Transcriptional Regulation of 2′,3′‐Cyclic Nucleotide 3′‐Phosphodiesterase Gene Expression by Cyclic AMP in C6 Cells

Gravel, Michel; Gao, Enoch; Hervouet-Zeiber, C.; Parsons, Victoria A.; Braun, Peter E.

doi:10.1046/j.1471-4159.2000.0751940.x

Cited by 18 publications

(13 citation statements)

References 49 publications

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“…phosphodiesterase expression in C6 astrocytoma cells (37). Activation of Sp1 and AP2 sites, alone on in concert with low levels of NFB activation, could therefore contribute to cAMPdependent induction of IB␣ expression.…”

Section: Discussionmentioning

confidence: 98%

Norepinephrine Increases IκBα Expression in Astrocytes

Gavrilyuk¹,

Russo²,

Heneka³

et al. 2002

Journal of Biological Chemistry

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The neurotransmitter norepinephrine (NE) can inhibit inflammatory gene expression in glial cells; however, the mechanisms involved are not clear. In primary astrocytes, NE dose-dependently increased the expression of inhibitory IB␣ protein accompanied by an increase in steady state levels of IB␣ mRNA. Maximal increases were observed at 30 -60 min for the mRNA and at 4 h for protein, and these effects were mediated by NE binding to ␤-adrenergic receptors. NE activated a 1.3-kilobase IB␣ promoter transfected into astrocytes or C6 glioma cells, and this activation was prevented by a ␤-antagonist and by protein kinase A inhibitors but not by an NFB inhibitor. NE increased IB␣ protein in both the cytosolic and the nuclear fractions, suggesting an increase in nuclear uptake of IB␣. IB␣ was detected in the frontal cortex of normal adult rats, and its levels were reduced if central NE levels were depleted by lesion of the locus ceruleus. The reduction of brain IB␣ levels was paralleled by increased inflammatory responses to lipopolysaccharide. These results demonstrate that IB␣ expression is regulated by NE at both transcriptional and post-transcriptional levels, which could contribute to the observed anti-inflammatory properties of NE in vitro and in vivo.The activation of inflammatory responses in brain is normally under tight regulation that prevents the accumulation of potentially cytotoxic mediators including cytokines and reactive oxygen species (1-3). It has therefore been suggested that intrinsic mechanisms exist that maintain the brain in a refractory state of inflammatory activation. In primary cultures of rat astrocytes, we showed that neurotransmitter norepinephrine (NE) 1 prevents induction of the inducible form of nitric oxide synthase (NOS2) (4, 5) by bacterial endotoxin lipopolysaccharide (LPS) or by a combination of proinflammatory cytokines (interleukin 1␤, tumor necrosis factor ␣, and interferon ␥). Similarly, others show that NE reduces glial expression of pro-inflammatory cytokines including interleukin 1␤ and tumor necrosis factor ␣ (6 -9) and of cell adhesion molecules (13). A similar role for NE in regulating inflammatory events in brain is supported by our recent findings that experimental depletion of brain NE levels by chemical lesion of the locus ceruleus (LC) increases the cortical inflammatory responses to injection of aggregated amyloid ␤ (14). The fact that LC neurons are lost in Alzheimer's disease (15) and that levels of ␤ 2 -adrenergic receptor (␤ARs) are reduced in astrocytes in multiple sclerosis patients (16,17) suggests that diminished NE levels or perturbations of the NE-signaling system contribute to the neuroinflammation that occurs in these diseases.The mechanism(s) by which NE reduces inflammatory gene expression is not yet well defined. In astrocytes, we found that NE induced protein binding to a 27-bp region of the rat NOS2 promoter, which is located immediately upstream of a NFB binding site located at bp position Ϫ107 to Ϫ96 (18). This 27-bp region contains several potenti...

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Section: Discussionmentioning

confidence: 98%

Norepinephrine Increases IκBα Expression in Astrocytes

Gavrilyuk¹,

Russo²,

Heneka³

et al. 2002

Journal of Biological Chemistry

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“…One of the stable NSC lines, designated 1464R, was cultured further for more than 50 passages with no obvious morphological alterations. To establish rat neural stem cell lines stably expressing EGFP or Sirius [49] under the control of TBB3, GFAP, or CNP promoter, the CMV promoter regions of pEGFPN1 (Clontech, Palo Alto, CA USA) and Sirius/pcDNA (Addgene plasmid 51957) plasmids were replaced by rat TBB3 [50] (-490 to +34; AF458477), GFAP [51] (-1589 to -3), or CNP [52] (-1330 to -10) promoter fragment obtained by genomic PCR (pTBB3pEGFP, pTBB3pSirius, pGFAPpEGFP and pCNPpEGFP). The 1464R cells seeded on PHEMA-coated 3.5-cm dishes were transfected with these plasmids using Fugene 6 Transfection Reagent (Promega, Madison, WI, USA) according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

Formation and spreading of TDP-43 aggregates in cultured neuronal and glial cells demonstrated by time-lapse imaging

et al. 2017

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TAR DNA-binding protein 43 (TDP-43) is a main constituent of cytoplasmic aggregates in neuronal and glial cells in cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We have previously demonstrated that adenovirus-transduced artificial TDP-43 cytoplasmic aggregates formation is enhanced by proteasome inhibition in vitro and in vivo. However, the relationship between cytoplasmic aggregate formation and cell death remains unclear. In the present study, rat neural stem cell lines stably transfected with EGFP- or Sirius-expression vectors under the control of tubulin beta III, glial fibrillary acidic protein, or 2′,3′-cyclic nucleotide 3′-phosphodiesterase promoter were differentiated into neurons, astrocytes, and oligodendrocytes, respectively, in the presence of retinoic acid. The differentiated cells were then transduced with adenoviruses expressing DsRed-tagged human wild type and C-terminal fragment TDP-43 under the condition of proteasome inhibition. Time-lapse imaging analyses revealed growing cytoplasmic aggregates in the transduced neuronal and glial cells, followed by collapse of the cell. The aggregates remained insoluble in culture media, consisted of sarkosyl-insoluble granular materials, and contained phosphorylated TDP-43. Moreover, the released aggregates were incorporated into neighboring neuronal cells, suggesting cell-to-cell spreading. The present study provides a novel tool for analyzing the detailed molecular mechanisms of TDP-43 proteinopathy in vitro.

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“…An important regulator of a number of epitheliumspecific genes, AP2a mediates transcriptional E-cadherin [Hennig et al, 1996;Batsche et al, 1998] and hST3Gal IV regulation [Taniguchi and Matsumoto, 1999] in epithelial cells. Retinoic acid, cAMP, and phorbol esters regulate AP2a activity [Imagawa et al, 1987;Gravel et al, 2000]. PMA can substitute for diacylglycerol, the endogenous PKC activator, and it has been used in an inflammatory stimulus model to study mucin signaling mechanisms Shao et al, 2003;Hewson et al, 2004;Shao and Nadel, 2005;Wu et al, 2007;Yuan-Chen Wu et al, 2007].…”

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confidence: 99%

AP2α is essential for MUC8 gene expression in human airway epithelial cells

Moon

Kim

Choi

et al. 2010

J of Cellular Biochemistry

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Mucins are high molecular weight proteins that make up the major components of mucus. Hypersecretion of mucus is a feature of several chronic inflammatory airway diseases. MUC8 is an important component of airway mucus, and its gene expression is upregulated in nasal polyp epithelium. Little is known about the molecular mechanisms of MUC8 gene expression. We first observed overexpression of activator protein-2 alpha (AP2 alpha) in human nasal polyp epithelium. We hypothesized that AP2 alpha overexpression in nasal polyp epithelium correlates closely with MUC8 gene expression. We demonstrated that phorbol 12-myristate 13-acetate (PMA) treatment of the airway epithelial cell line NCI-H292 increases MUC8 gene and AP2 alpha expression. In this study, we sought to determine which signal pathway is involved in PMA-induced MUC8 gene expression. The results show that the protein kinase C and mitogen-activating protein/ERK kinase (MAPK) pathways modulate MUC8 gene expression. PD98059 or ERK1/2 siRNA and RO-31-8220 or PKC siRNA significantly suppress AP2 alpha as well as MUC8 gene expression in PMA-treated cells. To verify the role of AP2 alpha, we specifically knocked down AP2 alpha expression with siRNA. A significant AP2 alpha knock-down inhibited PMA-induced MUC8 gene expression. While dominant negative AP2 alpha decreased PMA-induced MUC8 gene expression, overexpressing wildtype AP2 alpha increased MUC8 gene expression. Furthermore, using lentiviral vectors for RNA interference in human nasal polyp epithelial cells, we confirmed an essential role for AP2 alpha in MUC8 gene expression. From these results, we concluded that PMA induces MUC8 gene expression through a mechanism involving PKC, ERK1/2, and AP2 alpha activation in human airway epithelial cells.

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Transcriptional Regulation of 2′,3′‐Cyclic Nucleotide 3′‐Phosphodiesterase Gene Expression by Cyclic AMP in C6 Cells

Cited by 18 publications

References 49 publications

Norepinephrine Increases IκBα Expression in Astrocytes

Norepinephrine Increases IκBα Expression in Astrocytes

Formation and spreading of TDP-43 aggregates in cultured neuronal and glial cells demonstrated by time-lapse imaging

AP2α is essential for MUC8 gene expression in human airway epithelial cells

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