Up-regulation of Endothelial Nitric-oxide Synthase Promoter by the Phosphatidylinositol 3-Kinase γ/Janus Kinase 2/MEK-1-dependent Pathway

Cieslik, Katarzyna A.; Abrams, Charles S.; Wu, Kenneth K.

doi:10.1074/jbc.m005305200

Cited by 64 publications

(59 citation statements)

References 58 publications

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“…6, C-E). MEK-1-dependent pathways have recently been reported in endothelial cells (58), and this protein kinase has been found localized at the nucleus (59), consistent with ERK1/2 phosphorylation (Fig. 6C).…”

Section: Discussionsupporting

confidence: 66%

Proinflammatory Gene Induction by Platelet-Activating Factor Mediated Via Its Cognate Nuclear Receptor

Marrache

Gobeil

Bernier

et al. 2002

The Journal of Immunology

115

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It has been postulated that intracellular binding sites for platelet-activating factor (PAF) contribute to proinflammatory responses to PAF. Isolated nuclei from porcine cerebral microvascular endothelial cells (PCECs) produced PAF-molecular species in response to H2O2. Using FACS analysis, we demonstrated the expression of PAF receptors on cell and nuclear surfaces of PCECs. Confocal microscopy studies performed on PCECs, Chinese hamster ovary cells stably overexpressing PAF receptors, and isolated nuclei from PCECs also showed a robust nuclear distribution of PAF receptors. Presence of PAF receptors at the cell nucleus was further revealed in brain endothelial cells by radioligand binding experiments, immunoblotting, and in situ in brain by immunoelectron microscopy. Stimulation of nuclei with methylcarbamate-PAF evoked a decrease in cAMP production and a pertussis toxin-sensitive rise in nuclear calcium, unlike observations in plasma membrane, which exhibited a pertussis toxin-insensitive elevation in inositol phosphates. Moreover, on isolated nuclei methylcarbamate-PAF evoked the expression of proinflammatory genes inducible nitric oxide synthase and cyclooxygenase-2 (COX-2) and was associated with augmented extracellular signal-regulated kinase 1/2 phosphorylation and NF-κB binding to the DNA consensus sequence. COX-2 expression was prevented by mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 and NF-κB inhibitors. This study describes for the first time the nucleus as a putative organelle capable of generating PAF and expresses its receptor, which upon stimulation induces the expression of the proinflammatory gene COX-2.

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Section: Discussionsupporting

confidence: 66%

Proinflammatory Gene Induction by Platelet-Activating Factor Mediated Via Its Cognate Nuclear Receptor

Marrache

Gobeil

Bernier

et al. 2002

The Journal of Immunology

115

View full text Add to dashboard Cite

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“…The Dp85 construct lacks amino acid residues 478 ± 513 of p85 and functions as dominant negative mutant for PI3Ka, PI3Kb, and PI3Kd. Dp110g lacks 948 ± 981 amino acids of p110 and functions as dominant negative inhibitor for PI3Kg (Cieslik et al, 2001). As shown in Figure 5, co-transfection of these dominant negative recombinants did not support the elevated expression of reporter gene, either in the absence or in the presence of 2-AAF ( Figure 6).…”

Section: Activation Of Pi3k By 2-aafmentioning

confidence: 90%

“…76228 HMDRluc, 76042.HMDRluc, and 72930HMDRluc were constructed by inserting polymerase chain reaction product between 76228, 76042, and 72930, respectively, and+162, of MDR1 sequences into the KpnI site of pGL2-luciferase vector (Promega). Plasmids Dp85 and Dp110g were obtained from Charles S Abrams (Cieslik et al, 2001) and plasmid mp110 was obtained from Klippel et al (1996). pEXV-V12rac1 and pEVX-N17rac1 encoding constitutively active and dominant negative Rac1 cDNA, respectively, were described previously (Ridle et al, 1992) and obtained from T Finkel (National Institutes of Health).…”

Section: Reagentsmentioning

confidence: 99%

Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-κB signaling

et al. 2002

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The expression of P-glycoprotein encoded by the multidrug resistance (MDR1) gene is associated with the emergence of the MDR phenotype in cancer cells. Human MDR1 and its rodent homolog mdr1a and mdr1b are frequently overexpressed in liver cancers. However, the underlying mechanisms are largely unknown. The hepatocarcinogen 2-acetylamino¯uorene (2-AAF) e ciently activates rat mdr1b expression in cultured cells and in Fisher 344 rats. We recently reported that activation of rat mdr1b in cultured cells by 2-AAF involves a cis-activating element containing a NFkB binding site located 7167 to 7158 of the rat mdr1b promoter. 2-AAF activates IkB kinase (IKK), resulting in degradation of IkBb and activation of NF-kB. In this study, we report that 2-AAF could also activate the human MDR1 gene in human hepatoma and embryonic ®broblast 293 cells. Induction of MDR1 by AAF was mediated by DNA sequence located at 76092 which contains a NF-kB binding site. Treating hepatoma cells with 2-AAF activated phosphoinositide 3-kinase (PI3K) and its downstream e ectors Rac1, and NAD(P)H oxidase. Transient transfection assays demonstrated that constitutively activated PI3K and Rac1 enhanced the activation of the MDR1 promoter by 2-AAF. Treatment of hepatoma cells with 2-AAF also activated another PI3K downstream e ector Akt. Transfection of recombinant encoding a dominant activated Akt also enhanced the activation of MDR1 promoter activation by 2-AAF. These results demonstrated that 2-AAF up-regulates MDR1 expression is mediated by the multiple e ectors of the PI3K signaling pathway.

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“…Angiotensin II and laminar shear stress activate ERK2/1 via c-SRC, indicating that c-SRC activation is also necessary for eNOS upregulation in response to these stimuli [14][15]. Alternatively, activation of PI3K/AKT1 pathway mediated eNOS upregulation by VEGF [10], insulin [17], and lysophosphatidylcholine [18] in various endothelial cell systems. Contrasting to ERK2/1 and PI3K/AKT1, p38MAPK activation has been shown to actually down-regulate eNOS expression in various systems [29], while the role of JNK1/2 in regulating eNOS expression remains unknown to date.…”

Section: Discussionmentioning

confidence: 99%

“…ERK2/1 activation is necessary but not sufficient for eNOS upregulation by FGF2 in oFPAE cells [11]. In various endothelial cells, many signaling pathways have been shown to mediate eNOS upregulation by various stimuli [9][10][11][13][14][15][16][17][18]. Among them, ERK2/1 and/or PI3K/AKT1 mediate the upregulation of eNOS by most stimuli including VEGF, FGF2, estrogen, and insulin [10,11,13, and 17].…”

Section: Introductionmentioning

confidence: 99%

Differential Activation of Multiple Signalling Pathways Dictates eNOS Upregulation by FGF2 but not VEGF in Placental Artery Endothelial Cells

et al. 2008

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Fibroblast growth factor (FGF2), but not vascular endothelial growth factor (VEGF), upregulates endothelial nitric oxide synthase (eNOS) protein expression, at least in part, via activation of extracellular signal-regulated kinase 2/1 (ERK2/1) in ovine fetoplacental artery endothelial (oFPAE) cells. Herein we further investigated the temporal effects of FGF2 and VEGF on other signaling pathways including members (Jun N-terminal kinase JNK1/2 and p38MAPK) of mitogen-activated protein kinases (MAPK), phosphatidylinositol 3 kinase/v-akt murine thymoma viral oncogene homolog 1 (PI3K/AKT1), and the tyrosine kinase c-SRC, and examined if either one or more of these pathways play a role in the differential regulation of eNOS by FGF2 and VEGF. We first confirmed that in oFPAE cells, FGF2, but not VEGF, increased eNOS protein. FGF2 stimulated eNOS protein in a time and concentration dependent manner, which also depended on cell density. FGF2 provoked sustained (5 min to 12 h) whereas VEGF only stimulated transient (5 min) ERK2/1 phosphorylation. FGF2 was 1.7-fold more potent in stimulating ERK2/1 phosphorylation than VEGF. FGF2 and VEGF only transiently activated JNK1/2 and AKT1 within 5 min; however, FGF2 was a stronger stimulus than VEGF. FGF2 and VEGF did not significantly activate p38MAPK at 5 min; however, VEGF stimulated p38MAPK phosphorylation at 60 min. VEGF but not FGF2 significantly stimulated c-SRC phosphorylation. Inhibitors of MEK-ERK2/1 (PD98059), JNK1/2 (SP600125) and PI3K (wortmannin), but not p38MAPK (SB203580) and SRC (PP2), decreased the FGF2-increased eNOS protein expression. Thus, the FGF2-induced eNOS protein expression requires activation of multiple signaling pathways including ERK2/1, JNK1/2 and PI3K/AKT1. Differences in intensity and temporal patterns of activation of these pathways by FGF2 and VEGF may account for their differential effects on eNOS expression in OFPAE cells.

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Up-regulation of Endothelial Nitric-oxide Synthase Promoter by the Phosphatidylinositol 3-Kinase γ/Janus Kinase 2/MEK-1-dependent Pathway

Cited by 64 publications

References 58 publications

Proinflammatory Gene Induction by Platelet-Activating Factor Mediated Via Its Cognate Nuclear Receptor

Proinflammatory Gene Induction by Platelet-Activating Factor Mediated Via Its Cognate Nuclear Receptor

Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-κB signaling

Differential Activation of Multiple Signalling Pathways Dictates eNOS Upregulation by FGF2 but not VEGF in Placental Artery Endothelial Cells

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