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A dihydro-pyrido-indole potently inhibits HSV-1 infection by interfering the viral immediate early transcriptional events.
Bag P, Ojha D, Mukherjee H, Halder UC, Mondal S, Biswas A, Sharon A, Van Kaer L, Chakrabarty S, Das G, Mitra D, Chattopadhyay D
(2014) Antiviral Res 105: 126-34
MeSH Terms: Animals, Antiviral Agents, Disease Models, Animal, Female, Harmaline, Herpes Simplex, Herpesvirus 1, Human, Immediate-Early Proteins, Mice, Inbred BALB C, Rubiaceae, Transcription, Genetic
Show Abstract · Added March 20, 2014
In our continued quest for identifying novel molecules from ethnomedicinal source we have isolated an alkaloid 7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole, also known as Harmaline (HM), from an ethnomedicinal herb Ophiorrhiza nicobarica. The compound exhibited a potent anti-HSV-1 activity against both wild type and clinical isolates of HSV-1. Further we demonstrated that HM did not interfere in viral entry but the recruitment of lysine-specific demethylase-1 (LSD1) and the binding of immediate-early (IE) complex on ICP0 promoter. This leads to the suppression of viral IE gene synthesis and thereby the reduced expression of ICP4 and ICP27. Moreover, HM at its virucidal concentration is nontoxic and reduced virus yields in cutaneously infected Balb/C mice. Thus, the interference in the binding of IE complex, a decisive factor for HSV lytic cycle or latency by HM reveals an interesting target for developing non-nucleotide antiherpetic agent with different mode of action than Acyclovir.
Copyright © 2014 Elsevier B.V. All rights reserved.
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11 MeSH Terms
ATR and ATRIP are recruited to herpes simplex virus type 1 replication compartments even though ATR signaling is disabled.
Mohni KN, Livingston CM, Cortez D, Weller SK
(2010) J Virol 84: 12152-64
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Ataxia Telangiectasia Mutated Proteins, Blotting, Western, Cell Cycle Proteins, Chlorocebus aethiops, DNA Damage, DNA Primers, DNA-Binding Proteins, Fluorescent Antibody Technique, HeLa Cells, Herpesvirus 1, Human, Humans, Immediate-Early Proteins, Immunoprecipitation, Phosphorylation, Plasmids, Protein-Serine-Threonine Kinases, Replication Protein A, Signal Transduction, Ubiquitin-Protein Ligases, Vero Cells, Virus Replication
Show Abstract · Added March 11, 2014
Although the herpes simplex virus type 1 (HSV-1) genome might be expected to induce a DNA damage response, the ATR kinase is not activated in infected cells. We previously proposed that spatial uncoupling of ATR from its interaction partner, ATRIP, could be the basis for inactivation of the ATR kinase in infected cells; however, we now show that ATR and ATRIP are in fact both recruited to HSV-1 replication compartments and can be coimmunoprecipitated from infected-cell lysates. ATRIP and replication protein A (RPA) are recruited to the earliest detectable prereplicative sites, stage II microfoci. In a normal cellular DNA damage response, ATR/ATRIP are recruited to stretches of RPA-coated single-stranded DNA in an RPA- and kinase-dependent manner, resulting in the phosphorylation of RPA by ATR in damage foci. In contrast, in HSV-1-infected cells, RPA is not phosphorylated, and endogenous phosphorylated RPA is excluded from stage II microfoci; in addition, the recruitment of ATR/ATRIP is independent of RPA and the kinase activity of ATR. Furthermore, we show that ATR/ATRIP play a beneficial role in viral gene expression and virus production. Although ICP0 has been shown to be important for partial inactivation of other cellular DNA repair pathways, we show that ICP0 is not responsible for the inactivation of ATR signaling and, furthermore, that neither ATR nor ATRIP is a target of ICP0 degradation. Thus, ATR and ATRIP may function outside the context of the canonical ATR damage signaling pathway during HSV-1 infection to participate in the viral life cycle.
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23 MeSH Terms
The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor.
Schlisio S, Kenchappa RS, Vredeveld LC, George RE, Stewart R, Greulich H, Shahriari K, Nguyen NV, Pigny P, Dahia PL, Pomeroy SL, Maris JM, Look AT, Meyerson M, Peeper DS, Carter BD, Kaelin WG
(2008) Genes Dev 22: 884-93
MeSH Terms: Animals, Animals, Newborn, Apoptosis, Cells, Cultured, Child, Chromosome Mapping, Chromosomes, Mammalian, DNA-Binding Proteins, HeLa Cells, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases, Immediate-Early Proteins, Immunoblotting, Kinesin, Medulloblastoma, Mice, Mice, Knockout, Models, Biological, Mutation, Missense, Nerve Tissue Proteins, Neuroblastoma, Neurons, PC12 Cells, Pheochromocytoma, Procollagen-Proline Dioxygenase, RNA Interference, Rats, Tumor Suppressor Proteins
Show Abstract · Added March 5, 2014
VHL, NF-1, c-Ret, and Succinate Dehydrogenase Subunits B and D act on a developmental apoptotic pathway that is activated when nerve growth factor (NGF) becomes limiting for neuronal progenitor cells and requires the EglN3 prolyl hydroxylase as a downstream effector. Germline mutations of these genes cause familial pheochromocytoma and other neural crest-derived tumors. Using an unbiased shRNA screen we found that the kinesin KIF1Bbeta acts downstream from EglN3 and is both necessary and sufficient for neuronal apoptosis when NGF becomes limiting. KIF1Bbeta maps to chromosome 1p36.2, which is frequently deleted in neural crest-derived tumors including neuroblastomas. We identified inherited loss-of-function KIF1Bbeta missense mutations in neuroblastomas and pheochromocytomas and an acquired loss-of-function mutation in a medulloblastoma, arguing that KIF1Bbeta is a pathogenic target of these deletions.
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28 MeSH Terms
Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure.
Minamishima YA, Moslehi J, Bardeesy N, Cullen D, Bronson RT, Kaelin WG
(2008) Blood 111: 3236-44
MeSH Terms: Alleles, Animals, Cells, Cultured, DNA-Binding Proteins, Echocardiography, Enzyme Activation, Erythropoiesis, Gene Expression Regulation, Enzymologic, Heart Failure, Hypoxia-Inducible Factor-Proline Dioxygenases, Immediate-Early Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Polycythemia, Procollagen-Proline Dioxygenase, RNA, Messenger
Show Abstract · Added March 4, 2015
Pharmacologic activation of the heterodimeric HIF transcription factor appears promising as a strategy to treat diseases, such as anemia, myocardial infarction, and stroke, in which tissue hypoxia is a prominent feature. HIF accumulation is normally linked to oxygen availability because an oxygen-dependent posttranslational modification (prolyl hydroxylation) marks the HIFalpha subunit for polyubiquitination and destruction. Three enzymes (PHD1, PHD2, and PHD3) capable of catalyzing this reaction have been identified, although PHD2 (also called Egln1) appears to be the primary HIF prolyl hydroxylase in cell culture experiments. We found that conditional inactivation of PHD2 in mice is sufficient to activate a subset of HIF target genes, including erythropoietin, leading to striking increases in red blood cell production. Mice lacking PHD2 exhibit premature mortality associated with marked venous congestion and dilated cardiomyopathy. The latter is likely the result of hyperviscosity syndrome and volume overload, although a direct effect of chronic, high-level HIF stimulation on cardiac myocytes cannot be excluded.
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18 MeSH Terms
Characterization of a putative intrarenal serotonergic system.
Xu J, Yao B, Fan X, Langworthy MM, Zhang MZ, Harris RC
(2007) Am J Physiol Renal Physiol 293: F1468-75
MeSH Terms: Animals, Aromatic-L-Amino-Acid Decarboxylases, Cell Line, Connective Tissue Growth Factor, Immediate-Early Proteins, Immunohistochemistry, In Situ Hybridization, Intercellular Signaling Peptides and Proteins, Kidney Cortex, Kidney Tubules, Proximal, Male, Mice, Mitogen-Activated Protein Kinase Kinases, Phosphorylation, Podocytes, Rats, Rats, Sprague-Dawley, Receptor, Serotonin, 5-HT2A, Receptors, Serotonin, Serotonin, Serotonin Plasma Membrane Transport Proteins, Signal Transduction, Tissue Distribution, Transforming Growth Factor beta, Tryptophan Hydroxylase, Vascular Endothelial Growth Factor A
Show Abstract · Added January 28, 2014
Serotonin [5-hydroxytryptamine (5HT)] acts through multiple G protein-coupled 5-HT receptors, and its activity is also regulated by the 5-HT transporter. The current studies report the expression and localization of the 5-HT receptors and transporter in the kidney. In addition, the enzymatic pathway mediating 5-HT synthesis is present in renal cortex, especially in the proximal tubules and glomerular epithelial cells and mesangial cells. Expression of the 5-HT receptors and 5-HT transporter was detected by RT-PCR in cell lines of these cell types. In cultured proximal tubule cells and podocytes, 5-HT activated ERK1/2 and increased the expression of connective tissue growth factor and transforming growth factor-beta, two key mediators of extracellular matrix accumulation. Immunohistochemistry and real-time RT-PCR studies also indicated that 5-HT stimulated expression of vascular endothelial growth factor in podocytes in vitro and in vivo. Therefore, these results indicate the presence of an integrated intrarenal serotonergic system and suggest a possible role for 5-HT as a mediator of renal fibrosis in the kidney.
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26 MeSH Terms
Dexamethasone modulates ErbB tyrosine kinase expression and signaling through multiple and redundant mechanisms in cultured rat hepatocytes.
Scheving LA, Buchanan R, Krause MA, Zhang X, Stevenson MC, Russell WE
(2007) Am J Physiol Gastrointest Liver Physiol 293: G552-9
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Cell Cycle Proteins, Cell Proliferation, Cells, Cultured, DNA Replication, Dexamethasone, Dose-Response Relationship, Drug, Dual Specificity Phosphatase 1, ErbB Receptors, Glucocorticoids, Hepatocytes, Immediate-Early Proteins, Male, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Phosphatidylinositol 3-Kinases, Phosphoprotein Phosphatases, Phosphorylation, Protein Phosphatase 1, Protein Tyrosine Phosphatases, Proto-Oncogene Proteins c-akt, Rats, Rats, Sprague-Dawley, Receptor, ErbB-2, Receptor, ErbB-3, SOS1 Protein, Signal Transduction, Time Factors, Transforming Growth Factor alpha
Show Abstract · Added March 24, 2014
Glucocorticoids paradoxically exert both stimulatory and inhibitory effects on the proliferation of cultured rat hepatocytes. We studied the effects of dexamethasone, a synthetic glucocorticoid, on the proliferation of cultured rat hepatocytes. The timing of growth factor addition modified the action of high-dose dexamethasone (10(-6) M) on DNA synthesis. When we added transforming growth factor-alpha at the time of plating, 10(-6) M dexamethasone weakly stimulated DNA synthesis by 26% relative to cells cultured in dexamethasone-free media. When we delayed growth factor addition until 24-48 h after plating, 10(-6) M dexamethasone inhibited DNA synthesis by 50%. Using immunological methods, we analyzed the expression and signaling patterns of the ErbB kinases in dexamethasone-treated cells. High-dose dexamethasone stabilized the expression of epidermal growth factor receptor (EGFr) and ErbB3, and it suppressed the de novo expression of ErbB2 that occurs during the third and fourth day of culture in 10(-8) M dexamethasone. High-dose dexamethasone by 72 h suppressed basal and EGF-associated phosphorylation of ERK and Akt. The reduction in ERK1/2 phosphorylation correlated with suppression of a culture-dependent increase in Son-of sevenless 1 (Sos1) and ERK1/2 expression. High-dose dexamethasone in hepatocytes stabilized or upregulated several inhibitory effectors of EGFr/ErbB2 and ERK, including receptor-associated late transducer (RALT) and MKP-1, respectively. Thus 10(-6) M dexamethasone exerts a time-dependent and redundant inhibitory effect on EGFr-mediated proliferative signaling in hepatocytes, targeting not only the ErbB proteins but also their various positive and negative effectors.
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30 MeSH Terms
Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression.
Ijichi H, Chytil A, Gorska AE, Aakre ME, Fujitani Y, Fujitani S, Wright CV, Moses HL
(2006) Genes Dev 20: 3147-60
MeSH Terms: Adenocarcinoma, Aging, Animals, Carcinoma, Pancreatic Ductal, Connective Tissue Growth Factor, Disease Progression, Epithelium, Gene Expression, Genes, ras, Heterozygote, Immediate-Early Proteins, Intercellular Signaling Peptides and Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Neoplasm Invasiveness, Pancreas, Pancreatic Neoplasms, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Signal Transduction, Stromal Cells, Transcription Factors, Transforming Growth Factor beta, Tumor Cells, Cultured
Show Abstract · Added February 17, 2014
Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in humans. Transforming growth factor-beta (TGF-beta) signaling plays an important role in PDAC progression, as indicated by the fact that Smad4, which encodes a central signal mediator downstream from TGF-beta, is deleted or mutated in 55% and the type II TGF-beta receptor (Tgfbr2) gene is altered in a smaller subset of human PDAC. Pancreas-specific Tgfbr2 knockout mice have been generated, alone or in the context of active Kras (Kras(G12D)) expression, using the Cre-loxP system driven by the endogenous Ptf1a (pancreatic transcription factor-1a) locus. Pancreas-selective Tgfbr2 knockout alone gave no discernable phenotype in 1.5 yr. Pancreas-specific Kras(G12D) activation alone essentially generated only intraepithelial neoplasia within 1 yr. In contrast, the Tgfbr2 knockout combined with Kras(G12D) expression developed well-differentiated PDAC with 100% penetrance and a median survival of 59 d. Heterozygous deletion of Tgfbr2 with Kras(G12D) expression also developed PDAC, which indicated a haploinsufficiency of TGF-beta signaling in this genetic context. The clinical and histopathological manifestations of the combined Kras(G12D) expression and Tgfbr2 knockout mice recapitulated human PDAC. The data show that blockade of TGF-beta signaling and activated Ras signaling cooperate to promote PDAC progression.
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27 MeSH Terms
Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood.
Glorioso C, Sabatini M, Unger T, Hashimoto T, Monteggia LM, Lewis DA, Mirnics K
(2006) Mol Psychiatry 11: 633-48
MeSH Terms: Animals, Brain Diseases, Brain-Derived Neurotrophic Factor, Crosses, Genetic, Doxycycline, Gene Expression Profiling, Gene Expression Regulation, Developmental, Genes, Immediate-Early, Humans, Immediate-Early Proteins, Interneurons, Intracellular Signaling Peptides and Proteins, Mice, Mice, Knockout, Nerve Tissue Proteins, Neurons, Neuropeptide Y, Oligonucleotide Array Sequence Analysis, Organ Specificity, Phenotype, Prefrontal Cortex, Recombinant Fusion Proteins, Sequence Deletion, Somatostatin, Time Factors, Transcription, Genetic, gamma-Aminobutyric Acid
Show Abstract · Added May 19, 2014
Brain-derived neurotrophic factor (BDNF) has been reported to be critical for the development of cortical inhibitory neurons. However, the effect of BDNF on the expression of transcripts whose protein products are involved in gamma amino butric acid (GABA) neurotransmission has not been assessed. In this study, gene expression profiling using oligonucleotide microarrays was performed in prefrontal cortical tissue from mice with inducible deletions of BDNF. Both embryonic and adulthood ablation of BDNF gave rise to many shared transcriptome changes. BDNF appeared to be required to maintain gene expression in the SST-NPY-TAC1 subclass of GABA neurons, although the absence of BDNF did not alter their general phenotype as inhibitory neurons. Furthermore, we observed expression alterations in genes encoding early-immediate genes (ARC, EGR1, EGR2, FOS, DUSP1, DUSP6) and critical cellular signaling systems (CDKN1c, CCND2, CAMK1g, RGS4). These BDNF-dependent gene expression changes may illuminate the biological basis for transcriptome changes observed in certain human brain disorders.
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27 MeSH Terms
NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts.
Cucoranu I, Clempus R, Dikalova A, Phelan PJ, Ariyan S, Dikalov S, Sorescu D
(2005) Circ Res 97: 900-7
MeSH Terms: Actins, Cell Differentiation, Cells, Cultured, Connective Tissue Growth Factor, Fibroblasts, Fibrosis, Humans, Immediate-Early Proteins, Intercellular Signaling Peptides and Proteins, Myocardium, NADPH Oxidase 4, NADPH Oxidases, RNA, Messenger, Reactive Oxygen Species, Smad2 Protein, Smad3 Protein, Superoxides, Transforming Growth Factor beta, Transforming Growth Factor beta1
Show Abstract · Added February 17, 2016
Human cardiac fibroblasts are the main source of cardiac fibrosis associated with cardiac hypertrophy and heart failure. Transforming growth factor-beta1 (TGF-beta1) irreversibly converts fibroblasts into pathological myofibroblasts, which express smooth muscle alpha-actin (SM alpha-actin) de novo and produce extracellular matrix. We hypothesized that TGF-beta1-stimulated conversion of fibroblasts to myofibroblasts requires reactive oxygen species derived from NAD(P)H oxidases (Nox). We found that TGF-beta1 potently upregulates the contractile marker SM alpha-actin mRNA (7.5+/-0.8-fold versus control). To determine whether Nox enzymes are involved, we first performed quantitative real time polymerase chain reaction and found that Nox5 and Nox4 are abundantly expressed in cardiac fibroblasts, whereas Nox1 and Nox2 are barely detectable. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated by 16.2+/-0.8-fold (n=3, P<0.005), whereas Nox5 is downregulated. Small interference RNA against Nox4 downregulates Nox4 mRNA by 80+/-5%, inhibits NADPH-driven superoxide production in response to TGF-beta1 by 65+/-7%, and reduces TGF-beta1-induced expression of SM alpha-actin by 95+/-2% (n=6, P<0.05). Because activation of small mothers against decapentaplegic (Smads) 2/3 is critical for myofibroblast conversion in response to TGF-beta1, we also determined whether Nox4 affects Smad 2/3 phosphorylation. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation by 75+/-5% and 68+/-3%, respectively (n=7, P<0.0001). We conclude that Nox 4 mediates TGF-beta1-induced conversion of fibroblasts to myofibroblasts by regulating Smad 2/3 activation. Thus, Nox4 may play a critical role in the pathological activation of cardiac fibroblasts in cardiac fibrosis associated with human heart failure.
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19 MeSH Terms
Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer.
Lee S, Nakamura E, Yang H, Wei W, Linggi MS, Sajan MP, Farese RV, Freeman RS, Carter BD, Kaelin WG, Schlisio S
(2005) Cancer Cell 8: 155-67
MeSH Terms: Adrenal Gland Neoplasms, Apoptosis, Basic Helix-Loop-Helix Transcription Factors, DNA-Binding Proteins, Dioxygenases, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases, Immediate-Early Proteins, Mutation, Nerve Growth Factor, Neurons, Pheochromocytoma, Procollagen-Proline Dioxygenase, Protein Kinase C, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-jun, Proto-Oncogene Proteins c-ret, Receptor Protein-Tyrosine Kinases, Signal Transduction, Succinate Dehydrogenase, Sympathetic Nervous System, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added March 5, 2014
Germline NF1, c-RET, SDH, and VHL mutations cause familial pheochromocytoma. Pheochromocytomas derive from sympathetic neuronal precursor cells. Many of these cells undergo c-Jun-dependent apoptosis during normal development as NGF becomes limiting. NF1 encodes a GAP for the NGF receptor TrkA, and NF1 mutations promote survival after NGF withdrawal. We found that pheochromocytoma-associated c-RET and VHL mutations lead to increased JunB, which blunts neuronal apoptosis after NGF withdrawal. We also found that the prolyl hydroxylase EglN3 acts downstream of c-Jun and is specifically required among the three EglN family members for apoptosis in this setting. Moreover, EglN3 proapoptotic activity requires SDH activity because EglN3 is feedback inhibited by succinate. These studies suggest that failure of developmental apoptosis plays a role in pheochromocytoma pathogenesis.
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26 MeSH Terms