Gene interactions and pathways from curated databases and text-mining
Biochim Biophys Acta 2008, PMID: 18452714

PKC-delta/c-Src-mediated EGF receptor transactivation regulates thrombin-induced COX-2 expression and PGE(2) production in rat vascular smooth muscle cells.

Hsieh, Hsi-Lung; Sun, Chi-Chin; Wang, Tze-Shyuan; Yang, Chuen-Mao

The thrombin/proteinase-activated receptors (PARs) have been shown to regulate smooth muscle cell proliferation, migration, and vascular maturation. Thrombin up-regulates expression of several proteins including cyclooxygenase (COX)-2 in vascular smooth muscle cells (VSMCs) and contributes to vascular diseases. However, the mechanisms underlying thrombin-regulated COX-2 expression in VSMCs remain unclear. Western blotting, RT-PCR, and EIA kit analyses showed that thrombin induced the expression of COX-2 mRNA and protein and PGE(2) release in a time-dependent manner, which was attenuated by inhibitors of PKC (GF109203X and rottlerin), c-Src (PP1), EGF receptor (EGFR; AG1478) and MEK1/2 (U0126), or transfection with dominant negative mutants of PKC-delta, c-Src or extracellular regulated kinase (ERK) and ERK1 short hairpin RNA interference (shRNA). These results suggest that transactivation of EGFR participates in COX-2 expression induced by thrombin in VSMCs. Accordingly, thrombin stimulated phosphorylation of ERK1/2 which was attenuated by GF109203X, rottlerin, PP1, GM6001, CRM197, AG1478, or U0126, respectively. Furthermore, this up-regulation of COX-2 mRNA and protein was blocked by selective inhibitors of AP-1 and NF-kappaB, curcumin and helenalin, respectively. Moreover, thrombin-stimulated activation of NF-kappaB, AP-1, and COX-2 promoter activity was blocked by the inhibitors of c-Src, PKC, EGFR, MEK1/2, AP-1 and NF-kappaB, suggesting that thrombin induces COX-2 promoter activity mediated through PKC(delta)/c-Src-dependent EGFR transactivation, MEK-ERK1/2, AP-1, and NF-kappaB. These results demonstrate that in VSMCs, activation of ERK1/2, AP-1 and NF-kappaB pathways was essential for thrombin-induced COX-2 gene expression. Understanding the regulation of COX-2 expression and PGE(2) release by thrombin/PARs system on VSMCs may provide potential therapeutic targets of vascular inflammatory disorders including arteriosclerosis.

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Text Mining Data

EGF → PKC-delta/c-Src: " PKC-delta/c-Src mediated EGF receptor transactivation regulates thrombin induced COX-2 expression and PGE ( 2 ) production in rat vascular smooth muscle cells "

COX-2 → EGF: " PKC-delta/c-Src mediated EGF receptor transactivation regulates thrombin induced COX-2 expression and PGE ( 2 ) production in rat vascular smooth muscle cells "

AP-1 ⊣ c-Src: " Moreover, thrombin stimulated activation of NF-kappaB, AP-1 , and COX-2 promoter activity was blocked by the inhibitors of c-Src , PKC, EGFR, MEK1/2, AP-1 and NF-kappaB, suggesting that thrombin induces COX-2 promoter activity mediated through PKC ( delta ) /c-Src dependent EGFR transactivation, MEK-ERK1/2, AP-1, and NF-kappaB "

AP-1 ⊣ EGFR: " Moreover, thrombin stimulated activation of NF-kappaB, AP-1 , and COX-2 promoter activity was blocked by the inhibitors of c-Src, PKC, EGFR , MEK1/2, AP-1 and NF-kappaB, suggesting that thrombin induces COX-2 promoter activity mediated through PKC ( delta ) /c-Src dependent EGFR transactivation, MEK-ERK1/2, AP-1, and NF-kappaB "

AP-1 ⊣ MEK1/2: " Moreover, thrombin stimulated activation of NF-kappaB, AP-1 , and COX-2 promoter activity was blocked by the inhibitors of c-Src, PKC, EGFR, MEK1/2 , AP-1 and NF-kappaB, suggesting that thrombin induces COX-2 promoter activity mediated through PKC ( delta ) /c-Src dependent EGFR transactivation, MEK-ERK1/2, AP-1, and NF-kappaB "

AP-1 ⊣ NF-kappaB: " Moreover, thrombin stimulated activation of NF-kappaB, AP-1 , and COX-2 promoter activity was blocked by the inhibitors of c-Src, PKC, EGFR, MEK1/2, AP-1 and NF-kappaB , suggesting that thrombin induces COX-2 promoter activity mediated through PKC ( delta ) /c-Src dependent EGFR transactivation, MEK-ERK1/2, AP-1, and NF-kappaB "

NF-kappaB ⊣ c-Src: " Moreover, thrombin stimulated activation of NF-kappaB , AP-1, and COX-2 promoter activity was blocked by the inhibitors of c-Src , PKC, EGFR, MEK1/2, AP-1 and NF-kappaB, suggesting that thrombin induces COX-2 promoter activity mediated through PKC ( delta ) /c-Src dependent EGFR transactivation, MEK-ERK1/2, AP-1, and NF-kappaB "

NF-kappaB ⊣ EGFR: " Moreover, thrombin stimulated activation of NF-kappaB , AP-1, and COX-2 promoter activity was blocked by the inhibitors of c-Src, PKC, EGFR , MEK1/2, AP-1 and NF-kappaB, suggesting that thrombin induces COX-2 promoter activity mediated through PKC ( delta ) /c-Src dependent EGFR transactivation, MEK-ERK1/2, AP-1, and NF-kappaB "

NF-kappaB ⊣ MEK1/2: " Moreover, thrombin stimulated activation of NF-kappaB , AP-1, and COX-2 promoter activity was blocked by the inhibitors of c-Src, PKC, EGFR, MEK1/2 , AP-1 and NF-kappaB, suggesting that thrombin induces COX-2 promoter activity mediated through PKC ( delta ) /c-Src dependent EGFR transactivation, MEK-ERK1/2, AP-1, and NF-kappaB "

COX-2 ⊣ c-Src: " Moreover, thrombin stimulated activation of NF-kappaB, AP-1, and COX-2 promoter activity was blocked by the inhibitors of c-Src , PKC, EGFR, MEK1/2, AP-1 and NF-kappaB, suggesting that thrombin induces COX-2 promoter activity mediated through PKC ( delta ) /c-Src dependent EGFR transactivation, MEK-ERK1/2, AP-1, and NF-kappaB "

COX-2 ⊣ EGFR: " Moreover, thrombin stimulated activation of NF-kappaB, AP-1, and COX-2 promoter activity was blocked by the inhibitors of c-Src, PKC, EGFR , MEK1/2, AP-1 and NF-kappaB, suggesting that thrombin induces COX-2 promoter activity mediated through PKC ( delta ) /c-Src dependent EGFR transactivation, MEK-ERK1/2, AP-1, and NF-kappaB "

COX-2 ⊣ AP-1: " Moreover, thrombin stimulated activation of NF-kappaB, AP-1, and COX-2 promoter activity was blocked by the inhibitors of c-Src, PKC, EGFR, MEK1/2, AP-1 and NF-kappaB, suggesting that thrombin induces COX-2 promoter activity mediated through PKC ( delta ) /c-Src dependent EGFR transactivation, MEK-ERK1/2, AP-1, and NF-kappaB "

COX-2 ⊣ MEK1/2: " Moreover, thrombin stimulated activation of NF-kappaB, AP-1, and COX-2 promoter activity was blocked by the inhibitors of c-Src, PKC, EGFR, MEK1/2 , AP-1 and NF-kappaB, suggesting that thrombin induces COX-2 promoter activity mediated through PKC ( delta ) /c-Src dependent EGFR transactivation, MEK-ERK1/2, AP-1, and NF-kappaB "

COX-2 ⊣ NF-kappaB: " Moreover, thrombin stimulated activation of NF-kappaB, AP-1, and COX-2 promoter activity was blocked by the inhibitors of c-Src, PKC, EGFR, MEK1/2, AP-1 and NF-kappaB , suggesting that thrombin induces COX-2 promoter activity mediated through PKC ( delta ) /c-Src dependent EGFR transactivation, MEK-ERK1/2, AP-1, and NF-kappaB "

EGFR → /c-Src: " Moreover, thrombin stimulated activation of NF-kappaB, AP-1, and COX-2 promoter activity was blocked by the inhibitors of c-Src, PKC, EGFR, MEK1/2, AP-1 and NF-kappaB, suggesting that thrombin induces COX-2 promoter activity mediated through PKC ( delta ) /c-Src dependent EGFR transactivation, MEK-ERK1/2, AP-1, and NF-kappaB "

MEK-ERK1/2 → /c-Src: " Moreover, thrombin stimulated activation of NF-kappaB, AP-1, and COX-2 promoter activity was blocked by the inhibitors of c-Src, PKC, EGFR, MEK1/2, AP-1 and NF-kappaB, suggesting that thrombin induces COX-2 promoter activity mediated through PKC ( delta ) /c-Src dependent EGFR transactivation, MEK-ERK1/2 , AP-1, and NF-kappaB "

Manually curated Databases

No curated data.