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Results: 11 to 20 of 57

Publication Record


Lysosome-mediated processing of chromatin in senescence.
Ivanov A, Pawlikowski J, Manoharan I, van Tuyn J, Nelson DM, Rai TS, Shah PP, Hewitt G, Korolchuk VI, Passos JF, Wu H, Berger SL, Adams PD
(2013) J Cell Biol 202: 129-43
MeSH Terms: Autophagy, Biological Transport, Cell Membrane Permeability, Cell Nucleus, Cells, Cultured, Cellular Senescence, Chromatin, Chromatin Assembly and Disassembly, Cytoplasm, Fibroblasts, Histones, Humans, Laminin, Lysosomes, Nuclear Envelope, Proteolysis, Time-Lapse Imaging
Show Abstract · Added March 17, 2014
Cellular senescence is a stable proliferation arrest, a potent tumor suppressor mechanism, and a likely contributor to tissue aging. Cellular senescence involves extensive cellular remodeling, including of chromatin structure. Autophagy and lysosomes are important for recycling of cellular constituents and cell remodeling. Here we show that an autophagy/lysosomal pathway processes chromatin in senescent cells. In senescent cells, lamin A/C-negative, but strongly γ-H2AX-positive and H3K27me3-positive, cytoplasmic chromatin fragments (CCFs) budded off nuclei, and this was associated with lamin B1 down-regulation and the loss of nuclear envelope integrity. In the cytoplasm, CCFs were targeted by the autophagy machinery. Senescent cells exhibited markers of lysosomal-mediated proteolytic processing of histones and were progressively depleted of total histone content in a lysosome-dependent manner. In vivo, depletion of histones correlated with nevus maturation, an established histopathologic parameter associated with proliferation arrest and clinical benignancy. We conclude that senescent cells process their chromatin via an autophagy/lysosomal pathway and that this might contribute to stability of senescence and tumor suppression.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Interaction of p190RhoGAP with C-terminal domain of p120-catenin modulates endothelial cytoskeleton and permeability.
Zebda N, Tian Y, Tian X, Gawlak G, Higginbotham K, Reynolds AB, Birukova AA, Birukov KG
(2013) J Biol Chem 288: 18290-9
MeSH Terms: Adherens Junctions, Antigens, CD, Binding Sites, Blotting, Western, Cadherins, Catenins, Cell Membrane, Cell Membrane Permeability, Cells, Cultured, Cytoskeleton, Endothelial Cells, Fluorescent Antibody Technique, GTPase-Activating Proteins, Guanine Nucleotide Exchange Factors, HEK293 Cells, Humans, Mutation, Phosphatidylcholines, Protein Binding, Protein Interaction Mapping, Repressor Proteins, Thrombin, p21-Activated Kinases, rac1 GTP-Binding Protein
Show Abstract · Added March 7, 2014
p120-catenin is a multidomain intracellular protein, which mediates a number of cellular functions, including stabilization of cell-cell transmembrane cadherin complexes as well as regulation of actin dynamics associated with barrier function, lamellipodia formation, and cell migration via modulation of the activities of small GTPAses. One mechanism involves p120 catenin interaction with Rho GTPase activating protein (p190RhoGAP), leading to p190RhoGAP recruitment to cell periphery and local inhibition of Rho activity. In this study, we have identified a stretch of 23 amino acids within the C-terminal domain of p120 catenin as the minimal sequence responsible for the recruitment of p190RhoGAP (herein referred to as CRAD; catenin-RhoGAP association domain). Expression of the p120-catenin truncated mutant lacking the CRAD in endothelial cells attenuated effects of barrier protective oxidized phospholipid, OxPAPC. This effect was accompanied by inhibition of membrane translocation of p190RhoGAP, increased Rho signaling, as well as suppressed activation of Rac1 and its cytoskeletal effectors PAK1 (p21-activated kinase 1) and cortactin. Expression of p120 catenin-truncated mutant lacking CRAD also delayed the recovery process after thrombin-induced endothelial barrier disruption. Concomitantly, RhoA activation and downstream signaling were sustained for a longer period of time, whereas Rac signaling was inhibited. These data demonstrate a critical role for p120-catenin (amino acids 820-843) domain in the p120-catenin·p190RhoGAP signaling complex assembly, membrane targeting, and stimulation of p190RhoGAP activity toward inhibition of the Rho pathway and reciprocal up-regulation of Rac signaling critical for endothelial barrier regulation.
1 Communities
1 Members
0 Resources
24 MeSH Terms
Cell-permeant peptide inhibitors of vasospasm and intimal hyperplasia.
Osgood MJ, Flynn CR, Komalavilas P, Brophy C
(2013) Vascular 21: 46-53
MeSH Terms: Animals, Cell Membrane Permeability, Graft Occlusion, Vascular, Graft Survival, Heat-Shock Proteins, Humans, Hyperplasia, Neointima, Peptides, Vascular Grafting, Vascular Patency, Vasoconstriction, Veins
Show Abstract · Added December 10, 2013
Outcomes from vein graft bypass are limited by graft failure, leading causes of which include intimal hyperplasia and vasospasm. Intimal hyperplasia remains the most common cause of graft failure, but no therapeutic modalities have been shown to prevent intimal hyperplasia in humans. The small heat shock proteins are a class of naturally occurring proteins in vascular smooth muscle. These proteins have an integral role in maintenance of vascular tone and in cellular defense against various stressors. Transduction domains have enabled intracellular therapeutic delivery of peptide analogs of heat shock proteins, as well as peptide inhibitors of the kinases that phosphorylate these proteins. These cell-permeant peptides have been shown to prevent vasospasm and intimal hyperplasia in vitro. Since vascular bypass using vein grafts is analogous to autologous organ transplantation, ex vivo treatment of the vein graft with cell-permeant peptide inhibitors of vasospasm and intimal hyperplasia prior to implantation provides a unique opportunity for targeted treatment of the graft to improve patency.
0 Communities
2 Members
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13 MeSH Terms
Myofibroblast keratinocyte growth factor reduces tight junctional integrity and increases claudin-2 levels in polarized Caco-2 cells.
Kim TI, Poulin EJ, Blask E, Bukhalid R, Whitehead RH, Franklin JL, Coffey RJ
(2012) Growth Factors 30: 320-32
MeSH Terms: Amphiregulin, Caco-2 Cells, Cell Communication, Cell Line, Tumor, Cell Membrane Permeability, Cell Proliferation, Claudin-2, Culture Media, Conditioned, EGF Family of Proteins, Electric Impedance, ErbB Receptors, Fibroblast Growth Factor 7, Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, Intestinal Mucosa, Ligands, Myofibroblasts, Tight Junctions
Show Abstract · Added December 5, 2013
The colonic epithelium is composed of a polarized monolayer sheathed by a layer of pericryptal myofibroblasts (PCMFs). We mimicked these cellular compartments in vitro to assess the effects of paracrine-acting PCMF-derived factors on tight junction (TJ) integrity, as measured by transepithelial electrical resistance (TER). Coculture with 18Co PCMFs, or basolateral administration of 18Co conditioned medium, significantly reduced TER of polarized Caco-2 cells. Among candidate paracrine factors, only keratinocyte growth factor (KGF) reduced Caco-2 TER; basolateral KGF treatment led to time- and concentration-dependent increases in claudin-2 levels. We also demonstrate that amphiregulin (AREG), produced largely by Caco-2 cells, increased claudin-2 levels, leading to epidermal growth factor receptor-mediated TER reduction. We propose that colonic epithelial TJ integrity can be modulated by paracrine KGF and autocrine AREG through increased claudin-2 levels. KGF-regulated claudin-2 induction may have implications for inflammatory bowel disease, where both KGF and claudin-2 are upregulated.
2 Communities
2 Members
0 Resources
19 MeSH Terms
Illuminating the glomerular filtration barrier, two photons at a time.
Fissell WH
(2012) J Am Soc Nephrol 23: 373-5
MeSH Terms: Albumins, Animals, Cell Membrane Permeability, Female, Kidney Glomerulus, Kidney Tubules, Proximal, Male
Added August 21, 2013
0 Communities
1 Members
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7 MeSH Terms
Efficacy and potency of class I antiarrhythmic drugs for suppression of Ca2+ waves in permeabilized myocytes lacking calsequestrin.
Galimberti ES, Knollmann BC
(2011) J Mol Cell Cardiol 51: 760-8
MeSH Terms: Animals, Anti-Arrhythmia Agents, Calcium, Calcium Signaling, Calsequestrin, Cell Membrane Permeability, Cells, Cultured, Disease, Dose-Response Relationship, Drug, Flecainide, Humans, Inhibitory Concentration 50, Mice, Mice, Knockout, Microscopy, Confocal, Molecular Imaging, Myocytes, Cardiac, Propafenone, Saponins, Stereoisomerism, Tachycardia, Ventricular
Show Abstract · Added July 21, 2014
Ca(2+) waves can trigger ventricular arrhythmias such as catecholaminergic-polymorphic ventricular tachycardia (CPVT). Drugs that prevent Ca(2+) waves may have antiarrhythmic properties. Here, we use permeabilized ventricular myocytes from a CPVT mouse model lacking calsequestrin (casq2) to screen all clinically available class I antiarrhythmic drugs and selected other antiarrhythmic agents for activity against Ca(2+) waves. Casq2-/- myocytes were imaged in line-scan mode and the following Ca(2+) wave parameters analyzed: wave incidence, amplitude, frequency, and propagation speed. IC(50) (potency) and maximum inhibition (efficacy) were calculated for each drug. Drugs fell into 3 distinct categories. Category 1 drugs (flecainide and R-propafenone) suppressed wave parameters with the highest potency (IC(50)<10 μM) and efficacy (>50% maximum wave inhibition). Category 2 drugs (encainide, quinidine, lidocaine, and verapamil) had intermediate potency (IC(50) 20-40 μM) and efficacy (20-40% maximum wave inhibition). Category 3 drugs (procainamide, disopyramide, mexiletine, cibenzoline, and ranolazine) had no significant effects on Ca(2+) waves at the highest concentration tested (100 μM). Propafenone was stereoselective, with R-propafenone suppressing waves more potently than S-propafenone (IC(50): R-propafenone 2 ± 0.2 μM vs. S-propafenone 54 ± 18 μM). Both flecainide and R-propafenone decreased Ca(2+) spark mass and converted propagated Ca(2+) waves into non-propagated wavelets and frequent sparks, suggesting that reduction in spark mass, not spark frequency, was responsible for wave suppression. Among all class I antiarrhythmic drugs, flecainide and R-propafenone inhibit Ca(2+) waves with the highest potency and efficacy. Permeabilized casq2-/- myocytes are a simple in-vitro assay for finding drugs with activity against Ca(2+) waves. This article is part of a Special Issue entitled 'Possible Editorial'.
Copyright © 2011 Elsevier Ltd. All rights reserved.
1 Communities
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21 MeSH Terms
Kinetics of FKBP12.6 binding to ryanodine receptors in permeabilized cardiac myocytes and effects on Ca sparks.
Guo T, Cornea RL, Huke S, Camors E, Yang Y, Picht E, Fruen BR, Bers DM
(2010) Circ Res 106: 1743-52
MeSH Terms: Animals, Blotting, Western, Calcium Signaling, Cell Membrane Permeability, Circular Dichroism, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Fluorescence Recovery After Photobleaching, Heart Ventricles, Humans, Kinetics, Mice, Mice, Knockout, Microscopy, Confocal, Mutagenesis, Site-Directed, Mutation, Myocytes, Cardiac, Phosphorylation, Protein Binding, Rats, Ryanodine Receptor Calcium Release Channel, Sarcoplasmic Reticulum, Sirolimus, Swine, Tacrolimus Binding Protein 1A, Tacrolimus Binding Proteins
Show Abstract · Added May 27, 2014
RATIONALE - FK506-binding proteins FKBP12.6 and FKBP12 are associated with cardiac ryanodine receptors (RyR2), and cAMP-dependent protein kinase A (PKA)-dependent phosphorylation of RyR2 was proposed to interrupt FKBP12.6-RyR2 association and activate RyR2. However, the function of FKBP12.6/12 and role of PKA phosphorylation in cardiac myocytes are controversial.
OBJECTIVE - To directly measure in situ binding of FKBP12.6/12 to RyR2 in ventricular myocytes, with simultaneous Ca sparks measurements as a RyR2 functional index.
METHODS AND RESULTS - We used permeabilized rat and mouse ventricular myocytes, and fluorescently-labeled FKBP12.6/12. Both FKBP12.6 and FKBP12 concentrate at Z-lines, consistent with RyR2 and Ca spark initiation sites. However, only FKBP12.6 inhibits resting RyR2 activity. Assessment of fluorescent FKBP binding in myocyte revealed a high FKBP12.6-RyR2 affinity (K(d)=0.7+/-0.1 nmol/L) and much lower FKBP12-RyR2 affinity (K(d)=206+/-70 nmol/L). Fluorescence recovery after photobleach confirmed this K(d) difference and showed that it is mediated by k(off). RyR2 phosphorylation by PKA did not alter binding kinetics or affinity of FKBP12.6/12 for RyR2. Using quantitative immunoblots, we determined endogenous [FKBP12] in intact myocytes is approximately 1 micromol/L (similar to [RyR]), whereas [FKBP12.6] is CONCLUSIONS - Only 10% to 20% of endogenous myocyte RyR2s have FKBP12.6 associated, but virtually all myocyte FKBP12.6 is RyR2-bound (because of very high affinity). FKBP12.6 but not FKBP12 inhibits basal RyR2 activity. PKA-dependent RyR2 phosphorylation has no significant effect on binding of either FKBP12 or 12.6 to RyR2 in myocytes.
0 Communities
1 Members
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26 MeSH Terms
Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass.
Hilliard FA, Steele DS, Laver D, Yang Z, Le Marchand SJ, Chopra N, Piston DW, Huke S, Knollmann BC
(2010) J Mol Cell Cardiol 48: 293-301
MeSH Terms: Animals, Arrhythmias, Cardiac, Calcium, Calcium Channel Blockers, Calcium Signaling, Calcium-Binding Proteins, Cell Membrane Permeability, Flecainide, Humans, Mice, Myocytes, Cardiac, Rats, Ryanodine Receptor Calcium Release Channel, Sarcoplasmic Reticulum, Tetracaine
Show Abstract · Added December 6, 2012
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is linked to mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin. We recently found that the drug flecainide inhibits RyR2 channels and prevents CPVT in mice and humans. Here we compared the effects of flecainide and tetracaine, a known RyR2 inhibitor ineffective in CPVT myocytes, on arrhythmogenic Ca(2+) waves and elementary sarcoplasmic reticulum (SR) Ca(2+) release events, Ca(2+) sparks. In ventricular myocytes isolated from a CPVT mouse model, flecainide significantly reduced spark amplitude and spark width, resulting in a 40% reduction in spark mass. Surprisingly, flecainide significantly increased spark frequency. As a result, flecainide had no significant effect on spark-mediated SR Ca(2+) leak or SR Ca(2+) content. In contrast, tetracaine decreased spark frequency and spark-mediated SR Ca(2+) leak, resulting in a significantly increased SR Ca(2+) content. Measurements in permeabilized rat ventricular myocytes confirmed the different effects of flecainide and tetracaine on spark frequency and Ca(2+) waves. In lipid bilayers, flecainide inhibited RyR2 channels by open state block, whereas tetracaine primarily prolonged RyR2 closed times. The differential effects of flecainide and tetracaine on sparks and RyR2 gating can explain why flecainide, unlike tetracaine, does not change the balance of SR Ca(2+) fluxes. We suggest that the smaller spark mass contributes to flecainide's antiarrhythmic action by reducing the probability of saltatory wave propagation between adjacent Ca(2+) release units. Our results indicate that inhibition of the RyR2 open state provides a new therapeutic strategy to prevent diastolic Ca(2+) waves resulting in triggered arrhythmias, such as CPVT.
Copyright 2009 Elsevier Ltd. All rights reserved.
0 Communities
2 Members
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15 MeSH Terms
Single molecule-sensitive probes for imaging RNA in live cells.
Santangelo PJ, Lifland AW, Curt P, Sasaki Y, Bassell GJ, Lindquist ME, Crowe JE
(2009) Nat Methods 6: 347-9
MeSH Terms: Actin-Related Protein 2, Actins, Animals, Avian Proteins, Bacterial Proteins, Biotin, Carbocyanines, Cell Line, Tumor, Cell Membrane Permeability, Cell Survival, Cells, Cultured, Chick Embryo, DNA-Binding Proteins, Fibroblasts, Fluorescent Dyes, Humans, Image Processing, Computer-Assisted, Microscopy, Confocal, Microscopy, Fluorescence, Molecular Probe Techniques, Oligonucleotide Probes, Poly(A)-Binding Proteins, RNA, RNA, Messenger, RNA-Binding Proteins, Respiratory Syncytial Virus, Human, Streptavidin, Streptolysins, T-Cell Intracellular Antigen-1
Show Abstract · Added August 6, 2012
To visualize native or non-engineered RNA in live cells with single-molecule sensitivity, we developed multiply labeled tetravalent RNA imaging probes (MTRIPs). When delivered with streptolysin O into living human epithelial cancer cells and primary chicken fibroblasts, MTRIPs allowed the accurate imaging of native mRNAs and a non-engineered viral RNA, of RNA co-localization with known RNA-binding proteins, and of RNA dynamics and interactions with stress granules.
0 Communities
1 Members
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29 MeSH Terms
Inhibition of HSP27 phosphorylation by a cell-permeant MAPKAP Kinase 2 inhibitor.
Lopes LB, Flynn C, Komalavilas P, Panitch A, Brophy CM, Seal BL
(2009) Biochem Biophys Res Commun 382: 535-9
MeSH Terms: Amino Acid Sequence, Cell Membrane Permeability, Cells, Cultured, HSP27 Heat-Shock Proteins, Humans, Intracellular Signaling Peptides and Proteins, Molecular Sequence Data, Peptides, Phosphorylation, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Transforming Growth Factor beta1
Show Abstract · Added March 9, 2015
Heat shock protein 27 (HSP27) has been implicated in many intracellular signaling processes. Since the phosphorylation of HSP27 can modulate its activity, the ability to inhibit phosphorylation of HSP27 might have clinical relevance especially with regard to the treatment of fibrosis. We have developed a cell-permeant peptide inhibitor of MAPKAP Kinase 2 (MK2), an enzyme that phosphorylates HSP27, by combining a previously described peptide substrate of MK2 with a cell penetrating peptide. This novel MK2 inhibitor (MK2i) reduced HSP27 phosphorylation by MK2 in vitro. At 10 microM, MK2i inhibited TGF-beta1-induced HSP27 phosphorylation in serum-starved human keloid fibroblasts. In addition, 10 microM MK2i decreased TGF-beta1-induced expression of connective tissue growth factor and collagen type I within serum-starved keloid fibroblasts. Thus, MK2i represents a potential therapeutic for the treatment of fibrotic disorders.
0 Communities
2 Members
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12 MeSH Terms