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The Plk1 Piece of the Nuclear Envelope Disassembly Puzzle.
Dawson TR, Wente SR
(2017) Dev Cell 43: 115-117
MeSH Terms: Mitosis, Nuclear Envelope, Nuclear Pore, Nuclear Pore Complex Proteins, Phosphorylation
Show Abstract · Added March 30, 2018
Reporting in this issue of Developmental Cell, Linder et al. (2017) and Martino et al. (2017) reveal in highly complementary studies that Plk1 is recruited to the nuclear pore complex upon mitotic entry, where it acts with Cdk1 to hyperphosphorylate nucleoporin interfaces to promote NPC disassembly and nuclear envelope breakdown.
Copyright © 2017 Elsevier Inc. All rights reserved.
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5 MeSH Terms
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.
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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).
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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.
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16 MeSH Terms
Simple rules for passive diffusion through the nuclear pore complex.
Timney BL, Raveh B, Mironska R, Trivedi JM, Kim SJ, Russel D, Wente SR, Sali A, Rout MP
(2016) J Cell Biol 215: 57-76
MeSH Terms: Biological Transport, Computer Simulation, Diffusion, Fluorescence Recovery After Photobleaching, Kinetics, Macromolecular Substances, Molecular Weight, Mutation, Nuclear Pore, Nuclear Pore Complex Proteins, Permeability, Protein Domains, Saccharomyces cerevisiae, Substrate Specificity, Thermodynamics, Time Factors
Show Abstract · Added April 14, 2017
Passive macromolecular diffusion through nuclear pore complexes (NPCs) is thought to decrease dramatically beyond a 30-60-kD size threshold. Using thousands of independent time-resolved fluorescence microscopy measurements in vivo, we show that the NPC lacks such a firm size threshold; instead, it forms a soft barrier to passive diffusion that intensifies gradually with increasing molecular mass in both the wild-type and mutant strains with various subsets of phenylalanine-glycine (FG) domains and different levels of baseline passive permeability. Brownian dynamics simulations replicate these findings and indicate that the soft barrier results from the highly dynamic FG repeat domains and the diffusing macromolecules mutually constraining and competing for available volume in the interior of the NPC, setting up entropic repulsion forces. We found that FG domains with exceptionally high net charge and low hydropathy near the cytoplasmic end of the central channel contribute more strongly to obstruction of passive diffusion than to facilitated transport, revealing a compartmentalized functional arrangement within the NPC.
© 2016 Timney et al.
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16 MeSH Terms
Potentiation and tolerance of toll-like receptor priming in human endothelial cells.
Koch SR, Lamb FS, Hellman J, Sherwood ER, Stark RJ
(2017) Transl Res 180: 53-67.e4
MeSH Terms: Endothelial Cells, Extracellular Signal-Regulated MAP Kinases, Human Umbilical Vein Endothelial Cells, Humans, Immune Tolerance, Interferon Regulatory Factor-7, Interferons, Interleukin-6, Lipopeptides, Lipopolysaccharides, Nuclear Pore Complex Proteins, Phosphorylation, Poly I-C, RNA-Binding Proteins, Toll-Like Receptors, Up-Regulation
Show Abstract · Added August 28, 2016
Repeated challenge of lipopolysaccharide (LPS) alters the response to subsequent LPS exposures via modulation of toll-like receptor 4 (TLR4). Whether activation of other TLRs can modulate TLR4 responses, and vice versa, remains unclear. Specifically with regards to endothelial cells, a key component of innate immunity, the impact of TLR cross-modulation is unknown. We postulated that TLR2 priming (via Pam3Csk4) would inhibit TLR4-mediated responses while TLR3 priming (via Poly I:C) would enhance subsequent TLR4-inflammatory signaling. We studied human umbilical vein endothelial cells (HUVECs) and neonatal human dermal microvascular endothelial cells (HMVECs). Cells were primed with a combination of Poly I:C (10 μg/ml), Pam3Csk4 (10 μg/ml), or LPS (100 ng/ml), then washed and allowed to rest. They were then rechallenged with either Poly I:C, Pam3Csk4 or LPS. Endothelial cells showed significant tolerance to repeated LPS challenge. Priming with Pam3Csk4 also reduced the response to secondary LPS challenge in both cell types, despite a reduced proinflammatory response to Pam3Csk4 in HMVECs compared to HUVECs. Poly I:C priming enhanced inflammatory and interferon producing signals upon Poly I:C or LPS rechallenge, respectively. Poly I:C priming induced interferon regulatory factor 7, leading to enhancement of interferon production. Finally, both Poly I:C and LPS priming induced significant changes in receptor-interacting serine/threonine-protein kinase 1 activity. Pharmacological inhibition of receptor-interacting serine/threonine-protein kinase 1 or interferon regulatory factor 7 reduced the potentiated phenotype of TLR3 priming on TLR4 rechallenge. These results demonstrate that in human endothelial cells, prior activation of TLRs can have a significant impact on subsequent exposures and may contribute to the severity of the host response.
Copyright © 2016 Elsevier Inc. All rights reserved.
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16 MeSH Terms
A Novel Saccharomyces cerevisiae FG Nucleoporin Mutant Collection for Use in Nuclear Pore Complex Functional Experiments.
Adams RL, Terry LJ, Wente SR
(2015) G3 (Bethesda) 6: 51-8
MeSH Terms: Gene Expression, Genetic Association Studies, Mutation, Nuclear Pore Complex Proteins, Phenotype, Plasmids, Protein Interaction Domains and Motifs, Saccharomyces cerevisiae, Sequence Deletion
Show Abstract · Added February 15, 2016
FG nucleoporins (Nups) are the class of proteins that both generate the permeability barrier and mediate selective transport through the nuclear pore complex (NPC). The FG Nup family has 11 members in Saccharomyces cerevisiae, and the study of mutants lacking different FG domains has been instrumental in testing transport models. To continue analyzing the distinct functional roles of FG Nups in vivo, additional robust genetic tools are required. Here, we describe a novel collection of S. cerevisiae mutant strains in which the FG domains of different groups of Nups are absent (Δ) in the greatest number documented to date. Using this plasmid-based ΔFG strategy, we find that a GLFG domain-only pore is sufficient for viability. The resulting extensive plasmid and strain resources are available to the scientific community for future in-depth in vivo studies of NPC transport.
Copyright © 2016 Adams et al.
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9 MeSH Terms
HIV-1 Resistance to the Capsid-Targeting Inhibitor PF74 Results in Altered Dependence on Host Factors Required for Virus Nuclear Entry.
Zhou J, Price AJ, Halambage UD, James LC, Aiken C
(2015) J Virol 89: 9068-79
MeSH Terms: Amino Acid Substitution, Anti-HIV Agents, Binding Sites, CD4-Positive T-Lymphocytes, Capsid, Capsid Proteins, Cell Line, Drug Resistance, Viral, HIV Infections, HIV-1, Host-Pathogen Interactions, Humans, Indoles, Macrophages, Molecular Chaperones, Nuclear Pore Complex Proteins, Phenylalanine, Protein Binding, Protein Conformation, RNA Interference, RNA, Small Interfering, Virus Internalization, Virus Replication, beta Karyopherins, mRNA Cleavage and Polyadenylation Factors
Show Abstract · Added February 4, 2016
UNLABELLED - During HIV-1 infection of cells, the viral capsid plays critical roles in reverse transcription and nuclear entry of the virus. The capsid-targeting small molecule PF74 inhibits HIV-1 at early stages of infection. HIV-1 resistance to PF74 is complex, requiring multiple amino acid substitutions in the viral CA protein. Here we report the identification and analysis of a novel PF74-resistant mutant encoding amino acid changes in both domains of CA, three of which are near the pocket where PF74 binds. Interestingly, the mutant virus retained partial PF74 binding, and its replication was stimulated by the compound. The mutant capsid structure was not significantly perturbed by binding of PF74; rather, the mutations inhibited capsid interactions with CPSF6 and Nup153 and altered HIV-1 dependence on these host factors and on TNPO3. Moreover, the replication of the mutant virus was markedly impaired in activated primary CD4(+) T cells and macrophages. Our results suggest that HIV-1 escapes a capsid-targeting small molecule inhibitor by altering the virus's dependence on host factors normally required for entry into the nucleus. They further imply that clinical resistance to inhibitors targeting the PF74 binding pocket is likely to be strongly limited by functional constraints on HIV-1 evolution.
IMPORTANCE - The HIV-1 capsid plays critical roles in early steps of infection and is an attractive target for therapy. Here we show that selection for resistance to a capsid-targeting small molecule inhibitor can result in viral dependence on the compound. The mutant virus was debilitated in primary T cells and macrophages--cellular targets of infection in vivo. The mutations also altered the virus's dependence on cellular factors that are normally required for HIV-1 entry into the nucleus. This work provides new information regarding mechanisms of HIV-1 resistance that should be useful in efforts to develop clinically useful drugs targeting the HIV-1 capsid.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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25 MeSH Terms
Nuclear pore complex integrity requires Lnp1, a regulator of cortical endoplasmic reticulum.
Casey AK, Chen S, Novick P, Ferro-Novick S, Wente SR
(2015) Mol Biol Cell 26: 2833-44
MeSH Terms: Animals, Endoplasmic Reticulum, Membrane Proteins, Nuclear Envelope, Nuclear Pore, Nuclear Pore Complex Proteins, Saccharomyces cerevisiae Proteins, Vesicular Transport Proteins
Show Abstract · Added February 15, 2016
The nuclear envelope (NE) and endoplasmic reticulum (ER) are components of the same contiguous membrane system and yet have distinct cellular functions. Mounting evidence suggests roles for some ER proteins in the NE for proper nuclear pore complex (NPC) structure and function. In this study, we identify a NE role in Saccharomyces cerevisiae for Lnp1 and Sey1, proteins required for proper cortical ER formation. Both lnp1Δ and sey1Δ mutants exhibit synthetic genetic interactions with mutants in genes encoding key NPC structural components. Both Lnp1 and Sey1 physically associate with other ER components that have established NPC roles, including Rtn1, Yop1, Pom33, and Per33. Of interest, lnp1Δ rtn1Δ mutants but not rtn1Δ sey1Δ mutants exhibit defects in NPC distribution. Furthermore, the essential NPC assembly factor Ndc1 has altered interactions in the absence of Sey1. Lnp1 dimerizes in vitro via its C-terminal zinc finger motif, a property that is required for proper ER structure but not NPC integrity. These findings suggest that Lnp1's role in NPC integrity is separable from functions in the ER and is linked to Ndc1 and Rtn1 interactions.
© 2015 Casey 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).
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8 MeSH Terms
Loss of caspase-3 sensitizes colon cancer cells to genotoxic stress via RIP1-dependent necrosis.
Brown MF, Leibowitz BJ, Chen D, He K, Zou F, Sobol RW, Beer-Stolz D, Zhang L, Yu J
(2015) Cell Death Dis 6: e1729
MeSH Terms: Caspase 3, Cell Death, Colonic Neoplasms, DNA Damage, HCT116 Cells, HEK293 Cells, HT29 Cells, Humans, Nuclear Pore Complex Proteins, RNA-Binding Proteins, Transfection
Show Abstract · Added July 28, 2015
Caspase-3 is the best known executioner caspase in apoptosis. We generated caspase-3 knockout (C3KO) and knockdown human colorectal cancer cells, and found that they are unexpectedly sensitized to DNA-damaging agents including 5-fluorouracil (5-FU), etoposide, and camptothecin. C3KO xenograft tumors also displayed enhanced therapeutic response and cell death to 5-FU. C3KO cells showed intact apoptosis and activation of caspase-7 and -9, impaired processing of caspase-8, and induction of necrosis in response to DNA-damaging agents. This form of necrosis is associated with HMGB1 release and ROS production, and suppressed by genetic or pharmacological inhibition of RIP1, MLKL1, or caspase-8, but not inhibitors of pan-caspases or RIP3. 5-FU treatment led to the formation of a z-VAD-resistant pro-caspase-8/RIP1/FADD complex, which was strongly stabilized by caspase-3 KO. These data demonstrate a key role of caspase-3 in caspase-8 processing and suppression of DNA damage-induced necrosis, and provide a potentially novel way to chemosensitize cancer cells.
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11 MeSH Terms