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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
Expression and function of dopamine receptors in the developing medial frontal cortex and striatum of the rat.
Sillivan SE, Konradi C
(2011) Neuroscience 199: 501-14
MeSH Terms: Animals, Blotting, Northern, Blotting, Western, Corpus Striatum, Frontal Lobe, In Situ Hybridization, Neurogenesis, Rats, Rats, Sprague-Dawley, Receptors, Dopamine, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added May 27, 2014
The timeline of dopamine (DA) system maturation and the signaling properties of DA receptors (DRs) during rat brain development are not fully characterized. We used in situ hybridization and quantitative PCR to map DR mRNA transcripts in the medial frontal cortex (mFC) and striatum (STR) of the rat from embryonic day (E) 15 to E21. The developmental trajectory of DR mRNAs revealed distinct patterns of DA receptors 1 and 2 (DRD1, DRD2) in these brain regions. Whereas the mFC had a steeper increase in DRD1 mRNA, the STR had a steeper increase in DRD2 mRNA. Both DR mRNAs were expressed at a higher level in the STR compared with the mFC. To identify the functional properties of DRs during embryonic development, the phosphorylation states of cyclic AMP response element binding protein, extracellular signal-regulated kinase 1/2, and glycogen synthase kinase 3 beta were examined after DR stimulation in primary neuronal cultures obtained from E15 and E18 embryos and cultured for 3 days to ensure a stable baseline level. DR-mediated signaling cascades were functional in E15 cultures in both brain regions. Because DA fibers do not reach the mFC by E15, and DA was not present in cultures, these data indicate that DRs can become functional in the absence of DA innervation. Because activation of DR signal transduction pathways can affect network organization of the developing brain, maternal exposure to drugs that affect DR activity may be liable to interfere with fetal brain development.
Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
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11 MeSH Terms
Nicotinic acetylcholine receptor α1 promotes calpain-1 activation and macrophage inflammation in hypercholesterolemic nephropathy.
Zhang G, Thomas AL, Marshall AL, Kernan KA, Su Y, Zheng Y, Takano J, Saido TC, Eddy AA
(2011) Lab Invest 91: 106-23
MeSH Terms: Actins, Animals, Antigens, Differentiation, Apolipoproteins E, Blotting, Northern, Blotting, Western, Calcium-Binding Proteins, Calpain, Cell Line, Female, Hypercholesterolemia, Inflammation, Kidney, Kidney Diseases, Macrophages, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Monocytes, Nephrectomy, RNA Interference, Receptors, Nicotinic, Transforming Growth Factor beta1
Show Abstract · Added February 3, 2012
The nicotinic acetylcholine receptor α1 (nAChRα1) was investigated as a potential proinflammatory molecule in the kidney, given a recent report that it is an alternative urokinase plasminogen activator (uPA) receptor, in addition to the classical receptor uPAR. Two animal models and in vitro monocyte studies were involved: (1) In an ApoE(-/-) mouse model of chronic kidney disease, glomerular-resident cells and monocytes/macrophages were identified as the primary cell types that express nAChRα1 during hypercholesterolemia/uninephrectomy-induced nephropathy. Silencing of the nAChRα1 gene for 4 months (6 months on Western diet) prevented the increases in renal monocyte chemoattractant protein-1 and osteopontin expression levels and F4/80+ macrophage infiltration compared with the nonsilenced mice. These changes were associated with significantly reduced transforming growth factor-β1 mRNA (50% decrease) and α smooth muscle actin-positive (αSMA+) myofibroblasts (90% decrease), better glomerular and tubular basement membranes (GBM/TBM) preservation (threefold less disintegration), and better renal function preservation (serum creatinine 40% lower) in the nAChRα1-silenced mice. The nAChRα1 silencing was also associated with significantly reduced renal tissue calcium deposition (78% decrease) and calpain-1 (but not calpain-2) activation (70% decrease). (2) The nAChRα1 was expressed in vitro by mouse monocyte cell line WEHI-274.1. The silencing of nAChRα1 significantly reduced both calpain-1 and -2 activities, and reduced the degradation of the calpain substrate talin. (3) To further explore the role of calpain-1 activity in hypercholesterolemic nephropathy, disease severities were compared in CAST(-/-)ApoE(-/-) (calpain overactive) mice and ApoE(-/-) mice fed with Western diet for 10 months (n=12). Macrophages were the main cell type of renal calpain-1 production in the model. The number of renal F4/80+ macrophages was 10-fold higher in the CAST(-/-)ApoE(-/-) mice (P<0.05), and was associated with a significantly higher level of αSMA+ cells, increased GBM/TBM destruction, and higher serum creatinine levels. Our studies suggest that the receptor nAChRα1 is an important regulator of calpain-1 activation and inflammation in the chronic hypercholesterolemic nephropathy. This new proinflammatory pathway may also be relevant to other disorders beyond hyperlipidemic nephropathy.
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25 MeSH Terms
Rac1 promotes TGF-beta-stimulated mesangial cell type I collagen expression through a PI3K/Akt-dependent mechanism.
Hubchak SC, Sparks EE, Hayashida T, Schnaper HW
(2009) Am J Physiol Renal Physiol 297: F1316-23
MeSH Terms: Actins, Blotting, Northern, Collagen Type I, Fibrosis, Humans, Kidney, Kidney Cortex, Mesangial Cells, Oncogene Protein v-akt, Phosphatidylinositol 3-Kinases, Plasmids, RNA, Transfection, Transforming Growth Factor beta, rac1 GTP-Binding Protein, rho GTP-Binding Proteins, rhoA GTP-Binding Protein
Show Abstract · Added February 11, 2011
Transforming growth factor (TGF)-beta is a central mediator in the progression of glomerulosclerosis, leading to accumulation of aberrant extracellular matrix proteins and inappropriate expression of smooth muscle alpha-actin in the kidney. Previously, we reported that disrupting the cytoskeleton diminished TGF-beta-stimulated type I collagen accumulation in human mesangial cells. As cytoskeletal signaling molecules, including the Rho-family GTPases, have been implicated in fibrogenesis, we sought to determine the respective roles of RhoA and Rac1 in HMC collagen I expression. TGF-beta1 activated both RhoA and Rac1 within 5 min of treatment, and this activation was dependent on the kinase activity of the type I TGF-beta receptor. TGF-beta1-stimulated induction of type I collagen mRNA expression and promoter activity was diminished by inhibiting Rac1 activity and was increased by a constitutively active Rac1 mutant, whereas inhibiting RhoA activity had no such effect. Rac1 activation required phosphatidylinositol-3-kinase (PI3K) activity. Furthermore, the PI3K antagonist, LY294002, reduced TGF-beta1-stimulated COL1A2 promoter activity and Rac1 activation. It also partially blocked active Rac1-stimulated collagen promoter activity, suggesting that PI3K activity contributes to both TGF-beta activation of Rac1 and signal propagation downstream of Rac1. Thus, while both Rac1 and RhoA are rapidly activated in response to TGF-beta1 in human mesangial cells, only Rac1 activation enhances events that contribute to mesangial cell collagen expression, through a positive feedback loop involving PI3K.
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17 MeSH Terms
Regulation of zebrafish fin regeneration by microRNAs.
Thatcher EJ, Paydar I, Anderson KK, Patton JG
(2008) Proc Natl Acad Sci U S A 105: 18384-9
MeSH Terms: 3' Untranslated Regions, Animals, Base Sequence, Blotting, Northern, Blotting, Western, DNA Primers, Fluorescent Antibody Technique, MicroRNAs, Regeneration, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors, Zebrafish, Zebrafish Proteins
Show Abstract · Added May 27, 2014
A number of genes have been implicated in regeneration, but the regulation of these genes, particularly pertaining to regeneration in higher vertebrates, remains an interesting and mostly open question. We have studied microRNA (miRNA) regulation of regeneration and found that an intact miRNA pathway is essential for caudal fin regeneration in zebrafish. We also showed that miR-203 directly targets the Wnt signaling transcription factor Lef1 during this process. Repression of Lef1 by miR-203 blocks regeneration, whereas loss of miR-203 results in excess Lef1 levels and fin overgrowth. Expression of Lef1 from mRNAs lacking 3' UTR recognition elements can rescue the effects of excess miR-203, demonstrating that these effects are due to specific regulation of lef1 by miR-203. Our data support a model in which regulation of Lef1 protein levels by miR-203 is a key limiting step during regeneration.
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13 MeSH Terms
Molecular consequences of altered neuronal cholesterol biosynthesis.
Korade Z, Kenworthy AK, Mirnics K
(2009) J Neurosci Res 87: 866-75
MeSH Terms: Animals, Blotting, Northern, Cell Line, Cholesterol, Down-Regulation, Farnesyl-Diphosphate Farnesyltransferase, Fatty Acid Synthases, Fatty Acids, Gene Expression, Gene Expression Profiling, Intracellular Signaling Peptides and Proteins, Mice, Neurons, Oxidoreductases Acting on CH-CH Group Donors, Polymerase Chain Reaction, Proprotein Convertases, RNA, Small Interfering, Serine Endopeptidases, Sterol Regulatory Element Binding Protein 2, Sterols, Transfection, Vesicular Transport Proteins
Show Abstract · Added December 10, 2013
The first dedicated step in de novo cholesterol biosynthesis begins with formation of squalene and ends with the reduction of 7-dehydrocholesterol by 7-dehydrocholesterol reductase (Dhcr7) into cholesterol, which is an essential structural and signaling molecule. Mutations in the Dhcr7 gene lead to Smith-Lemli-Opitz syndrome (SLOS), which is characterized by developmental deformities, incomplete myelination, and mental retardation. To understand better the molecular consequences of Dhcr7 deficiency in neuronal tissue, we analyzed the effect of cholesterol deficiency on the transcriptome in Neuro2a cells. Transient down-regulation of Dhcr7 by siRNA led to altered expression of multiple molecules that play critical roles in intracellular signaling or vesicular transport or are inserted into membrane rafts (e.g. Egr1, Snx, and Adam19). A similar down-regulation was also observed in stable Dhrc7-shRNA-transfected cell lines, and the findings were verified by qPCR. Furthermore, we investigated the Dhcr7-deficient and control cells for the expression of several critical genes involved in lipid biosynthesis. Among these, fatty acid synthase, sterol-regulatory element binding protein 2, SREBF chaperone, site-1 protease, and squalene synthase showed a significant down-regulation, suggesting that, in a neuronal cell line, Dhcr7 is a potent regulator of lipid biosynthesis. Importantly, the gene expression changes were present in both lipid-containing and cholesterol-deficient media, suggesting that intrinsic cholesterol biosynthesis is necessary for normal neuronal function and cannot be supplemented from extrinsic sources.
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22 MeSH Terms
Expression of Keratin 8 and TNF-Related Apoptosis-I Inducing Ligand (TRAIL) in Down Syndrome Placentas.
Klugman SD, Gross SJ, Liang J, Livne K, Gross B, Khabele D, Lopez-Jones M, Cordero DR, Reznik S
(2008) Placenta 29: 382-4
MeSH Terms: Blotting, Northern, Cell Membrane, Down Syndrome, Female, GPI-Linked Proteins, Gene Expression Profiling, Humans, Immunohistochemistry, Karyotyping, Keratin-8, Placenta, Pregnancy, Receptors, TNF-Related Apoptosis-Inducing Ligand, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Member 10c, TNF-Related Apoptosis-Inducing Ligand, Trophoblasts, Tumor Necrosis Factor Decoy Receptors, Tumor Necrosis Factor-alpha
Added March 5, 2014
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19 MeSH Terms
Regulation of cyclooxygenase-2 (COX-2) expression in human pancreatic carcinoma cells by the insulin-like growth factor-I receptor (IGF-IR) system.
Stoeltzing O, Liu W, Fan F, Wagner C, Stengel K, Somcio RJ, Reinmuth N, Parikh AA, Hicklin DJ, Ellis LM
(2007) Cancer Lett 258: 291-300
MeSH Terms: Adaptor Proteins, Signal Transducing, Blotting, Northern, Blotting, Western, Cell Line, Tumor, Cyclooxygenase 2, Enzyme Inhibitors, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Insulin Receptor Substrate Proteins, Insulin-Like Growth Factor I, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Models, Biological, Pancreatic Neoplasms, Phosphatidylinositol 3-Kinases, Phosphorylation, RNA, Messenger, RNA, Small Interfering, Receptor, IGF Type 1, Signal Transduction, Transfection
Show Abstract · Added June 26, 2014
Both the insulin-like growth factor-I receptor (IGF-IR) and cyclooxygenase-2 (COX-2) are frequently overexpressed in pancreatic cancer. We hypothesized that IGF-IR is directly involved in induction of COX-2 and sought to investigate signaling pathways mediating this effect. Pancreatic cancer cells (L3.6pl) were stably transfected with a dominant-negative receptor (IGF-IR DN) construct or empty vector (pcDNA). Cells were stimulated with IGF-I to determine activated signaling intermediates and induction of COX-2. Signaling pathways mediating COX-2 induction were identified using signaling inhibitors. IGF-I up-regulated COX-2 selectively via the MAPK/(Erk-1/2) pathway. In addition, IGF-IR DN cells showed a marked decrease in constitutive COX-2 and a blunted response to IGF-I. Similarly, treatment with an anti-IGF-IR antibody effectively inhibited IGF-IR and MAPK/Erk activation and decreased COX-2 in parental cells. In conclusion, activation of IGF-IR mediates COX-2 expression in human pancreatic cancer cells.
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23 MeSH Terms
Integrative characterization of germ cell-specific genes from mouse spermatocyte UniGene library.
Choi E, Lee J, Oh J, Park I, Han C, Yi C, Kim DH, Cho BN, Eddy EM, Cho C
(2007) BMC Genomics 8: 256
MeSH Terms: Animals, Blotting, Northern, Blotting, Western, Cell Line, Fluorescent Antibody Technique, Gene Expression Profiling, Gene Expression Regulation, Developmental, Gene Library, Green Fluorescent Proteins, Male, Mice, Proteins, Reverse Transcriptase Polymerase Chain Reaction, Spermatids, Spermatocytes, Spermatogenesis, Spermatozoa, Testis, Transcription, Genetic, Transfection
Show Abstract · Added April 7, 2010
BACKGROUND - The primary regulator of spermatogenesis, a highly ordered and tightly regulated developmental process, is an intrinsic genetic program involving male germ cell-specific genes.
RESULTS - We analyzed the mouse spermatocyte UniGene library containing 2155 gene-oriented transcript clusters. We predict that 11% of these genes are testis-specific and systematically identified 24 authentic genes specifically and abundantly expressed in the testis via in silico and in vitro approaches. Northern blot analysis disclosed various transcript characteristics, such as expression level, size and the presence of isoform. Expression analysis revealed developmentally regulated and stage-specific expression patterns in all of the genes. We further analyzed the genes at the protein and cellular levels. Transfection assays performed using GC-2 cells provided information on the cellular characteristics of the gene products. In addition, antibodies were generated against proteins encoded by some of the genes to facilitate their identification and characterization in spermatogenic cells and sperm. Our data suggest that a number of the gene products are implicated in transcriptional regulation, nuclear integrity, sperm structure and motility, and fertilization. In particular, we found for the first time that Mm.333010, predicted to contain a trypsin-like serine protease domain, is a sperm acrosomal protein.
CONCLUSION - We identify 24 authentic genes with spermatogenic cell-specific expression, and provide comprehensive information about the genes. Our findings establish a new basis for future investigation into molecular mechanisms underlying male reproduction.
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20 MeSH Terms
Comprehensive identification and characterization of novel cardiac genes in mouse.
Park I, Hong SE, Kim TW, Lee J, Oh J, Choi E, Han C, Lee H, Han Kim D, Cho C
(2007) J Mol Cell Cardiol 43: 93-106
MeSH Terms: Animals, Blotting, Northern, COS Cells, Calcium, Cell Line, Cercopithecus aethiops, Computational Biology, Gene Expression Regulation, Developmental, Gene Library, Genes, Genome, Mice, Myocardium, Oligonucleotide Array Sequence Analysis, Protein Transport, RNA, Messenger, Subcellular Fractions, Tissue Distribution
Show Abstract · Added April 7, 2010
Comprehensive understanding of the molecular and physiological events occurring in cardiac muscle requires identification of unknown genes expressed in this tissue. We analyzed the mouse cardiac muscle UniGene library containing 827 gene-oriented transcript clusters, predicting that 19% of these genes are unknown. We systematically identified 15 authentic novel genes abundantly expressed in cardiac muscle. Northern blot analysis revealed transcriptional characteristics of the genes, such as transcript size and presence of isoforms. Transfection assays performed using various cell lines including mouse cardiac muscle cells provided information on the cellular characteristics of the novel proteins. Using correlation analysis, we identified co-regulated genes from previously reported microarray data sets. Our in silico and in vitro data suggest that a number of the novel genes are implicated in calcium metabolism, mitochondrial functions and gene transcription. In particular, we obtained new and direct evidence that one of the novel proteins is a calcium-binding protein. Taken together, we identified and characterized a number of novel cardiac genes by integrative approach. Our inclusive data establish a firm basis for future investigation into the cardiac gene network and functions of these genes.
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18 MeSH Terms