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Aubrey R Morrison - One of the best experts on this subject based on the ideXlab platform.
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the proximal region of the 3 untranslated region of cyclooxygenase 2 is recognized by a multimeric protein complex containing hur tia 1 tiar and the heteroGeneous nuclear ribonucleoprotein u
Journal of Biological Chemistry, 2003Co-Authors: Stephen J Acton, Aubrey R MorrisonAbstract:Abstract Cyclooxygenase-2 (COX-2) is an Early Response Gene induced in renal mesangial cells by interleukin-1β (IL-1β). The 3′-untranslated region (3′-UTR) of COX-2 mRNA plays an important role in IL-1β induction by regulating message stability and translational efficiency. The first 60 nucleotides of the 3′-UTR of COX-2 are highly conserved and contain multiple copies of the regulatory sequence AUUUA. Introduction of the 60-nucleotide sequence into the 3′-UTR of a heterologous reporter Gene resulted in a 70% decrease in reporter Gene expression. Electrophoretic mobility shift assays (EMSAs) demonstrated that mesangial cell nuclear fractions contain a multimeric protein complex that bound this region of COX-2 mRNA in a sequence-specific manner. We identified four members of the protein-RNA complex as HuR, TIA-1, TIAR, and the heteroGeneous nuclear ribonucleoprotein U (hnRNP U). Treatment of mesangial cells with IL-1β caused an increase in cytosolic HuR, which was accompanied by an increase in COX-2 mRNA that co-immunoprecipitated with cytosolic HuR. Therefore, we propose that HuR binds to the proximal region of the 3′-UTR of COX-2 following stimulation by IL-1β and increases the expression of COX-2 mRNA by facilitating its transport out of the nucleus.
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the proximal region of the 3 untranslated region of cyclooxygenase 2 is recognized by a multimeric protein complex containing hur tia 1 tiar and the heteroGeneous nuclear ribonucleoprotein u
Journal of Biological Chemistry, 2003Co-Authors: Steven J Cok, Stephen J Acton, Aubrey R MorrisonAbstract:Cyclooxygenase-2 (COX-2) is an Early Response Gene induced in renal mesangial cells by interleukin-1beta (IL-1beta). The 3'-untranslated region (3'-UTR) of COX-2 mRNA plays an important role in IL-1beta induction by regulating message stability and translational efficiency. The first 60 nucleotides of the 3'-UTR of COX-2 are highly conserved and contain multiple copies of the regulatory sequence AUUUA. Introduction of the 60-nucleotide sequence into the 3'-UTR of a heterologous reporter Gene resulted in a 70% decrease in reporter Gene expression. Electrophoretic mobility shift assays (EMSAs) demonstrated that mesangial cell nuclear fractions contain a multimeric protein complex that bound this region of COX-2 mRNA in a sequence-specific manner. We identified four members of the protein-RNA complex as HuR, TIA-1, TIAR, and the heteroGeneous nuclear ribonucleoprotein U (hnRNP U). Treatment of mesangial cells with IL-1beta caused an increase in cytosolic HuR, which was accompanied by an increase in COX-2 mRNA that co-immunoprecipitated with cytosolic HuR. Therefore, we propose that HuR binds to the proximal region of the 3'-UTR of COX-2 following stimulation by IL-1beta and increases the expression of COX-2 mRNA by facilitating its transport out of the nucleus.
Heiner Schäfer - One of the best experts on this subject based on the ideXlab platform.
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The Early Response Gene IEX-1 attenuates NF-κB activation in 293 cells, a possible counter-regulatory process leading to enhanced cell death
Oncogene, 2003Co-Authors: Alexander Arlt, Marie-luise Kruse, Maike Breitenbroich, André Gehrz, Bülent Koc, Jörg Minkenberg, Ulrich R. Fölsch, Heiner SchäferAbstract:The Early Response Gene IEX-1 attenuates NF- κ B activation in 293 cells, a possible counter-regulatory process leading to enhanced cell death
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The proliferation-associated Early Response Gene p22/PRG1 is a novel p53 target Gene.
Oncogene, 1998Co-Authors: Heiner Schäfer, Ulrich R. Fölsch, Anna Trauzold, Thorsten Sebens, Wolfgang Deppert, Wolfgang E. SchmidtAbstract:The novel Early Response Gene p22/PRG1 is linked to cell cycle entry and the induction of proliferation in various cell types although its exact function is still unknown. The p22/PRG1 promoter region contains a 20 bp sequence matching the consensus binding motif for the tumor suppressor protein p53. Gel shift assays demonstrated that p53 specifically binds to an oligonucleotide derived from the p53 binding site of the p22/PRG1 promoter. Chloramphenicol acetyltransferase (CAT) reporter Gene assays confirmed that this site confers p53-dependent transcriptional activity to the p22/PRG1 promoter. In Hela cells, p22/PRG1 promoter constructs induced CAT expression only when cotransfected with an expression plasmid for wild-type, but not for mutant p53. Similarly, CAT expression was inducible at the permissive (31 degrees C) but not at the non-permissive temperature (39 degrees C) in the rat embryo fibroblast-derived cell line clone-6 that expresses a temperature-sensitive mutant p53. Conversion of this mutant p53 to a functional p53 at the permissive temperature was accompanied by a significant increase of endogenous p22/PRG1 mRNA level in this cell line. Gamma-irradiation of rat splenocytes or doxorubicin-treatment of Hela cells increased p53 levels followed by transcriptional activation of p22/PRG1 and p21/Waf1 in parallel. Our data demonstrate that p22/PRG1 transcription is induced by p53 during p53-dependent cell cycle arrest and apoptosis. Therefore, p22/PRG1 represents a novel target for transcriptional activation by p53.
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prg1 a novel Early Response Gene transcriptionally induced by pituitary adenylate cyclase activating polypeptide in a pancreatic carcinoma cell line
Cancer Research, 1996Co-Authors: Heiner Schäfer, Ulrich R. Fölsch, Anna Trauzold, E G Siegel, Wolfgang E. SchmidtAbstract:The rat pancreatic carcinoma cell line AR4-2J was screened for growth-associated Genes linked to the mitogenic effect of the novel gut brain hormone, pituitary adenylate cyclase activating polypeptide (PACAP). Using the mRNA differential display technique, we identified and sequenced an unknown rat Gene, PACAP-responsive Gene 1 ( PRG1 ), which is highly homologous to gly96 , a novel murine Gene of unknown function. The PRG1 cDNA sequence of 1.1 kb encodes a 160-amino acid protein. Using targeted PCR, the Gene structure of PRG1 , constituting 0.6 kb of the promotor region, and the DNA coding region, including a single 107-bp intron, were established from rat genomic DNA. In AR4-2J cells, PACAP(1–38) increased PRG1 mRNA levels up to 10-fold in a rapid (30 min), translent (3–6 h), and dose-dependent (ED50, <1 nm) fashion. The growth-stimulating gastrointestinal hormones cholecystokinin and gastrin showed a similar degree of PRG1 induction, and the PACAP-related peptides vasoactive intestinal peptide and secretin were without effect. The transcriptional inhibitor actinomycin D, various protein kinase C inhibitors, and the calmodulin inhibitor W-7 strongly reduced PRG1 induction by PACAP, whereas the translational inhibitor cycloheximide potently increased PRG1 mRNA levels in unstimulated and PACAP-stimulated cells. Feedback-mediated hyperplasia of the rat exocrine pancreas induced by oral treatment of rats with the protease inhibitor camostate ( FOY-305 ) was preceded by a 15-fold transient elevation of PRG1 mRNA levels. These data suggest that PRG1 is an Early-Response Gene linked to PACAP-induced growth of AR4-2J cells as well as to hyperplasia of the rat exocrine pancreas in vivo .
Fudong Liu - One of the best experts on this subject based on the ideXlab platform.
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Knockout of vascular Early Response Gene worsens chronic stroke outcomes in neonatal mice
Brain research bulletin, 2013Co-Authors: Mehwish A Mirza, Louise D. Mccullough, Lori A. Capozzi, Fudong LiuAbstract:Abstract Vascular Early Response Gene (Verge) is a novel immediate Early Gene that is highly expressed during developmental angioGenesis and after ischemic insults in adult brain. However, the role of Verge after neonatal injury is not known. In the present study, we investigated the hypothesis that Verge contributes to vascular remodeling and tissue repair after neonatal ischemic injury. The Rice–Vanucci model (RVM) was employed to induce neonatal stroke in both Verge knockout (KO) and wild-type (WT) postnatal day 10 (P10) mice. Histological and behavioral outcomes at acute (24 h), subacute (7 days) and chronic (30 days) phases were evaluated. AngioGenesis, neuroGenesis, and glial scar formation were also examined in the ischemic brain. No significant differences in outcomes were found between WT and Verge mice at 24 h or 7 days after stroke. However Genetic deletion of Verge led to pronounced cystic cavitation, decreased angioGenensis and glial scar formation in the ischemic hemisphere compared to WT mice at 30 days. Verge KO mice also had significantly worse functional outcomes at 30 days which was accompanied by decreased neuroGenesis and angioGenesis in the ischemic hemisphere. Our study suggests that Verge plays an important role in the induction of neuroGenesis and angioGenesis after ischemia, contributes to improved tissue repair, and enhances chronic functional recovery.
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Loss of Vascular Early Response Gene Reduces Edema Formation After Experimental Stroke
Experimental & translational stroke medicine, 2012Co-Authors: Fudong Liu, Jean B. Regard, Paul F. Worley, L. Christine Turtzo, Neer Zeevi, Louise D. McculloughAbstract:Vascular Early Response Gene (Verge) is an immediate Early Gene (IEG) that is up-regulated in endothelial cells in Response to a number of stressors, including ischemic stroke. Endothelial cell lines that stably express Verge show enhanced permeability. Increased Verge expression has also been associated with blood brain barrier breakdown. In this study we investigated the role of Verge in ischemic injury induced by middle cerebral artery occlusion (MCAO) in both Verge knockout (KO) and wild type (WT) mice. Verge KO mice had significantly less cerebral edema formation after MCAO compared to WT mice. However, stroke outcome (infarct size and neurological deficit scores) evaluated at either 24 or 72 hours after stroke showed no differences between the two genotypes. Verge deletion leads to decreased edema formation after ischemia; however acute stroke outcomes were unchanged.
Louise D. Mccullough - One of the best experts on this subject based on the ideXlab platform.
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Knockout of vascular Early Response Gene worsens chronic stroke outcomes in neonatal mice
Brain research bulletin, 2013Co-Authors: Mehwish A Mirza, Louise D. Mccullough, Lori A. Capozzi, Fudong LiuAbstract:Abstract Vascular Early Response Gene (Verge) is a novel immediate Early Gene that is highly expressed during developmental angioGenesis and after ischemic insults in adult brain. However, the role of Verge after neonatal injury is not known. In the present study, we investigated the hypothesis that Verge contributes to vascular remodeling and tissue repair after neonatal ischemic injury. The Rice–Vanucci model (RVM) was employed to induce neonatal stroke in both Verge knockout (KO) and wild-type (WT) postnatal day 10 (P10) mice. Histological and behavioral outcomes at acute (24 h), subacute (7 days) and chronic (30 days) phases were evaluated. AngioGenesis, neuroGenesis, and glial scar formation were also examined in the ischemic brain. No significant differences in outcomes were found between WT and Verge mice at 24 h or 7 days after stroke. However Genetic deletion of Verge led to pronounced cystic cavitation, decreased angioGenensis and glial scar formation in the ischemic hemisphere compared to WT mice at 30 days. Verge KO mice also had significantly worse functional outcomes at 30 days which was accompanied by decreased neuroGenesis and angioGenesis in the ischemic hemisphere. Our study suggests that Verge plays an important role in the induction of neuroGenesis and angioGenesis after ischemia, contributes to improved tissue repair, and enhances chronic functional recovery.
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Loss of Vascular Early Response Gene Reduces Edema Formation After Experimental Stroke
Experimental & translational stroke medicine, 2012Co-Authors: Fudong Liu, Jean B. Regard, Paul F. Worley, L. Christine Turtzo, Neer Zeevi, Louise D. McculloughAbstract:Vascular Early Response Gene (Verge) is an immediate Early Gene (IEG) that is up-regulated in endothelial cells in Response to a number of stressors, including ischemic stroke. Endothelial cell lines that stably express Verge show enhanced permeability. Increased Verge expression has also been associated with blood brain barrier breakdown. In this study we investigated the role of Verge in ischemic injury induced by middle cerebral artery occlusion (MCAO) in both Verge knockout (KO) and wild type (WT) mice. Verge KO mice had significantly less cerebral edema formation after MCAO compared to WT mice. However, stroke outcome (infarct size and neurological deficit scores) evaluated at either 24 or 72 hours after stroke showed no differences between the two genotypes. Verge deletion leads to decreased edema formation after ischemia; however acute stroke outcomes were unchanged.
Francoise Porteu - One of the best experts on this subject based on the ideXlab platform.
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ATM-dependent expression of IEX-1 controls nuclear accumulation of Mcl-1 and the DNA damage Response
Cell Death and Differentiation, 2010Co-Authors: Francoise Porteu, Rajiv Kumar, Patrycja Pawlikowska, Isabelle Leray, Bérengère De Laval, Soizic Guihard, Filippo RosselliAbstract:The Early-Response Gene product IEX-1 (also known as IER3) was recently found to interact with the anti-apoptotic Bcl-2 family member, Myeloid Cell Leukemia-1 (Mcl-1). We show here that this interaction specifically and timely controls the accumulation of Mcl-1 in the nucleus in Response to DNA damage. The IEX-1 protein is rapidly induced by irradiation, genotoxic agents or replication inhibitors, in a way dependent on Ataxia Telangiectasia mutated (ATM) activity and is necessary for Mcl-1 nuclear translocation. Conversely, IEX-1 protein proteasomal degradation triggers the return of Mcl-1 to the cytosol. IEX-1 and Mcl-1 are integral components of the DNA damage Response. Loss of IEX-1 or Mcl-1 leads to genomic instability and increased sensitivity to genotoxic and replicative stresses. The two proteins cooperate to maintain Chk1 activation and G2 checkpoint arrest. Mcl-1 nuclear translocation may foster checkpoint and improve the tumor resistance to DNA damage-based cancer therapies. Deciphering the pathways involved in IEX-1 degradation should lead to the discovery of new therapeutic targets to increase sensitivity of tumor cells to chemotherapy.
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inhibition of b56 containing protein phosphatase 2as by the Early Response Gene iex 1 leads to control of akt activity
Journal of Biological Chemistry, 2007Co-Authors: Geraldine Rocher, Claire Letourneux, Philippe Lenormand, Francoise PorteuAbstract:The importance of PP2A in the regulation of Akt/PKB activity has long been recognized but the nature of the holoenzyme involved and the mechanisms controlling dephosphorylation are not yet known. We identified IEX-1, an Early Gene product with proliferative and survival activities, as a specific inhibitor of B56 regulatory subunit-containing PP2A. IEX-1 inhibits B56-PP2A activity by allowing the phosphorylation of B56 by ERK. This leads to sustained ERK activation. IEX-1 has no effect on PP2A containing other B family subunits. Thus, studying IEX-1 contribution to signaling should help the discovery of new pathways controlled by B56-PP2A. By using overexpression and RNA interference, we show here that IEX-1 increases Akt/PKB activity in Response to various growth factors by preventing Akt dephosphorylation on both Thr(308) and Ser(473) residues. PP2A-B56beta and gamma subunits have the opposite effect and reverse IEX-1-mediated Akt activation. The effect of IEX-1 on Akt is ERK-dependent. Indeed: (i) a IEX-1 mutant deficient in ERK binding had no effect on Akt; (ii) ERK dominant-negative mutants reduced IEX-1-mediated increase in pAkt; (iii) a B56beta mutant that cannot be phosphorylated in the ERK.IEX-1 complex showed an enhanced ability to compete with IEX-1. These results identify B56-containing PP2A holoenzymes as Akt phosphatases. They suggest that IEX-1 behaves as a General inhibitor of B56 activity, enabling the control of both ERK and Akt signaling downstream of ERK.
