Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 86

Publication Record

Connections

Nup42 and IP coordinate Gle1 stimulation of Dbp5/DDX19B for mRNA export in yeast and human cells.
Adams RL, Mason AC, Glass L, Aditi , Wente SR
(2017) Traffic 18: 776-790
MeSH Terms: Active Transport, Cell Nucleus, DEAD-box RNA Helicases, Humans, Nuclear Pore, Nuclear Pore Complex Proteins, Nucleocytoplasmic Transport Proteins, Phytic Acid, RNA, Messenger, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Show Abstract · Added March 30, 2018
The mRNA lifecycle is driven through spatiotemporal changes in the protein composition of mRNA particles (mRNPs) that are triggered by RNA-dependent DEAD-box protein (Dbp) ATPases. As mRNPs exit the nuclear pore complex (NPC) in Saccharomyces cerevisiae, this remodeling occurs through activation of Dbp5 by inositol hexakisphosphate (IP )-bound Gle1. At the NPC, Gle1 also binds Nup42, but Nup42's molecular function is unclear. Here we employ the power of structure-function analysis in S. cerevisiae and human (h) cells, and find that the high-affinity Nup42-Gle1 interaction is integral to Dbp5 (hDDX19B) activation and efficient mRNA export. The Nup42 carboxy-terminal domain (CTD) binds Gle1/hGle1B at an interface distinct from the Gle1-Dbp5/hDDX19B interaction site. A nup42-CTD/gle1-CTD/Dbp5 trimeric complex forms in the presence of IP . Deletion of NUP42 abrogates Gle1-Dbp5 interaction, and disruption of the Nup42 or IP binding interfaces on Gle1/hGle1B leads to defective mRNA export in S. cerevisiae and human cells. In vitro, Nup42-CTD and IP stimulate Gle1/hGle1B activation of Dbp5 and DDX19B recombinant proteins in similar, nonadditive manners, demonstrating complete functional conservation between humans and S. cerevisiae. Together, a highly conserved mechanism governs spatial coordination of mRNP remodeling during export. This has implications for understanding human disease mutations that perturb the Nup42-hGle1B interaction.
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
0 Communities
1 Members
0 Resources
10 MeSH Terms
A role for Gle1, a regulator of DEAD-box RNA helicases, at centrosomes and basal bodies.
Jao LE, Akef A, Wente SR
(2017) Mol Biol Cell 28: 120-127
MeSH Terms: Active Transport, Cell Nucleus, Adenosine Triphosphatases, Antigens, Basal Bodies, Centrosome, DEAD-box RNA Helicases, Nuclear Pore, Nuclear Pore Complex Proteins, Nucleocytoplasmic Transport Proteins, Protein Binding, RNA Transport, RNA, Messenger, RNA-Binding Proteins, Zebrafish Proteins
Show Abstract · Added April 14, 2017
Control of organellar assembly and function is critical to eukaryotic homeostasis and survival. Gle1 is a highly conserved regulator of RNA-dependent DEAD-box ATPase proteins, with critical roles in both mRNA export and translation. In addition to its well-defined interaction with nuclear pore complexes, here we find that Gle1 is enriched at the centrosome and basal body. Gle1 assembles into the toroid-shaped pericentriolar material around the mother centriole. Reduced Gle1 levels are correlated with decreased pericentrin localization at the centrosome and microtubule organization defects. Of importance, these alterations in centrosome integrity do not result from loss of mRNA export. Examination of the Kupffer's vesicle in Gle1-depleted zebrafish revealed compromised ciliary beating and developmental defects. We propose that Gle1 assembly into the pericentriolar material positions the DEAD-box protein regulator to function in localized mRNA metabolism required for proper centrosome function.
© 2017 Jao et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
0 Communities
1 Members
0 Resources
14 MeSH Terms
Nup100 regulates replicative life span by mediating the nuclear export of specific tRNAs.
Lord CL, Ospovat O, Wente SR
(2017) RNA 23: 365-377
MeSH Terms: Active Transport, Cell Nucleus, Basic-Leucine Zipper Transcription Factors, Blotting, Northern, Cell Division, Cell Nucleus, Culture Media, Gene Expression Regulation, Fungal, In Situ Hybridization, Fluorescence, Karyopherins, Nuclear Pore, Nuclear Pore Complex Proteins, RNA, Fungal, RNA, Transfer, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Time Factors
Show Abstract · Added April 14, 2017
Nuclear pore complexes (NPCs), which are composed of nucleoporins (Nups) and regulate transport between the nucleus and cytoplasm, significantly impact the replicative life span (RLS) of We previously reported that deletion of the nonessential gene increases RLS, although the molecular basis for this effect was unknown. In this study, we find that nuclear tRNA accumulation contributes to increased longevity in Δ cells. Fluorescence in situ hybridization (FISH) experiments demonstrate that several specific tRNAs accumulate in the nuclei of Δ mutants. Protein levels of the transcription factor Gcn4 are increased when is deleted, and is required for the elevated life spans of Δ mutants, similar to other previously described tRNA export and ribosomal mutants. Northern blots indicate that tRNA splicing and aminoacylation are not significantly affected in Δ cells, suggesting that Nup100 is largely required for nuclear export of mature, processed tRNAs. Distinct tRNAs accumulate in the nuclei of Δ and Δ mutants, while Los1-GFP nucleocytoplasmic shuttling is unaffected by Nup100. Thus, we conclude that Nup100 regulates tRNA export in a manner distinct from Los1 or Msn5. Together, these experiments reveal a novel Nup100 role in the tRNA life cycle that impacts the life span.
© 2017 Lord et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Nuclear LC3 Associates with Slowly Diffusing Complexes that Survey the Nucleolus.
Kraft LJ, Manral P, Dowler J, Kenworthy AK
(2016) Traffic 17: 369-99
MeSH Terms: Active Transport, Cell Nucleus, Cell Nucleolus, HeLa Cells, Humans, Microtubule-Associated Proteins, Protein Binding, RNA, Ribosomal Proteins, Tubulin
Show Abstract · Added February 12, 2016
MAP1LC3B (microtubule-associated protein 1 light chain 3, LC3) is a key component of the autophagy pathway, contributing to both cargo selection and autophagosome formation in the cytoplasm. Emerging evidence suggests that nuclear forms of LC3 are also functionally important; however, the mechanisms that facilitate the nuclear targeting and trafficking of LC3 between the nucleus and cytoplasm under steady-state conditions are poorly understood. In this study, we examine how residues known to regulate the interactions between LC3 and other proteins or RNA (F52 L53, R68-R70 and G120) contribute to its nuclear targeting, nucleocytoplasmic transport and association with nucleoli and other nuclear components. We find that residues F52 L53 and R68-70, but not G120, regulate targeting of LC3 to the nucleus, its rates of nucleocytoplasmic transport and the apparent sizes of LC3-associated complexes in the nucleus inferred from fluorescence recovery after photobleaching (FRAP) measurements. We also show that LC3 is enriched in nucleoli and its triple arginine motif is especially important for nucleolar targeting. Finally, we identify a series of candidate nuclear LC3-interacting proteins using mass spectrometry, including MAP1B, tubulin and several 40S ribosomal proteins. These findings suggest LC3 is retained in the nucleus in association with high-molecular weight complexes that continuously scan the nucleolus.
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
0 Communities
1 Members
0 Resources
9 MeSH Terms
LASP-1: a nuclear hub for the UHRF1-DNMT1-G9a-Snail1 complex.
Duvall-Noelle N, Karwandyar A, Richmond A, Raman D
(2016) Oncogene 35: 1122-33
MeSH Terms: Active Transport, Cell Nucleus, Adaptor Proteins, Signal Transducing, Breast Neoplasms, CCAAT-Enhancer-Binding Proteins, Cell Line, Tumor, Chemokine CXCL12, Cytoskeletal Proteins, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases, Epigenesis, Genetic, Gene Knockdown Techniques, Heterocyclic Compounds, Histocompatibility Antigens, Histone-Lysine N-Methyltransferase, Histones, Humans, LIM Domain Proteins, Prognosis, Proteomics, Signal Transduction, Snail Family Transcription Factors, Transcription Factors, Tumor Microenvironment
Show Abstract · Added May 20, 2015
Nuclear LASP-1 (LIM and SH3 protein-1) has a direct correlation with overall survival of breast cancer patients. In this study, immunohistochemical analysis of a human breast TMA showed that LASP-1 is absent in normal human breast epithelium but the expression increases with malignancy and is highly nuclear in aggressive breast cancer. We investigated whether the chemokines and growth factors present in the tumor microenvironment could trigger nuclear translocation of LASP-1.Treatment of human breast cancer cells with CXCL12, EGF and HRG, and HMEC-CXCR2 cells with CXCL8 facilitated nuclear shuttling of LASP-1. Data from the biochemical analysis of the nuclear and cytosolic fractions further confirmed the nuclear translocation of LASP-1 upon chemokine and growth factor treatment. CXCL12-dependent nuclear import of LASP-1 could be blocked by CXCR4 antagonist, AMD-3100. Knock down of LASP-1 resulted in alterations in gene expression leading to an increased level of cell-junction and extracellular matrix proteins and an altered cytokine secretory profile. Three-dimensional cultures of human breast cancer cells on Matrigel revealed an altered colony growth, morphology and arborization pattern in LASP-1 knockdown cells. Functional analysis of the LASP-1 knockdown cells revealed increased adhesion to collagen IV and decreased invasion through the Matrigel. Proteomic analysis of immunoprecipitates of LASP-1 and subsequent validation approaches revealed that LASP-1 associated with the epigenetic machinery especially UHRF1, DNMT1, G9a and the transcription factor Snail1. Interestingly, LASP-1 associated with UHRF1, G9a, Snail1 and di- and tri-methylated histoneH3 in a CXCL12-dependent manner based on immunoprecipitation and proximity ligation assays. LASP-1 also directly bound to Snail1 which may stabilize Snail1. Thus, nuclear LASP-1 appears to functionally serve as a hub for the epigenetic machinery.
2 Communities
2 Members
0 Resources
23 MeSH Terms
Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis.
Soutto M, Romero-Gallo J, Krishna U, Piazuelo MB, Washington MK, Belkhiri A, Peek RM, El-Rifai W
(2015) Oncotarget 6: 17911-22
MeSH Terms: Active Transport, Cell Nucleus, Adenocarcinoma, Animals, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Down-Regulation, Gastric Mucosa, Gene Expression Regulation, Neoplastic, HEK293 Cells, Helicobacter Infections, Helicobacter pylori, Host-Pathogen Interactions, Humans, Mice, Knockout, Peptides, RNA, Messenger, Signal Transduction, Stomach Neoplasms, Transfection, Trefoil Factor-1, Tumor Suppressor Proteins, beta Catenin
Show Abstract · Added September 28, 2015
Using in vitro and in vivo models, we investigated the role of TFF1 in suppressing H. pylori-mediated activation of oncogenic β-catenin in gastric tumorigenesis. A reconstitution of TFF1 expression in gastric cancer cells decreased H. pylori-induced β-catenin nuclear translocation, as compared to control (p < 0.001). These cells exhibited significantly lower β-catenin transcriptional activity, measured by pTopFlash reporter, and induction of its target genes (CCND1 and c-MYC), as compared to control. Because of the role of AKT in regulating β-catenin, we performed Western blot analysis and demonstrated that TFF1 reconstitution abrogates H. pylori-induced p-AKT (Ser473), p-β-catenin (Ser552), c-MYC, and CCND1 protein levels. For in vivo validation, we utilized the Tff1-KO gastric neoplasm mouse model. Following infection with PMSS1 H. pylori strain, we detected an increase in the nuclear staining for β-catenin and Ki-67 with a significant induction in the levels of Ccnd1 and c-Myc in the stomach of the Tff1-KO, as compared to Tff1-WT mice (p < 0.05). Only 10% of uninfected Tff1-KO mice, as opposed to one-third of H. pylori-infected Tff1-KO mice, developed invasive adenocarcinoma (p = 0.03). These findings suggest that loss of TFF1 could be a critical step in promoting the H. pylori-mediated oncogenic activation of β-catenin and gastric tumorigenesis.
0 Communities
3 Members
0 Resources
23 MeSH Terms
Altering nuclear pore complex function impacts longevity and mitochondrial function in S. cerevisiae.
Lord CL, Timney BL, Rout MP, Wente SR
(2015) J Cell Biol 208: 729-44
MeSH Terms: Active Transport, Cell Nucleus, Cell Nucleus, Membrane Transport Proteins, Microbial Viability, Mitochondria, Monomeric GTP-Binding Proteins, Nuclear Pore, Nuclear Pore Complex Proteins, Nuclear Proteins, Permeability, Receptors, Cytoplasmic and Nuclear, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Show Abstract · Added February 15, 2016
The eukaryotic nuclear permeability barrier and selective nucleocytoplasmic transport are maintained by nuclear pore complexes (NPCs), large structures composed of ∼ 30 proteins (nucleoporins [Nups]). NPC structure and function are disrupted in aged nondividing metazoan cells, although it is unclear whether these changes are a cause or consequence of aging. Using the replicative life span (RLS) of Saccharomyces cerevisiae as a model, we find that specific Nups and transport events regulate longevity independent of changes in NPC permeability. Mutants lacking the GLFG domain of Nup116 displayed decreased RLSs, whereas longevity was increased in nup100-null mutants. We show that Nup116 mediates nuclear import of the karyopherin Kap121, and each protein is required for mitochondrial function. Both Kap121-dependent transport and Nup116 levels decrease in replicatively aged yeast. Overexpression of GSP1, the small GTPase that powers karyopherin-mediated transport, rescued mitochondrial and RLS defects in nup116 mutants and increased longevity in wild-type cells. Together, these studies reveal that specific NPC nuclear transport events directly influence aging.
© 2015 Lord et al.
0 Communities
1 Members
0 Resources
13 MeSH Terms
The "genomic storm" induced by bacterial endotoxin is calmed by a nuclear transport modifier that attenuates localized and systemic inflammation.
DiGiandomenico A, Veach RA, Zienkiewicz J, Moore DJ, Wylezinski LS, Hutchens MA, Hawiger J
(2014) PLoS One 9: e110183
MeSH Terms: Active Transport, Cell Nucleus, Animals, Bone Marrow Cells, Cell Nucleus, Cell-Penetrating Peptides, Chemokines, Gene Expression Regulation, Genome, Human, Humans, Lipopolysaccharides, Macrophages, Mice, Pneumonia, Shock, Septic, Transcription Factors, Transcriptome
Show Abstract · Added October 21, 2014
Lipopolysaccharide (LPS) is a potent microbial virulence factor that can trigger production of proinflammatory mediators involved in the pathogenesis of localized and systemic inflammation. Importantly, the role of nuclear transport of stress responsive transcription factors in this LPS-generated "genomic storm" remains largely undefined. We developed a new nuclear transport modifier (NTM) peptide, cell-penetrating cSN50.1, which targets nuclear transport shuttles importin α5 and importin β1, to analyze its effect in LPS-induced localized (acute lung injury) and systemic (lethal endotoxic shock) murine inflammation models. We analyzed a human genome database to match 46 genes that encode cytokines, chemokines and their receptors with transcription factors whose nuclear transport is known to be modulated by NTM. We then tested the effect of cSN50.1 peptide on proinflammatory gene expression in murine bone marrow-derived macrophages stimulated with LPS. This NTM suppressed a proinflammatory transcriptome of 37 out of 84 genes analyzed, without altering expression of housekeeping genes or being cytotoxic. Consistent with gene expression analysis in primary macrophages, plasma levels of 23 out of 26 LPS-induced proinflammatory cytokines, chemokines, and growth factors were significantly attenuated in a murine model of LPS-induced systemic inflammation (lethal endotoxic shock) while the anti-inflammatory cytokine, interleukin 10, was enhanced. This anti-inflammatory reprogramming of the endotoxin-induced genomic response was accompanied by complete protection against lethal endotoxic shock with prophylactic NTM treatment, and 75% protection when NTM was first administered after LPS exposure. In a murine model of localized lung inflammation caused by direct airway exposure to LPS, expression of cytokines and chemokines in the bronchoalveolar space was suppressed with a concomitant reduction of neutrophil trafficking. Thus, calming the LPS-triggered "genomic storm" by modulating nuclear transport with cSN50.1 peptide attenuates the systemic inflammatory response associated with lethal shock as well as localized lung inflammation.
1 Communities
2 Members
0 Resources
16 MeSH Terms
Normal telomere length maintenance in Saccharomyces cerevisiae requires nuclear import of the ever shorter telomeres 1 (Est1) protein via the importin alpha pathway.
Hawkins C, Friedman KL
(2014) Eukaryot Cell 13: 1036-50
MeSH Terms: Active Transport, Cell Nucleus, Amino Acid Sequence, Cell Nucleus, Molecular Sequence Data, Nuclear Localization Signals, Nucleocytoplasmic Transport Proteins, RNA-Binding Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Telomerase, Telomere Homeostasis, beta Karyopherins
Show Abstract · Added January 20, 2015
The Est1 (ever shorter telomeres 1) protein is an essential component of yeast telomerase, a ribonucleoprotein complex that restores the repetitive sequences at chromosome ends (telomeres) that would otherwise be lost during DNA replication. Previous work has shown that the telomerase RNA component (TLC1) transits through the cytoplasm during telomerase biogenesis, but mechanisms of protein import have not been addressed. Here we identify three nuclear localization sequences (NLSs) in Est1p. Mutation of the most N-terminal NLS in the context of full-length Est1p reduces Est1p nuclear localization and causes telomere shortening-phenotypes that are rescued by fusion with the NLS from the simian virus 40 (SV40) large-T antigen. In contrast to that of the TLC1 RNA, Est1p nuclear import is facilitated by Srp1p, the yeast homolog of importin α. The reduction in telomere length observed at the semipermissive temperature in a srp1 mutant strain is rescued by increased Est1p expression, consistent with a defect in Est1p nuclear import. These studies suggest that at least two nuclear import pathways are required to achieve normal telomere length homeostasis in yeast.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Activation of MAPK and FoxO by manganese (Mn) in rat neonatal primary astrocyte cultures.
Exil V, Ping L, Yu Y, Chakraborty S, Caito SW, Wells KS, Karki P, Lee E, Aschner M
(2014) PLoS One 9: e94753
MeSH Terms: Active Transport, Cell Nucleus, Animals, Animals, Newborn, Astrocytes, Cell Nucleus, Cells, Cultured, Enzyme Activation, Enzyme Induction, Forkhead Box Protein O3, Forkhead Transcription Factors, Manganese, Mitogen-Activated Protein Kinases, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Phosphorylation, Proto-Oncogene Proteins c-akt, Pyrrolidonecarboxylic Acid, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species, Signal Transduction, Superoxide Dismutase, Thiazolidines, Time Factors, Transcription Factors
Show Abstract · Added April 11, 2016
Environmental exposure to manganese (Mn) leads to a neurodegenerative disease that has shared clinical characteristics with Parkinson's disease (PD). Mn-induced neurotoxicity is time- and dose-dependent, due in part to oxidative stress. We ascertained the molecular targets involved in Mn-induced neurodegeneration using astrocyte culture as: (1) Astrocytes are vital for information processing within the brain, (2) their redox potential is essential in mitigating reactive oxygen species (ROS) levels, and (3) they are targeted early in the course of Mn toxicity. We first tested protein levels of Mn superoxide dismutase -2 (SOD-2) and glutathione peroxidase (GPx-1) as surrogates of astrocytic oxidative stress response. We assessed levels of the forkhead winged-helix transcription factor O (FoxO) in response to Mn exposure. FoxO is highly regulated by the insulin-signaling pathway. FoxO mediates cellular responses to toxic stress and modulates adaptive responses. We hypothesized that FoxO is fundamental in mediating oxidative stress response upon Mn treatment, and may be a biomarker of Mn-induced neurodegeneration. Our results indicate that 100 or 500 µM of MnCl2 led to increased levels of FoxO (dephosphorylated and phosphorylated) compared with control cells (P<0.01). p-FoxO disappeared from the cytosol upon Mn exposure. Pre-treatment of cultured cells with (R)-(-)-2-oxothiazolidine-4-carboxylic acid (OTC), a cysteine analog rescued the cytosolic FoxO. At these concentrations, MAPK phosphorylation, in particular p38 and ERK, and PPAR gamma coactivator-1 (PGC-1) levels were increased, while AKT phosphorylation remained unchanged. FoxO phosphorylation level was markedly reduced with the use of SB203580 (a p38 MAPK inhibitor) and PD98059 (an ERK inhibitor). We conclude that FoxO phosphorylation after Mn exposure occurs in parallel with, and independent of the insulin-signaling pathway. FoxO levels and its translocation into the nucleus are part of early events compensating for Mn-induced neurotoxicity and may serve as valuable targets for neuroprotection in the setting of Mn-induced neurodegeneration.
0 Communities
1 Members
0 Resources
24 MeSH Terms