LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism

Sun, Haipeng; Xu, Beibei; Шевелева, Елена; Chen, Qin M.

doi:10.1016/j.taap.2008.05.024

Cited by 13 publications

(6 citation statements)

References 59 publications

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“…PI3K/Akt is a well-established upstream kinase phosphorylating GSK-3 at Ser residues, leading to inhibition of GSK-3 activity. Previous studies from our laboratory have demonstrated that CT does not activate PI3K/AKT pathway [21]. Here we found that CT treatment did not affect intracellular distribution of GSK-3 or GSK-3 phosphorylation, either at Ser or Tyr residues.…”

Section: Discussionsupporting

confidence: 49%

Inhibitors of GSK-3 Prevent Corticosterone from Inducing COX-1 Expression in Cardiomyocytes

Sun

Chen

2008

Cardiovasc Toxicol

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Our recent study has demonstrated that glucocorticoids (GCs) induce cyclooxygenase-1 (COX-1) gene expression in rat cardiomyocytes. While investigating the mechanism underlying corticosterone (CT) induced COX-1, we found that three structurally and mechanistically distinct GSK-3 inhibitors, LiCl, SB216763, and (2'Z,3'E)-6-Bromoindirubin-3'-oxime (BIO), inhibited COX-1 transcription and protein induction. A genetic approach of expressing wild type GSK-3beta increased COX-1 promoter activity, which was abolished by LiCl. LiCl increased inhibitory GSK-3alpha/beta phosphorylation at Ser21/Ser9, while BIO or SB216763 prevented stimulatory phosphorylation at Tyr279/Tyr216 of GSK-3alpha/beta. GSK inhibitors failed to block nuclear translocation of glucocorticoid receptor (GR) or activation of glucocorticoid response element (GRE) by CT treatment. While Sp3 transcription factor mediates CT induced COX-1 expression, GSK inhibitors did not change the level of Sp3 protein or binding of Sp3 transcription factor to COX-1 promoter. The observed effect of GSK-3 inhibitors appears to be unique to COX-1 since LiCl or BIO does not prevent CT from inducing COX-2 gene. We conclude that GSK-3 inhibitors block CT from inducing COX-1 gene expression via a mechanism beyond GR and Sp3 transcription factor.

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Section: Discussionsupporting

confidence: 49%

Inhibitors of GSK-3 Prevent Corticosterone from Inducing COX-1 Expression in Cardiomyocytes

Sun

Chen

2008

Cardiovasc Toxicol

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“…On the other hand, the mRNA level of DNA-PK is much higher in 4-AP group and shows a slight change in TEA group. Previous research reported that DNA-PK failed to prevent expression of cyclooxygenase-2 expression; however, TEA attenuates expression of cyclooxygenase-2 (33). It provides evidence that TEA and DNA-PK mediate different pathways in COX-2 expression, and the same is true in the apoptotic process.…”

Section: Tea Inhibits Hela Cell Proliferation and Induces Cellmentioning

confidence: 71%

The Evidence of HeLa Cell Apoptosis Induced with Tetraethylammonium Using Proteomics and Various Analytical Methods

Huang

2014

Journal of Biological Chemistry

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Background: Tetraethylammonium is a broad potassium channel blocker applied in neuron research. Results: Tetraethylammonium has the ability to lead cell apoptotic process; various biological and proteomics methods prove this result. Conclusion: Novel biomarkers candidates are found to reveal mechanism of tetraethylammonium-induced apoptosis. Significance: This provides new details on the new molecular pathway involved in apoptosis and gives a broader context in therapeutic strategies.

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“…A previous finding has demonstrated that PI3K plays a key role in corticosterone-induced COX-2 expression (52). Several studies have shown that EGFR kinase-mediated activation of the PI3K/Akt pathway is required for Zn 2ϩ -induced COX-2 expression (55).…”

Section: Involvement Of Egfr and Pdgfr In Cse-induced Cox-2 Expressiomentioning

confidence: 98%

Cigarette smoke extract induces COX-2 expression via a PKCα/c-Src/EGFR, PDGFR/PI3K/Akt/NF-κB pathway and p300 in tracheal smooth muscle cells

Yang

Lee

Lin³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Exposure to cigarette smoke extract (CSE) leads to airway or lung inflammation, which may be mediated through cyclooxygenase-2 (COX-2) expression and its product prostaglandin E2 (PGE2) synthesis. The aim of this study was to investigate the molecular mechanisms underlying CSE-induced COX-2 expression in human tracheal smooth muscle cells (HTSMCs). Here, we describe that COX-2 induction is dependent on PKCalpha/c-Src/EGFR, PDGFR/PI3K/Akt/NF-kappaB signaling in HTSMCs. CSE stimulated the phosphorylation of c-Src, EGFR, PDGFR, and Akt, which were inhibited by pretreatment with the inhibitor of PKCalpha (Gö6976 or Gö6983), c-Src (PP1), EGFR (AG1478), PDGFR (AG1296), or PI3K (LY294002). Moreover, CSE induced a significant increase in COX-2 expression, which was reduced by pretreatment with these inhibitors or transfection with siRNA of PKCalpha, Src, or Akt. Furthermore, CSE-stimulated NF-kappaB p65 phosphorylation and translocation were also attenuated by pretreatment with Gö6976, PP1, AG1478, AG1296, or LY294002. CSE-induced COX-2 expression was also mediated through the recruitment of p300 associated with NF-kappaB in HTSMCs, revealed by coimmunoprecipitation and Western blot analysis. In addition, pretreatment with the inhibitors of NF-kappaB (helenalin) and p300 (garcinol) or transfection with p65 siRNA and p300 siRNA markedly inhibited CSE-regulated COX-2 expression. However, CSE-induced PGE2 generation was reduced by pretreatment with the inhibitor of COX-2 (NS-398). These results demonstrated that in HTSMCs, CSE-induced COX-2-dependent PGE2 generation was mediated through PKCalpha/c-Src/EGFR, PDGFR/PI3K/Akt leading to the recruitment of p300 with NF-kappaB complex.

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LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism

Cited by 13 publications

References 59 publications

Inhibitors of GSK-3 Prevent Corticosterone from Inducing COX-1 Expression in Cardiomyocytes

Inhibitors of GSK-3 Prevent Corticosterone from Inducing COX-1 Expression in Cardiomyocytes

The Evidence of HeLa Cell Apoptosis Induced with Tetraethylammonium Using Proteomics and Various Analytical Methods

Cigarette smoke extract induces COX-2 expression via a PKCα/c-Src/EGFR, PDGFR/PI3K/Akt/NF-κB pathway and p300 in tracheal smooth muscle cells

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