Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclooxygenase-2 (COX-2) plays an important role in tumorigenesis of several tissues, including skin. We report here that troglitazone, a thiazolidinedione class of antidiabetic drug, induced COX-2 expression at both the protein and mRNA levels and increased production of prostaglandin E2 (PGE2) in cultured keratinocytes. Troglitazone-induced COX-2 expression in keratinocytes was likely peroxisome proliferator-activated receptor gamma (PPARgamma)-independent. Troglitazone treatment of these cells also resulted in a sustained increase in phosphorylation of ERK. We show that induction of COX-2 by troglitazone was almost completely inhibited by specific inhibitors of ERK activation. These data suggest that troglitazone is capable of inducing COX-2 expression through an ERK-dependent mechanism in mouse skin keratinocytes.
...
PMID:Troglitazone induction of COX-2 expression is dependent on ERK activation in keratinocytes. 1644 79

The significance of cyclooxygenase-2 (COX-2) expression in mesenchymal tumors has not been completely described. We analyzed clinicopathologic variables and COX-2 protein expression in all mesenchymal tumors of the GI tract that were treated at our institution between 1990 and 2002. Paraffin-embedded specimens were immunohistochemically stained for KIT and COX-2 protein. KIT-positive tumors were diagnosed as gastrointestinal stromal tumors (GIST). Among 42 available specimens, 38 tumors were diagnosed as GIST and four were non-GIST mesenchymal GI tumors (KIT negative). The median overall survival for the GIST patients was 34 months. Ninety-two percent of GIST expressed COX-2 protein. COX-2 protein was not expressed in any of the non-GIST tumors. GIST patients with negative or low COX-2 expression developed disease recurrence and/or died of their disease in 37% of the cases, compared with 18% for GIST patients with high COX-2 expression (difference not statistically significant). The vast majority of mesenchymal tumors of the GI tract are GIST that express COX-2 protein. As opposed to known predictors of GIST behavior such as tumor size and mitotic count, levels of COX-2 protein expression did not correlate with clinical outcome.
...
PMID:Cyclooxygenase-2 expression and clinical outcome in gastrointestinal stromal tumors. 1645 68

To more clearly understand the molecular mechanisms involved in synergistic enhancement of cancer preventive activity with the green tea polyphenol (-)-epigallocatechin gallate (EGCG), we examined the effects of cotreatment with EGCG plus celecoxib, a cyclooxygenase-2 selective inhibitor. We specifically looked for induction of apoptosis and expression of apoptosis related genes, with emphasis on growth arrest and DNA damage-inducible 153 (GADD153) gene, in human lung cancer cell line PC-9: Cotreatment with EGCG plus celecoxib strongly induced the expression of both GADD153 mRNA level and protein in PC-9 cells, while neither EGCG nor celecoxib alone did. However, cotreatment did not induce expression of other apoptosis related genes, p21(WAF1) and GADD45. Judging by upregulation of GADD153, only cotreatment with EGCG plus celecoxib synergistically induced apoptosis of PC-9 cells. Synergistic effects with the combination were also observed in 2 other lung cancer cell lines, A549 and ChaGo K-1. Furthermore, EGCG did not enhance GADD153 gene expression or apoptosis induction in PC-9 cells in combination with N-(4-hydroxyphenyl)retinamide or with aspirin. Thus, upregulation of GADD153 is closely correlated with synergistic enhancement of apoptosis with EGCG. Cotreatment also activated the mitogen-activated protein kinases (MAPKs), such as ERK1/2 and p38 MAPK: Preteatment with PD98059 (ERK1/2 inhibitor) and UO126 (selective MEK inhibitor) abrogated both upregulation of GADD153 and synergistic induction of apoptosis of PC-9 cells, while SB203580 (p38 MAPK inhibitor) did not do so, indicating that GADD153 expression was mediated through the ERK signaling pathway. These findings indicate that high upregulation of GADD153 is a key requirement for cancer prevention in combination with EGCG.
...
PMID:Green tea polyphenol stimulates cancer preventive effects of celecoxib in human lung cancer cells by upregulation of GADD153 gene. 1646 83

Mechanical loading of bone generates fluid flow within the mineralized matrix that exerts fluid shear stress (FSS) on cells. We examined effects of FSS on receptor activator of nuclear factor kappa B ligand (RANKL), a critical factor for osteoclast formation. Primary murine osteoblasts were subjected to pulsatile FSS (5 Hz, 10 dynes/cm(2)) for 1 h and then returned to static culture for varying times (post-FSS). Protein levels were measured by Western analysis and mRNA by Northern analysis, RT-PCR and quantitative PCR. There were 20- to 40-fold increases in RANKL mRNA at 2-4 h post-FSS. RANKL protein was induced by 2 h post-FSS and remained elevated for at least 8 h. Effects were independent of cyclooxygenase-2 activity. Small increases (up to three-fold) in mRNA of the decoy receptor for RANKL, osteoprotegerin, were seen. Five min of FSS, followed by static culture, was as effective in stimulating RANKL mRNA as 4 h of continuous FSS. FSS induced cAMP activity, and H-89, a protein kinase A (PKA) inhibitor, blocked the FSS induction of RANKL. H-89 also inhibited the PKC pathway, but specific PKC inhibitors, GF109203X and Go6983, did not inhibit FSS-induced RANKL. FSS induced phosphorylation of ERK1/2, and PD98059, an inhibitor of the ERK pathway, inhibited the FSS induction of RANKL mRNA 60%-90%. Thus, brief exposure to FSS resulted in sustained induction of RANKL expression after stopping FSS, and this induction was dependent on PKA and ERK signaling pathways. Increased RANKL after mechanical loading may play a role in initiating bone remodeling.
...
PMID:Fluid flow induces Rankl expression in primary murine calvarial osteoblasts. 1651 40

Cyclooxygenase-2 (COX-2) is an important inducible enzyme in inflammation and is overexpressed in a variety of cancers. Evidence is rapidly accumulating that chronic inflammation may contribute to carcinogenesis through increase of cell proliferation, angiogenesis, and metastasis in a number of neoplasms, including colorectal carcinoma. In the present study, we investigated some mechanistic aspects of DFX-induced hypoxia-driven COX-2 expression. Desferrioxamine (DFX), an iron chelator, is known to upregulate inflammatory mediators. DFX induced the expression of COX-2 and accumulation of HIF-1alpha protein in dose-dependent manners, but hypoxia mimetic agent cobalt chloride (CoCl2) induced accumulation of HIF-1alpha protein but not increase of COX-2 expression. DFX-induced increase of COX-2 expression and HIF-1alpha protein level was attenuated by addition of ferric citrate. This result suggested that the iron chelating function of DFX was important to induce the increase of COX-2 and HIF-1alpha protein. PD98059 significantly inhibited the induction of COX-2 protein and accumulation of HIF-1alpha, suggesting that DFX-induced increase of HIF-1alpha and COX-2 protein was mediated, at least in part, through the ERK signaling pathway. In addition, pretreatment with NS-398 to inhibit COX-2 activity also effectively suppressed DFX-induced HIF-1alpha accumulation in human colon cancer cells, providing the evidence that COX-2 plays as a regulator of HIF-1alpha accumulation in DFX-treated colon cancer cells. Together, our findings suggest that iron metabolism may regulate stabilization of HIF-1alpha protein by modulating cyclooxygenase-2 signaling pathway.
...
PMID:Desferrioxamine, an iron chelator, enhances HIF-1alpha accumulation via cyclooxygenase-2 signaling pathway. 1652 54

Renal cell carcinoma (RCC) is the most common malignancy of the kidney. Unfortunately, RCCs are highly refractory to conventional chemotherapy, radiation therapy, and even immunotherapy. Thus, novel therapeutic targets need to be sought for the successful treatment of RCCs. We now report that 6-anilino-5,8-quinolinequinone (LY83583), an inhibitor of cyclic GMP production, induced growth arrest and apoptosis of the RCC cell line 786-0. It did not prove deleterious to normal renal epithelial cells, an important aspect of chemotherapy. To address the cellular mechanism(s), we used both genetic and pharmacological approaches. LY83583 induced a time- and dose-dependent increase in RCC apoptosis through dephosphorylation of mitogen-activated protein kinase kinase 1/2 and its downstream extracellular signal-regulated kinases (ERK) 1 and -2. In addition, we observed a decrease in Elk-1 phosphorylation and cyclooxygenase-2 (COX-2) down-regulation. We were surprised that we failed to observe an increase in either c-Jun NH(2)-terminal kinase or p38alpha and -beta mitogen-activated protein kinase activation. In contradiction, reintroduction of p38delta by stable transfection or overexpression of p38gamma dominant negative abrogated the apoptotic effect. Cell death was associated with a decrease and increase in Bcl-x(L) and Bax expression, respectively, as well as release of cytochrome c and translocation of apoptosis-inducing factor. These events were associated with an increase in reactive oxygen species formation. The antioxidant N-acetyl l-cysteine, however, opposed LY83583-mediated mitochondrial dysfunction, ERK1/2 inactivation, COX-2 down-regulation, and apoptosis. In conclusion, our results suggest that LY83583 may represent a novel therapeutic agent for the treatment of RCC, which remains highly refractory to antineoplastic agents. Our data provide a molecular basis for the anticancer activity of LY83583.
...
PMID:Induction of apoptosis in renal cell carcinoma by reactive oxygen species: involvement of extracellular signal-regulated kinase 1/2, p38delta/gamma, cyclooxygenase-2 down-regulation, and translocation of apoptosis-inducing factor. 1654 92

A variety of human cancers show constitutive activation of signal transducer and activator of transcription-3 (Stat3) and overexpression of cyclooxygenase-2 (COX-2). This study describes a novel cross-talk between the COX-2-controlled prostaglandin E(2) (PGE(2)) and Stat3 signaling pathways that coordinately regulate human cancer cell growth. COX-2-derived PGE(2) induces interleukin-6 production through activation of EP(4) receptor and subsequent phosphorylation of gp130/Stat3 in human cholangiocarcinoma cells. In parallel, activation of COX-2/PGE(2) signaling also enhances Stat3 phosphorylation and reporter activity through EP(1) receptor-induced activation of c-Src and EGFR in these cells. Moreover, the observations that EP(1) receptor is detected in the nucleus as well as in the Stat3.DNA binding complex and that activation of EP(1) receptor in the nuclei enhances Stat3 activation depicts a previously undescribed G protein-coupled receptor in the nucleus for Stat3 activation and tumor cell growth.
...
PMID:Modulation of Stat3 activation by the cytosolic phospholipase A2alpha and cyclooxygenase-2-controlled prostaglandin E2 signaling pathway. 2618 44

Dysregulation of pleiotropic growth factors, receptors and their downstream signaling pathway components represent a central protumorigenic principle in human hepatocarcinogenesis. Especially the Insulin-like Growth Factor/IGF-1 receptor (IGF/IGF-1R), Hepatocyte Growth Factor (HGF/MET), Wingless (Wnt/beta-catenin/FZD), Transforming Growth Factor alpha/Epidermal Growth Factor receptor (TGFalpha/EGFR) and Transforming Growth Factor beta (TGFbeta/TbetaR) pathways contribute to proliferation, antiapoptosis and invasive behavior of tumor cells. This review focuses on the relevant alterations in these pathways identified in human human hepatocellular carcinomas (HCCs). Resultant functional effects are modulated by multiple cross-talks between the different signaling pathways and additional tumor-relevant factors, such as cyclooxygenase-2 and p53. Several specific strategies are currently under development such as receptor kinase inhibitors, neutralizing antibodies and antagonistic proteins, which may improve the systemic treatment of human HCCs.
...
PMID:Dysregulation of growth factor signaling in human hepatocellular carcinoma. 1679 20

The treatment of advanced stage thymomas and thymic carcinomas is a multimodal therapy. New therapeutic targets are currently under investigation, including the epidermal growth factor receptor (EGFR) as well as KIT. A number of studies have shown protumorigenic potential of Cyclooxygenase-2 (COX-2) in a variety of human malignancies, but so far it is unknown whether COX-2 is expressed in primary malignancies of the thymus. Using tissue microarrays, the expression of COX-2, microsomal-PGES-1 and -PGES-2 (mPGES-1 and mPGES-2), as well as EGFR was evaluated in different subtypes of thymoma and thymic carcinomas. COX-2 was expressed in all subtypes as determined by immunohistochemistry. Some cases of type B2 and thymic carcinomas had COX-2 staining levels classified as mild to moderate. However, when measuring the optical color intensity, no significant differences could be detected. Concerning the expression levels, a weak correlation between the expression of COX-2, mPGES-1 and mPGES-2 as well as EGFR was found. Furthermore, additional cases of thymomas and thymic carcinomas were analyzed by COX-2 Western immunoblot analysis and were compared to normal thymi. The analysis showed that thymomas and thymic carcinomas had a significantly stronger COX-2 expression than that of the normal thymi (p < 0.04). In summary, COX-2 is expressed in all subtypes of thymomas and thymic carcinomas and thus represents, in addition to EGFR and KIT, a potential therapeutic target. Further studies are needed in order to determine whether a combined therapy using COX-2 inhibitors in addition to the evolving anti-EGFR antibody therapy may be considered as a treatment option.
...
PMID:COX-2 upregulation in thymomas and thymic carcinomas. 1682 44

Inflammatory bowel diseases are associated with reduced colonic contractility and induction of cyclooxygenase-2. In this study a possible role of cyclooxygenase-2 in and the underlying mechanism of the reduced contractility were investigated in experimental colitis. The effects of meloxicam, a cyclooxygenase-2 selective inhibitor were examined on colonic contractility and MAP kinase p38 and ERK(1/2) expression. Colitis was induced in Sprague-Dawley male rats by intra-colonic instillation of trinitrobenzenesulphonic acid (TNBS; 40 mg/rat in 50 ethanol). The animals were divided into three groups. Group 1 (n=9) received meloxicam (3 mg/kg-day) gavage 1 h before and 1 day (Group 2) after induction of colitis. Group 3 (n=9) received phosphate buffered saline (PBS) in a similar manner and served as colitic control. The non colitic control animals received meloxicam in a similar manner. The animals were sacrificed after 5 days of treatment, colon was cleaned with PBS and colonic smooth muscle was obtained which was used in this study. Meloxicam treatment given 1 h before or 1 day after administration of colitis restored the reduced colonic contractility without affecting the sensitivity to carbachol. The levels of colonic smooth muscle IL-1beta mRNA, PGE(2), ERK(1/2), p38, malondialdehyde, myeloperoxidase activity and colonic mass were increased, whereas the body weight was decreased due to TNBS. The changes except colonic muscle mass and p38 expression were reversed by meloxicam treatment. These findings indicate that restoration of reduced colonic contractility by meloxicam is mediated by ERK(1/2), and that ERK(1/2) may serve as an important anti inflammatory target for treatment of colitis.
...
PMID:Mechanism underlying the reversal of contractility dysfunction in experimental colitis by cyclooxygenase-2 inhibition. 1683 10


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---