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Methotrexate inhibits NF-κB activity via long intergenic (noncoding) RNA-p21 induction.
Spurlock CF, Tossberg JT, Matlock BK, Olsen NJ, Aune TM
(2014) Arthritis Rheumatol 66: 2947-57
MeSH Terms: Adult, Antirheumatic Agents, Arthritis, Rheumatoid, Cell Line, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p21, DNA-Activated Protein Kinase, Dose-Response Relationship, Drug, Female, Humans, Male, Methotrexate, Middle Aged, Monocytes, NF-kappa B, Nuclear Proteins, RNA, Long Noncoding, T-Lymphocytes, Tumor Suppressor Protein p53, eIF-2 Kinase
Show Abstract · Added January 21, 2015
OBJECTIVE - To determine interrelationships between the expression of long intergenic (noncoding) RNA-p21 (lincRNA-p21), NF-κB activity, and responses to methotrexate (MTX) in rheumatoid arthritis (RA) by analyzing patient blood samples and cell culture models.
METHODS - Expression levels of long noncoding RNA and messenger RNA (mRNA) were determined by quantitative reverse transcription-polymerase chain reaction. Western blotting and flow cytometry were used to quantify levels of intracellular proteins. Intracellular NF-κB activity was determined using an NF-κB luciferase reporter plasmid.
RESULTS - Patients with RA expressed reduced basal levels of lincRNA-p21 and increased basal levels of phosphorylated p65 (RelA), a marker of NF-κB activation. Patients with RA who were not treated with MTX expressed lower levels of lincRNA-p21 and higher levels of phosphorylated p65 compared with RA patients treated with low-dose MTX. In cell culture using primary cells and transformed cell lines, MTX induced lincRNA-p21 through a DNA-dependent protein kinase catalytic subunit (DNA PKcs)-dependent mechanism. Deficiencies in the levels of PRKDC mRNA in patients with RA were also corrected by MTX in vivo. Furthermore, MTX reduced NF-κB activity in tumor necrosis factor α-treated cells through a DNA PKcs-dependent mechanism via induction of lincRNA-p21. Finally, we observed that depressed levels of TP53 and lincRNA-p21 increased NF-κB activity in cell lines. Decreased levels of lincRNA-p21 did not alter NFKB1 or RELA transcripts; rather, lincRNA-p21 physically bound to RELA mRNA.
CONCLUSION - Our findings support a model whereby depressed levels of lincRNA-p21 in RA contribute to increased NF-κB activity. MTX decreases basal levels of NF-κB activity by increasing lincRNA-p21 levels through a DNA PKcs-dependent mechanism.
Copyright © 2014 by the American College of Rheumatology.
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20 MeSH Terms
Neuroprotective targets through which 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), a sigma receptor ligand, mitigates the effects of methamphetamine in vitro.
Kaushal N, Robson MJ, Rosen A, McCurdy CR, Matsumoto RR
(2014) Eur J Pharmacol 724: 193-203
MeSH Terms: Animals, Apoptosis, Benzoxazoles, Caspases, Cell Line, Tumor, Fever, Ligands, Methamphetamine, Mice, Necrosis, Neuroprotective Agents, Piperazines, Reactive Nitrogen Species, Reactive Oxygen Species, Receptors, sigma, eIF-2 Kinase
Show Abstract · Added August 26, 2015
Exposure to high or repeated doses of methamphetamine can cause hyperthermia and neurotoxicity, which are thought to increase the risk of developing a variety of neurological conditions. Sigma receptor antagonism can prevent methamphetamine-induced hyperthermia and neurotoxicity, but the underlying cellular targets through which the neuroprotection is conveyed remain unknown. Differentiated NG108-15 cells were thus used as a model system to begin elucidating the neuroprotective mechanisms targeted by sigma receptor antagonists to mitigate the effects of methamphetamine. In differentiated NG108-15 cells, methamphetamine caused the generation of reactive oxygen/nitrogen species, an increase in PERK-mediated endoplasmic reticulum stress and the activation of caspase-3, -8 and -9, ultimately resulting in apoptosis at micromolar concentrations, and necrotic cell death at higher concentrations. The sigma receptor antagonist, 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), attenuated methamphetamine-induced increases in reactive oxygen/nitrogen species, activation of caspase-3, -8 and -9 and accompanying cellular toxicity. In contrast, 1,3-di(2-tolyl)-guanidine (DTG), a sigma receptor agonist, shifted the dose response curve of methamphetamine-induced cell death towards the left. To probe the effect of temperature on neurotoxicity, NG108-15 cells maintained at an elevated temperature (40 °C) exhibited a significant and synergistic increase in cell death in response to methamphetamine, compared to cells maintained at a normal cell culture temperature (37 °C). SN79 attenuated the enhanced cell death observed in the methamphetamine-treated cells at 40 °C. Together, the data demonstrate that SN79 reduces methamphetamine-induced reactive oxygen/nitrogen species generation and caspase activation, thereby conveying neuroprotective effects against methamphetamine under regular and elevated temperature conditions.
Copyright © 2014 Elsevier B.V. All rights reserved.
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16 MeSH Terms
Activation of protein kinase R is required for induction of stress granules by respiratory syncytial virus but dispensable for viral replication.
Lindquist ME, Mainou BA, Dermody TS, Crowe JE
(2011) Virology 413: 103-10
MeSH Terms: Cell Line, Cytoplasmic Granules, Enzyme Activation, Humans, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses, Virus Replication, eIF-2 Kinase
Show Abstract · Added December 10, 2013
We performed experiments to determine the effect of PKR activation on respiratory syncytial virus (RSV) replication. We first determined that RSV infection activates PKR which induces the phosphorylation of eIF2α, resulting in the formation of host stress granules. We used RNA interference to decrease endogenous PKR levels. RSV replication was not altered in cells deficient for PKR expression. However, RSV-mediated stress granule formation was significantly reduced in PKR-knockdown cells. As an alternative method to block PKR activation, we used treatment with the kinase inhibitor 2-aminopurine (2-AP). We observed that 2-AP treatment significantly reduced viral replication. We also treated PKR-knockdown cells with 2-AP and inoculated with RSV. Under these conditions, 2-AP treatment diminished viral replication in the absence of PKR expression. These results suggest that PKR activation has a minimal effect on RSV replication and that the antiviral effect of 2-AP during RSV infection likely occurs via a PKR-independent mechanism.
Copyright © 2011 Elsevier Inc. All rights reserved.
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8 MeSH Terms
The early interferon response to rotavirus is regulated by PKR and depends on MAVS/IPS-1, RIG-I, MDA-5, and IRF3.
Sen A, Pruijssers AJ, Dermody TS, García-Sastre A, Greenberg HB
(2011) J Virol 85: 3717-32
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, DEAD Box Protein 58, DEAD-box RNA Helicases, Gene Deletion, Gene Expression Regulation, Interferon Regulatory Factor-3, Interferon-Induced Helicase, IFIH1, Interferon-beta, Mice, Mice, Knockout, Rotavirus, eIF-2 Kinase
Show Abstract · Added December 10, 2013
In mouse embryonic fibroblasts (MEFs), the bovine rotavirus (UK strain) but not the simian rhesus rotavirus (RRV) robustly triggers beta interferon (IFN-β) secretion, resulting in an IFN-dependent restriction of replication. We now find that both rotavirus strains trigger antiviral transcriptional responses early during infection and that both transcriptional responses and IFN-β secretion are completely abrogated in MAVS/IPS-1(-/-) MEFs. Replication of UK virus could be rescued in MAVS/IPS-1(-/-) MEFs, and synthesis of viral RNA significantly increased early during virus infection. UK virus induced IFN-β secretion and transcription of IFN-stimulated genes (ISGs) in both RIG-I(-/-) and MDA-5(-/-) MEFs, and neither receptor was essential by itself for the antiviral response to UK rotavirus. However, when receptors RIG-I and MDA-5 were depleted using RNA interference, we found that both contribute to the magnitude of the IFN response. IRF3 was found to be essential for MAVS/IPS-1-directed ISG transcription and IFN-β secretion during rotavirus infection. Interestingly, absence of the double-stranded RNA-dependent protein kinase PKR led to a profound defect in the capacity of host cells to secrete IFN-β in response to virus. Both PKR and IRF3 restricted the early replication of UK as indicated by significant increases in viral RNA in fibroblasts lacking either gene. Despite the loss in IFN-β secretion in PKR(-/-) MEFs, we did not observe decreased IRF3- or NF-κB-dependent early ISG transcription in these cells. Levels of transcripts encoding IFN-α4, IFN-α5, and IFN-β were high in infected PKR(-/-) MEFs, indicating that during rotavirus infection, PKR functions at a stage between IFN gene transcription and subsequent IFN-β secretion. These findings reveal that activation of the antiviral response by rotavirus is dependent on MAVS/IPS-1 and IRF3 and involves both RIG-I and MDA-5 and that IFN-β secretion during rotavirus infection is regulated by PKR.
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13 MeSH Terms
Regulation of G(1) arrest and apoptosis in hypoxia by PERK and GCN2-mediated eIF2alpha phosphorylation.
Liu Y, László C, Liu Y, Liu W, Chen X, Evans SC, Wu S
(2010) Neoplasia 12: 61-8
MeSH Terms: Animals, Apoptosis, Blotting, Western, Cell Hypoxia, Cell Survival, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p21, Embryo, Mammalian, Eukaryotic Initiation Factor-2, Fibroblasts, G1 Phase, Mice, Mice, Knockout, Phosphorylation, Protein-Serine-Threonine Kinases, Tumor Suppressor Protein p53, eIF-2 Kinase
Show Abstract · Added June 14, 2013
Hypoxia is a common microenvironment in solid tumors and is correlated with tumor progression by regulating cancer cell survival. Recent studies suggest that activation of double-stranded RNA-dependent protein kinase-like endoplasmic reticulum-related kinase (PERK) and phosphorylation of alpha subunit of eIF2 (eIF2alpha) confer cell adaptation to hypoxic stress. However, eIF2alpha is still phosphorylated at a lowered level in PERK knockout cells under hypoxic conditions. The mechanism for eIF2alpha kinase(s) (eIF2AK)-increased cell survival is not clear. In this report, we provide evidence that another eIF2AK, the amino acid starvation-dependent general control of amino acid biosynthesis kinase (GCN2), is also involved in hypoxia-induced eIF2alpha phosphorylation. We demonstrate that both GCN2 and PERK mediate the cell adaptation to hypoxic stress. High levels of eIF2alpha phosphorylation lead to G(1) arrest and protect cells from hypoxia-induced apoptosis. Reduced phosphorylation of eIF2alpha by knocking out either PERK or GCN2 suppresses hypoxia-induced G(1) arrest and promotes apoptosis in accompany with activation of p53 signal cascade. However, totally abolishing phosphorylation of eIF2alpha inhibits G(1) arrest without promoting apoptosis. On the basis of our results, we propose that the levels of eIF2alpha phosphorylation serve as a "switch" in regulation of G(1) arrest or apoptosis under hypoxic conditions.
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17 MeSH Terms
PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice.
Iida K, Li Y, McGrath BC, Frank A, Cavener DR
(2007) BMC Cell Biol 8: 38
MeSH Terms: Animals, Cell Death, Female, Male, Mice, Mice, Knockout, Pancreas, Exocrine, Pancreatitis, Tissue Survival, eIF-2 Kinase
Show Abstract · Added August 13, 2010
BACKGROUND - Deficiency of the PERK eIF2 alpha kinase in humans and mice results in postnatal exocrine pancreatic atrophy as well as severe growth and metabolic anomalies in other organs and tissues. To determine if the exocrine pancreatic atrophy is due to a cell-autonomous defect, the Perk gene was specifically ablated in acinar cells of the exocrine pancreas in mice.
RESULTS - We show that expression of PERK in the acinar cells is required to maintain their viability but is not required for normal protein synthesis and secretion. Exocrine pancreatic atrophy in PERK-deficient mice was previously attributed to uncontrolled ER-stress followed by apoptotic cell death based on studies in cultured fibroblasts. However, we have found no evidence for perturbations in the endoplasmic reticulum or ER-stress and show that acinar cells succumb to a non-apoptotic form of cell death, oncosis, which is associated with a pronounced inflammatory response and induction of the pancreatitis stress response genes. We also show that mice carrying a knockout mutation of PERK's downstream target, ATF4, exhibit pancreatic deficiency caused by developmental defects and that mice ablated for ATF4's transcriptional target CHOP have a normal exocrine pancreas.
CONCLUSION - We conclude that PERK modulates secretory capacity of the exocrine pancreas by regulating cell viability of acinar cells.
1 Communities
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10 MeSH Terms
PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis.
Zhang W, Feng D, Li Y, Iida K, McGrath B, Cavener DR
(2006) Cell Metab 4: 491-7
MeSH Terms: Animals, Animals, Newborn, Cell Differentiation, Cell Proliferation, Diabetes Mellitus, Fetus, Gene Expression Regulation, Developmental, Gene Expression Regulation, Enzymologic, Glucose, Homeostasis, Humans, Infant, Newborn, Insulin-Secreting Cells, Mice, Mice, Knockout, Proinsulin, eIF-2 Kinase
Show Abstract · Added August 13, 2010
Mutations in PERK (EIF2AK3) result in permanent neonatal diabetes as well as several other anomalies that underlie the human Wolcott-Rallison syndrome, and these anomalies are mirrored in Perk knockout mice. To identify the cause of diabetes in PERK-deficient mice, we generated a series of tissue- and cell-specific knockouts of the Perk gene and performed a developmental analysis of the progression to overt diabetes. We discovered that PERK is specifically required in the insulin-secreting beta cells during the fetal and early neonatal period as a prerequisite for postnatal glucose homeostasis. However, PERK expression in beta cells is not required at the adult stage to maintain beta cell functions and glucose homeostasis. We show that PERK-deficient mice exhibit severe defects in fetal/neonatal beta cell proliferation and differentiation, resulting in low beta cell mass, defects in proinsulin trafficking, and abrogation of insulin secretion that culminate in permanent neonatal diabetes.
1 Communities
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17 MeSH Terms
Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response.
Jiang HY, Wek SA, McGrath BC, Lu D, Hai T, Harding HP, Wang X, Ron D, Cavener DR, Wek RC
(2004) Mol Cell Biol 24: 1365-77
MeSH Terms: Activating Transcription Factor 3, Activating Transcription Factor 4, Animals, CCAAT-Enhancer-Binding Proteins, Eukaryotic Initiation Factor-2, Mice, Phosphorylation, Phosphotransferases, Protein Kinases, Protein-Serine-Threonine Kinases, RNA, Messenger, Transcription Factor CHOP, Transcription Factors, eIF-2 Kinase
Show Abstract · Added August 13, 2010
In response to environmental stress, cells induce a program of gene expression designed to remedy cellular damage or, alternatively, induce apoptosis. In this report, we explore the role of a family of protein kinases that phosphorylate eukaryotic initiation factor 2 (eIF2) in coordinating stress gene responses. We find that expression of activating transcription factor 3 (ATF3), a member of the ATF/CREB subfamily of basic-region leucine zipper (bZIP) proteins, is induced in response to endoplasmic reticulum (ER) stress or amino acid starvation by a mechanism requiring eIF2 kinases PEK (Perk or EIF2AK3) and GCN2 (EIF2AK4), respectively. Increased expression of ATF3 protein occurs early in response to stress by a mechanism requiring the related bZIP transcriptional regulator ATF4. ATF3 contributes to induction of the CHOP transcriptional factor in response to amino acid starvation, and loss of ATF3 function significantly lowers stress-induced expression of GADD34, an eIF2 protein phosphatase regulatory subunit implicated in feedback control of the eIF2 kinase stress response. Overexpression of ATF3 in mouse embryo fibroblasts partially bypasses the requirement for PEK for induction of GADD34 in response to ER stress, further supporting the idea that ATF3 functions directly or indirectly as a transcriptional activator of genes targeted by the eIF2 kinase stress pathway. These results indicate that ATF3 has an integral role in the coordinate gene expression induced by eIF2 kinases. Given that ATF3 is induced by a very large number of environmental insults, this study supports involvement of eIF2 kinases in the coordination of gene expression in response to a more diverse set of stress conditions than previously proposed.
1 Communities
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14 MeSH Terms
The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas.
Zhang P, McGrath B, Li S, Frank A, Zambito F, Reinert J, Gannon M, Ma K, McNaughton K, Cavener DR
(2002) Mol Cell Biol 22: 3864-74
MeSH Terms: Animals, Apoptosis, Bone Development, Bone Diseases, Developmental, Cell Survival, Collagen Type I, Diabetes Mellitus, Endoplasmic Reticulum, Rough, Eukaryotic Initiation Factor-2, Gene Expression, Glucose, Growth Disorders, Humans, Mice, Mice, Knockout, Pancreas, Phosphorylation, eIF-2 Kinase
Show Abstract · Added January 6, 2014
Phosphorylation of eukaryotic initiation factor 2 alpha (eIF-2 alpha) is typically associated with stress responses and causes a reduction in protein synthesis. However, we found high phosphorylated eIF-2 alpha (eIF-2 alpha[P]) levels in nonstressed pancreata of mice. Administration of glucose stimulated a rapid dephosphorylation of eIF-2 alpha. Among the four eIF-2 alpha kinases present in mammals, PERK is most highly expressed in the pancreas, suggesting that it may be responsible for the high eIF-2 alpha[P] levels found therein. We describe a Perk knockout mutation in mice. Pancreata of Perk(-/-) mice are morphologically and functionally normal at birth, but the islets of Langerhans progressively degenerate, resulting in loss of insulin-secreting beta cells and development of diabetes mellitus, followed later by loss of glucagon-secreting alpha cells. The exocrine pancreas exhibits a reduction in the synthesis of several major digestive enzymes and succumbs to massive apoptosis after the fourth postnatal week. Perk(-/-) mice also exhibit skeletal dysplasias at birth and postnatal growth retardation. Skeletal defects include deficient mineralization, osteoporosis, and abnormal compact bone development. The skeletal and pancreatic defects are associated with defects in the rough endoplasmic reticulum of the major secretory cells that comprise the skeletal system and pancreas. The skeletal, pancreatic, and growth defects are similar to those seen in human Wolcott-Rallison syndrome.
2 Communities
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18 MeSH Terms