropin deficiency in metabolic homeostasis, we generated adropin knockout mice (AdrKO) on the C57BL/6J background. AdrKO displayed a 50%-increase in increase in adiposity, although food intake and energy expenditure were normal. AdrKO also exhibited dyslipidemia and impaired suppression of endogenous glucose production (EndoR(a)) in hyperinsulinemic-euglycemic clamp conditions, suggesting insulin resistance. While homo- and heterozygous carriers of the null adropin allele exhibited normal DIO relative to controls, impaired glucose tolerance associated with weight gain was more severe in both groups. In summary, adropin is a peptide hormone regulated by fasting and feeding. In fed conditions, adropin levels are regulated dietary macronutrients, and increase with dietary fat content. Adropin is not required for regulating food intake, however, its functions impact on adiposity and are involved in preventing insulin resistance, dyslipidemia, and impaired glucose tolerance.
1 Communities
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19 MeSH Terms
Cdk1 phosphorylation of the kinetochore protein Nsk1 prevents error-prone chromosome segregation.
Chen JS, Lu LX, Ohi MD, Creamer KM, English C, Partridge JF, Ohi R, Gould KL
(2011) J Cell Biol 195: 583-93
MeSH Terms: CDC2 Protein Kinase, Cell Cycle Proteins, Chromosome Segregation, Chromosomes, Fungal, Dyneins, Kinetochores, Microtubules, Mitosis, Phosphorylation, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Spindle Apparatus
Show Abstract · Added March 5, 2014
Cdk1 controls many aspects of mitotic chromosome behavior and spindle microtubule (MT) dynamics to ensure accurate chromosome segregation. In this paper, we characterize a new kinetochore substrate of fission yeast Cdk1, Nsk1, which promotes proper kinetochore-MT (k-MT) interactions and chromosome movements in a phosphoregulated manner. Cdk1 phosphorylation of Nsk1 antagonizes Nsk1 kinetochore and spindle localization during early mitosis. A nonphosphorylatable Nsk1 mutant binds prematurely to kinetochores and spindle, cementing improper k-MT attachments and leading to high rates of lagging chromosomes that missegregate. Accordingly, cells lacking nsk1 exhibit synthetic growth defects with mutations that disturb MT dynamics and/or kinetochore structure, and lack of proper phosphoregulation leads to even more severe defects. Intriguingly, Nsk1 is stabilized by binding directly to the dynein light chain Dlc1 independently of the dynein motor, and Nsk1-Dlc1 forms chainlike structures in vitro. Our findings establish new roles for Cdk1 and the Nsk1-Dlc1 complex in regulating the k-MT interface and chromosome segregation.
© 2011 Chen et al.
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12 MeSH Terms
Golgi-derived CLASP-dependent microtubules control Golgi organization and polarized trafficking in motile cells.
Miller PM, Folkmann AW, Maia AR, Efimova N, Efimov A, Kaverina I
(2009) Nat Cell Biol 11: 1069-80
MeSH Terms: Biological Transport, Cell Line, Cell Movement, Cell Polarity, Centrosome, Dyneins, Golgi Apparatus, Humans, Microtubule-Associated Proteins, Microtubules, Mitosis
Show Abstract · Added December 10, 2013
Microtubules are indispensable for Golgi complex assembly and maintenance, which are integral parts of cytoplasm organization during interphase in mammalian cells. Here, we show that two discrete microtubule subsets drive two distinct, yet simultaneous, stages of Golgi assembly. In addition to the radial centrosomal microtubule array, which positions the Golgi in the centre of the cell, we have identified a role for microtubules that form at the Golgi membranes in a manner dependent on the microtubule regulators CLASPs. These Golgi-derived microtubules draw Golgi ministacks together in tangential fashion and are crucial for establishing continuity and proper morphology of the Golgi complex. We propose that specialized functions of these two microtubule arrays arise from their specific geometries. Further, we demonstrate that directional post-Golgi trafficking and cell migration depend on Golgi-associated CLASPs, suggesting that correct organization of the Golgi complex by microtubules is essential for cell polarization and motility.
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11 MeSH Terms
Asunder is a critical regulator of dynein-dynactin localization during Drosophila spermatogenesis.
Anderson MA, Jodoin JN, Lee E, Hales KG, Hays TS, Lee LA
(2009) Mol Biol Cell 20: 2709-21
MeSH Terms: Animals, Animals, Genetically Modified, Cell Cycle Proteins, Cell Nucleus, Chromosome Segregation, Drosophila Proteins, Drosophila melanogaster, Dynactin Complex, Dyneins, Fertility, Green Fluorescent Proteins, HeLa Cells, Humans, Immunoblotting, Infertility, Male, Male, Meiosis, Microscopy, Fluorescence, Microtubule-Associated Proteins, Mutation, Reverse Transcriptase Polymerase Chain Reaction, Spermatids, Spermatocytes, Spermatogenesis, Spindle Apparatus, Transfection
Show Abstract · Added March 5, 2014
Spermatogenesis uses mitotic and meiotic cell cycles coordinated with growth and differentiation programs to generate functional sperm. Our analysis of a Drosophila mutant has revealed that asunder (asun), which encodes a conserved protein, is an essential regulator of spermatogenesis. asun spermatocytes arrest during prophase of meiosis I. Strikingly, arrested spermatocytes contain free centrosomes that fail to stably associate with the nucleus. Spermatocytes that overcome arrest exhibit severe defects in meiotic spindle assembly, chromosome segregation, and cytokinesis. Furthermore, the centriole-derived basal body is detached from the nucleus in asun postmeiotic spermatids, resulting in abnormalities later in spermatogenesis. We find that asun spermatocytes and spermatids exhibit drastic reduction of perinuclear dynein-dynactin, a microtubule motor complex. We propose a model in which asun coordinates spermatogenesis by promoting dynein-dynactin recruitment to the nuclear surface, a poorly understood process required for nucleus-centrosome coupling at M phase entry and fidelity of meiotic divisions.
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26 MeSH Terms
Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice.
Allocca M, Doria M, Petrillo M, Colella P, Garcia-Hoyos M, Gibbs D, Kim SR, Maguire A, Rex TS, Di Vicino U, Cutillo L, Sparrow JR, Williams DS, Bennett J, Auricchio A
(2008) J Clin Invest 118: 1955-64
MeSH Terms: ATP-Binding Cassette Transporters, Animals, Antigens, Neoplasm, Dependovirus, Dyneins, Electroretinography, Gene Transfer Techniques, Genetic Therapy, Genetic Vectors, Humans, Mice, Mice, Inbred BALB C, Mice, Knockout, Molecular Sequence Data, Myosins, Neoplasm Proteins, Retina, Serotyping
Show Abstract · Added January 20, 2015
Vectors derived from adeno-associated virus (AAV) are promising for human gene therapy, including treatment for retinal blindness. One major limitation of AAVs as vectors is that AAV cargo capacity has been considered to be restricted to 4.7 kb. Here we demonstrate that vectors with an AAV5 capsid (i.e., rAAV2/5) incorporated up to 8.9 kb of genome more efficiently than 6 other serotypes tested, independent of the efficiency of the rAAV2/5 production process. Efficient packaging of the large murine Abca4 and human MYO7A and CEP290 genes, which are mutated in common blinding diseases, was obtained, suggesting that this packaging efficiency is independent of the specific sequence packaged. Expression of proteins of the appropriate size and function was observed following transduction with rAAV2/5 carrying large genes. Intraocular administration of rAAV2/5 encoding ABCA4 resulted in protein localization to rod outer segments and significant and stable morphological and functional improvement of the retina in Abca4(-/-) mice. This use of rAAV2/5 may be a promising therapeutic strategy for recessive Stargardt disease, the most common form of inherited macular degeneration. The possibility of packaging large genes in AAV greatly expands the therapeutic potential of this vector system.
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18 MeSH Terms