Nuclear envelope barrier leak induced by dexamethasone

Kastrup, Lilian; Oberleithner, Hans; Ludwig, Yvonne; Schäfer, Claudia; Shahin, Victor

doi:10.1002/jcp.20479

Cited by 50 publications

(53 citation statements)

References 54 publications

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“…We assume that resting NPCs in the neighborhood of hots spots will be recruited if the stimulus is strong and persisting. Table 1 summarizes the results obtained in previous experiments [17,19,24,29,30] and in the present study. It documents the chronological sequence of cargo import into the nucleus upon steroid stimulation.…”

Section: Discussionmentioning

confidence: 61%

Hot Spot Formation in the Nuclear Envelope of Oocytes in Response to Steroids

Ludwig

Schäfer

Kramer

et al. 2006

Cell Physiol Biochem

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hormone stimulation with bidirectional exchange of specific macromolecules between cytosol and nucleus. Glucocorticoid-initiated macromolecules (GIMs) must overcome the nuclear envelope (NE) to enter or leave the nucleus. GIM translocation occurs through nuclear pore complexes (NPCs) that span the NE. We investigated the question whether transport of GIMs through NPCs occurs random or involves selected groups of NPCs (hot spots). Glucocorticoid receptors were expressed in Xenopus laevis oocytes and GIM transport was activated by triamcinolone acetonide, a potent synthetic glucocorticoid analogon. Glucocorticoid receptors associated with the NE and the chromatin were identified using western blot analysis and, at single molecule level, atomic force microscopy. Fluorescence-labeled dextran was used to describe passive NE permeability. We observed that after hormone injection (i) small GIMs, most likely GRs, localize within seconds on both sides of the NE. (ii) large GIMs, most likely ribonucleoproteins, localize within minutes on NPCs at the nucleoplasmic side (iii) both small and large GIMs accumulate on selected NPC clusters (iv) NE permeability transiently decreases when GIMs attach to NPCs. We conclude that GIM transport across the nuclear barrier does not randomly take place but is carried out by a selected population of NPCs.

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Section: Discussionmentioning

confidence: 61%

Hot Spot Formation in the Nuclear Envelope of Oocytes in Response to Steroids

Ludwig

Schäfer

Kramer

et al. 2006

Cell Physiol Biochem

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“…Homogeneous dilatation of the central pore, which has also been observed to occur experimentally in response to the presence of calcium ions [77], ATP [78], and steroids [79][80][81], first appears at the considerably higher mode number 27, whose frequency is approximately twice that of the elliptical normal modes. This significant difference in harmonic frequency suggests that this latter mode of deformation is considerably less favorable mechanically.…”

Section: Nuclear Pore Complexmentioning

confidence: 64%

Conformational dynamics of supramolecular protein assemblies

Kim

Nguyen

Bathe

2011

Journal of Structural Biology

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Supramolecular protein assemblies including molecular motors, cytoskeletal filaments, chaperones, and ribosomes play a central role in a broad array of cellular functions ranging from cell division and motility to RNA and protein synthesis and folding. Single-particle reconstructions of such assemblies have been growing rapidly in recent years, providing increasingly high resolution structural information under native conditions. While the static structure of these assemblies provides essential insight into their mechanism of biological function, their dynamical motions provide additional important information that cannot be inferred from structure alone. Here we present an unsupervised computational framework for the analysis of high molecular weight assemblies and use it to analyze the conformational dynamics of structures deposited in the Electron Microscopy Data Bank. Protein assemblies are modeled using a recently introduced coarse-grained modeling framework based on the finite element method, which is used to compute equilibrium thermal fluctuations, elastic strain energy distributions associated with specific conformational transitions, and dynamical correlations in distant molecular domains. Results are presented in detail for the ribosome-bound termination factor RF2 from Escherichia coli, the nuclear pore complex from Dictyostelium discoideum, and the chaperonin GroEL from E. coli. Elastic strain energy distributions reveal hinge-regions associated with specific conformational change pathways, and correlations in collective molecular motions reveal dynamical coupling between distant molecular domains that suggest new, as well as confirm existing, allosteric mechanisms. Results are publically available for use in further investigation and interpretation of biological function including cooperative transitions, allosteric communication, and molecular mechanics, as well as in further classification and refinement of electron microscopy based structures.

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“…Dexamethasone (Dexa), an effective, synthetic glucocorticoid, could bind to the glucocorticoid receptor after cellular entry and translocate the complexes into the nucleus. [15][16][17][18][19][20] The results of these studies have confirmed that Dexa-conjugated vector/DNA complexes could be efficiently delivered into the nucleus with the glucocorticoid receptor, resulting in increased transgene expression.…”

Section: Introductionmentioning

confidence: 81%

Transferrin-PEG-PE modified dexamethasone conjugated cationic lipid carrier mediated gene delivery system for tumor-targeted transfection

Wang¹,

Zhou²,

Ge³

et al. 2012

IJN

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Background:The main barriers to non-viral gene delivery include cellular and nuclear membranes. As such, the aim of this study was to develop a type of vector that can target cells through receptor-mediated pathways and by using nuclear localization signal (NLS) to increase the nuclear uptake of genetic materials. Methods: A dexamethasone (Dexa)-conjugated lipid was synthesized as the material of the solid lipid nanoparticles (SLNs), and transferrin (Tf) was linked onto polyethylene glycolphosphatidylethanolamine (PEG-PE) to obtain Tf-PEG-PE ligands for the surface modification of the carriers. The in vitro transfection efficiency of the novel modified vectors was evaluated in human hepatoma carcinoma cell lines, and in vivo effects were observed in an animal model. Results: Tf-PEG-PE modified SLNs/enhanced green fluorescence protein plasmid (pEGFP) had a particle size of 222 nm and a gene loading quantity of 90%. Tf-PEG-PE-modified SLNs/ pEGFP (Tf-SLNs/pEGFP) displayed remarkably higher transfection efficiency than non-modified SLNs/pEGFP and the vectors not containing Dexa, both in vitro and in vivo. Conclusion: It can be concluded that Tf and Dexa could function as an excellent active targeting ligand to improve the cell targeting and nuclear targeting ability of the carriers, and the resulting nanomedicine could be a promising active targeting drug/gene delivery system.

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Nuclear envelope barrier leak induced by dexamethasone

Cited by 50 publications

References 54 publications

Hot Spot Formation in the Nuclear Envelope of Oocytes in Response to Steroids

Hot Spot Formation in the Nuclear Envelope of Oocytes in Response to Steroids

Conformational dynamics of supramolecular protein assemblies

Transferrin-PEG-PE modified dexamethasone conjugated cationic lipid carrier mediated gene delivery system for tumor-targeted transfection

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