Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, we have reported that basic calcium phosphate (BCP) crystals stimulate mitogenesis and synthesis of matrix metalloproteinases in cultured human foreskin and synovial fibroblasts. However, the detailed mechanisms involved are still unclear. In the present study, using RT-PCR and Egr-1 promoter analysis we showed that BCP crystals could stimulate early growth response gene Egr-1 transcription through a PKCalpha-dependent p44/p42 MAPK pathway. Using a retrovirus gene expression system (Clontech) to overexpress Egr-1 in human fibroblast BJ-1 cells resulted in promotion of mitogenesis measured either by MTT cell proliferation analysis or by direct cell counting. The results demonstrate that Egr-1 may play a key role in mediating BCP crystal-induced synovial fibroblast mitogenesis.
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PMID:Basic calcium phosphate crystal-induced Egr-1 expression stimulates mitogenesis in human fibroblasts. 1580 48

Zoledronic acid (ZOL), the most potent known bisphosphonate, is clinically efficacious against advanced prostate cancer, although the molecular mechanism by which bisphosphonates prevent prostate cancer cell growth remains unknown. Because Ras is the most thoroughly characterized member of the small G-proteins involved in the regulation of many cellular functions including several oncogenic pathways, the aim of this study was to clarify whether Ras is the molecular target of ZOL in prostate cancer cells. The prostate cancer cell lines PC-3, DU145, and LNCaP were used. Cell proliferation was determined by a modified MTT assay. Geranylgeranyol (GGOH) and famesol (FOH) were used as analogues of geranylgeranyl-pyrophosphate and farnesyl-pyrophosphate, respectively. Changes in expression and/or membrane localization of Ras, Rap1, and phosphorylated MAPK were evaluated by Western blotting. ZOL mediated growth inhibition of prostate cancer cells in a dose- and time-dependent manner. The ZOL-induced growth inhibitory effect was circumvented by the addition of GGOH. In contrast, FOH did not reverse the growth inhibitory effect of ZOL. The amount of membrane-anchored Ras was clearly independent of ZOL-mediated growth inhibition. Unexpectedly, ZOL induced N- and H-Ras expression of the cytosolic fraction. Ras does not appear to be the molecular target for ZOL-induced growth inhibition. Prevention of geranylgeranylation rather than farnesylation is an important therapeutic target in prostate cancer.
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PMID:Zoledronic acid mediates Ras-independent growth inhibition of prostate cancer cells. 1583 1

The Raf/MEK/ERK signaling cascade has been extensively studied for its roles in growth and differentiation of a variety of cell types. Confliciting evidence exists regarding the function of classical MAPK signaling with regards to the development of chemotherapeutic drug resistance; some reports describe an pro-survival role, whereas others have suggested that activation of Raf/MEK/ERK is essential for drug-induced death. To elucidate the importance of MAPK signaling in the development of advanced prostate cancer drug resistance, DU145 and PC3 prostate cells were stably-infected/transfected with constitutively-activated mutants of both Raf-1 and B-Raf. Results from MTT analyses suggested that activation of either Raf-1 or B-Raf is inconsequential in prostate cancer chemoresistance. To confirm these findings, the MAPK signal transduction cascade was activated with EGF and response to doxorubicin or paclitaxel was measured in the presence/absence of the MEK-specific inhibitor, U0126. These results showed that inhibition of signals transduced by the MAPK pathway are insufficient to affect the chemoresistance profile of advanced prostate cancer cells. Together, these data demonstrate that the response of prostatic tumors to the chemotherapeutic compounds doxorubicin and paclitaxel is independent of Raf/MEK/ERK signaling.
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PMID:Modulation of Raf/MEK/ERK kinase activity does not affect the chemoresistance profile of advanced prostate cancer cells. 1587 Aug 80

The present study describes the ability of an anthraquinone derivative aloe emodin (AE) to reduce the cytotoxic activity of the platinum(II)-based anticancer agent cisplatin toward murine L929 fibrosarcoma and C6 glioma cell lines. The protective effect of AE was demonstrated by MTT and crystal violet assays for cell viability, and involved supression of cisplatin-induced apoptosis and necrosis, as assessed by lactate dehydrogenase release and flow cytometric analysis of DNA fragmentation or phosphatidylserine exposure. Cell-based ELISA and Western blot analysis revealed that AE abolished cisplatin-triggered activation of extracellular signal-regulated kinase (ERK) in tumor cells, while activation of c-Jun N-terminal kinase was not significantly altered. A selective blockade of ERK activation with PD98059 mimicked the protective effect of AE treatment in both tumor cell lines. Moreover, AE failed to protect tumor cells against the ERK-independent toxicity of the Pt(IV)-based complex tetrachloro(O,O-dibutyl-ethylenediamine-N,N'-di-3-propanoate)platinum(IV). Taken together, these data indicate that herbal anthraquinone AE can downregulate the anticancer activity of cisplatin by blocking the activation of ERK in tumor cells.
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PMID:Aloe emodin decreases the ERK-dependent anticancer activity of cisplatin. 1590 60

The aim of this study was to investigate the cytoprotective effects of CT-1 against non-ischemic death stimuli in adult cardiomyocytes. Primary cultures of cardiomyocytes isolated from adult rats were stimulated with either angiotensin II (Ang II) or H(2)O(2) in the presence or absence of CT-1. Cell death was determined by trypan blue exclusion, cell viability by MTT assay and apoptosis by TUNEL-Annexin-V staining. Intracellular pathways were analyzed by the employment of chemical inhibitors and by the assessment of signalling intermediates phosphorylation by Western blot analysis. CT-1 reduced (p<0.01) total cell death and apoptosis induced by either Ang II or H(2)O(2), and increased (p<0.01) cell viability in cardiomyocytes exposed to these stimuli. These effects of CT-1 were abolished in the presence of antibodies specific for gp130 or LIFR and did not require RNA or protein synthesis. Both Wortmannin and PD98059 abolished protective effects of CT-1 against H(2)O(2), whereas only Wortmannin inhibited protection against Ang II. In both cases, Akt kinase activation and Bad phosphorylation were observed. These findings suggest that CT-1 protects adult cardiomyocytes against Ang II- and oxidative stress-induced cell death, via gp130/LIFR and by means of the PI3K/Akt and the p42/44 MAPK intracellular cascades.
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PMID:Characterization of the protective effects of cardiotrophin-1 against non-ischemic death stimuli in adult cardiomyocytes. 1592 54

Previously, we reported that ouabain and other cardiotonic steroids (CTS) kill renal epithelial and vascular endothelial cells via their interaction with the Na+,K+-ATPase alpha-subunit, but independently of elevation of the [Na+]i/[K+]i ratio. In distinct cell types, side-by-side with inhibition of Na+,K+-ATPase-mediated ion fluxes, CTS trigger [Ca2+]i oscillation, activation of Ras, mitogen-activated protein kinases (MAPK), phosphoinositide-3 kinase (PI3K), and protein kinase C as well as the production of reactive oxygen species and cytoskeleton reorganization. This study examined the potential involvement of the above-listed intermediates in death signaling triggered by ouabain in C7-Madin-Darby canine kidney cells. In these cells, twofold decreased staining with dimethylthiazol diphenyltetrazolium (MTT) and detachment of up to 80% of dead cells were detected in 6 and 24 h of ouabain addition, respectively. We did not observe any effect of extra- (EGTA) and intracellular (BAPTA) Ca2+-chelators, [Ca2+]i-raising compounds (thapsigargin, ATP), inhibitors of Ras signaling (alpha-hydroxyfarnesyl-sulphosphoric acid), PI3K (wortmannin), MAPK ERK1/2 kinase (PD98059), tyrosine kinases (genistein) as well as activators (4beta-PMA, 8-Br-cAMP, 8-Br-cGMP, forskolin) and inhibitors (calphostin) of serine-threonine kinases on MTT staining and death of ouabain-treated cells. Ouabain did not affect cellular redox state and the production of superoxide anion and hydroperoxide. Neither N-acetylcysteine nor reduced gluthatione suppressed the death of ouabain-treated cells. Thus, our results show that none of the above-listed signaling systems plays a major role in the development of Nai+,Ki+-independent death machinery triggered by CTS interaction with the Na+,K+-ATPase alpha-subunit.
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PMID:Search for intermediates of Na+,K+-ATPase-mediated [Na+]i/[K+]i-independent death signaling triggered by cardiotonic steroids. 1602 61

Total glucosides of paeony (TGP) are active compounds extracted from the roots of Paeonia lactiflora Pall. In this study, we investigated the mechanisms of total glucosides of paeony (TGP) in the treatment of adjuvant arthritis (AA). AA in rats was established. Synoviocytes proliferation and activity of IL-1 were determined by 3-(4, 5-2dimethylthiazal-2yl) 2, 5-diphenyltetrazoliumbromide (MTT) assay. Tumor necrosis factor alpha (TNF-alpha) and prostaglandin E2 (PGE2) were measured by radioimmunoassay. Ultrastructure of synovioctes was observed under transmission electron microscope. Phosphorylation of c-Jun N-terminal kinase (JNK), extracellular regulating kinase (ERK) and p38 kinase and expression of matrix metalloproteinases (MMPs) were detected by Western blot analysis. TGP (25, 50 and 100 mg kg(-1), ig, days 14-21) inhibited secondary inflammatory reaction, bone destruction and ultrastructure change of synoviocytes in AA rats. The administration of TGP (50 and 100 mg/kg, ig, days 14-21) in AA rats significantly decreased the production of IL-1, PGE2 and TNF-alpha by macrophage-like synoviocytes (MLS). TGP (25 mg/kg) also decreased the production of PGE(2) by MLS in AA rats. Furthermore, the increased phosphorylation of MAPKs, cell proliferation, and MMPs expression in fibroblast-like synoviocytes (FLS) stimulated by supernatants of MLS in AA rats could also be inhibited by TGP (50 and 100 mg/kg, ig, days 14-21). The results suggest that TGP possesses anti-inflammatory effects by modulating the pro-inflammatory mediators production from MLS and phosphorylation of MAPKs from FLS.
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PMID:Total glucosides of paeony suppresses adjuvant arthritis in rats and intervenes cytokine-signaling between different types of synoviocytes. 1602 8

Betulinic acid (BA), a pentacyclic triterpene first identified less than a decade ago, has served as a melanoma-specific cytotoxic agent, and yet its specificity is being challenged. Recently, we found that human melanoma cells exhibited less sensitivity to betulinic acid than human skin keratinocytes. This study was designed to investigate the cell signaling pathway leading human melanoma cells to increased resistance to betulinic acid treatment. In vitro experiments using cultured human melanoma cells indicated that betulinic acid transiently induced survivin expression. The expression of survivin started 30 min post-betulinic acid treatment, peaked at 2 h, remained elevated for 8 h and returned to basal level within 24 h. Similarly, epithelial growth factor (EGF) treatment induced expression of survivin in a time-dependent manner. Since epithelial growth factor receptor (EGFR) activation leads to the activation of cell signaling components that are important to cell survival, we next examined whether BA-induced survivin expression is mediated by the EGFR pathway. The results showed that BA induced EGFR tyrosine phosphorylation in a time-dependent manner. Further, BA strongly induced AKT phosphorylation in a similar pattern. AKT activation started 15 min post-treatment, peaked at approximately 1 h, remained elevated for 4 h and returned to basal level within 8 h. BA also induced ERK activation and, in contrast, weakly induced JNK and p38 activation. Pretreatment of EGFR inhibitor PD153035 blocked BA-induced EGFR phosphorylation, ERK and AKT activation, and survivin expression. Results of the MTT dye assay showed that a combination of PD153035 and BA enhanced melanoma cell death. Collectively, we conclude that betulinic acid transiently activated the EGFR/AKT cell survival pathway and induced survivin expression, contributing to less sensitivity in human melanoma cells. The data suggest that a combination of the EGFR inhibitor and betulinic acid may be a better clinical option to treat human melanoma.
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PMID:Transient activation of EGFR/AKT cell survival pathway and expression of survivin contribute to reduced sensitivity of human melanoma cells to betulinic acid. 1607 34

Human lactoferrin (hLF) is a member of the transferrin family and is found in most body fluids of human. Recent study showed that hLF played some roles in the regulation of cell growth. However, the biological function of hLF in the central nervous system and neuronal cells is still unclear. The MTT was used to assay cell viability, ELISA tests were used to assay caspase activities, and TUNEL staining was used to test the cytotoxicity of hLF to the cells. Our result showed that 700 microg/ml hLF significantly reduced the cell viability and increased the caspase 3 and 8 activities in PC12 neuronal cells. TUNEL staining further showed that 700 microg/ml hLF was cytotoxic to the PC12 through apoptosis-mediated pathway. In addition, 700 microg/ml hLF significantly decreased the protein expressions of phosphorylated extracellular-signal-regulated kinase 1/2 (ERK1/2) and Bcl-2 in PC12 cells, whereas 50 microg/ml hLF significantly increased the phosphorylation of ERK1/2 which could be specifically inhibited by PD98059. Furthermore, 50 microg/ml hLF could not only up-regulate the Bcl-2 expression but also protect PC12 cells from FasL-induced apoptosis. In conclusion, hLF plays a crucial role in the regulation of apoptosis and anti-apoptosis in PC12 neuronal cells via ERK1/2 phosphorylation pathway.
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PMID:Human lactoferrin exerts bi-directional actions on PC12 cell survival via ERK1/2 pathway. 1618 36

An alpha-tocopherol, beta-carotene supplementation trial (ATBC) and a chemoprevention trial with beta-carotene and retinoids (CARET trial) were conducted in the 1990s in populations at risk for the development of lung cancer. Both trials had to be discontinued due to significant increases in lung cancer and cardiovascular mortality. Clinical trials to test the cancer preventive effects of beta-carotene are still ongoing, and high concentrations of this provitamin are contained in numerous dietary supplements. Using a cell line derived from a human pulmonary adenocarcinoma (PAC) of Clara cell lineage and immortalized human small airway epithelial cells, our data show that low concentrations of beta-carotene that can be realistically expected in human tissues after oral administration caused a significant increase in intracellular cAMP and activated PKA, as well as in phosphorylation of ERK1/2 and CREB. Furthermore, the proliferation of cells was significantly stimulated by identical concentrations of beta-carotene as monitored by MTT assays. Control experiments with retinol also showed stimulation of cell proliferation and activation of PKA in both cell lines. In light of the fact that PAC is the leading type of lung cancer, these findings suggest that the growth promoting effects of beta-carotene on this cancer type observed in our experiments may have contributed to the unfortunate outcome of the ATBC and CARET trials. This interpretation is supported by the fact that elevated levels of cAMP in the cardiovascular system play a major role in the genesis of cardiovascular disease, which was also greatly promoted in the CARET trial. Our data challenge the widely accepted view that beta-carotene may be useful as a cancer preventive agent.
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PMID:Growth stimulation of human pulmonary adenocarcinoma cells and small airway epithelial cells by beta-carotene via activation of cAMP, PKA, CREB and ERK1/2. 1620 75


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