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

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Query: EC:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosine kinases play central roles in the growth and differentiation of normal and tumor cells. In this study, we have analyzed the general tyrosine kinase expression profile of a prostate carcinoma (PCA) xenograft, CWR22. We describe here an improved reverse transcriptase-PCR approach that permits identification of nearly 40 different kinases in a single screening; several of these kinases are newly cloned kinases and some are novel. According to this, there are 11 receptor kinases, 9 nonreceptor kinases, and at least 7 dual kinases expressed in the xenograft tissue. The receptor kinases include erbB2, erbB3, Ret, platelet-derived growth factor receptor, sky, nyk, eph, htk, sek (eph), ddr, and tkt. The nonreceptor kinases are lck, yes, abl, arg, JakI, tyk2, and etk/bmx. Most of the dual kinases are in the mitogen-activating protein (MAP) kinase-kinase (MKK) family, which includes MKK3, MKK4, MEK5, and a novel one. As a complementary approach, we also analyzed by specific reverse transcriptase-PCR primers the expression profile of erbB/epidermal growth factor receptor family receptors in a variety of PCA specimens, cell lines, and benign prostatic hyperplasia. We found that erbB1, -2, and -3 are often coexpressed in prostate tissues, but not in erbB4. The information established here should provide a base line to study the possible growth and oncogenic signals of PCA.
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PMID:A tyrosine kinase profile of prostate carcinoma. 865 Feb 1

Extracellular signal-regulated kinase (ERK) is an important intermediate in signal transduction pathways that are initiated by many types of cell surface receptors. It is thought to play a pivotal role in integrating and transmitting transmembrane signals required for growth and differentiation. Constitutive activation of ERK in fibroblasts elicits oncogenic transformation, and recently, constitutive activation of ERK has been observed in some human malignancies, including acute leukemia. However, mechanisms underlying constitutive activation of ERK have not been well characterized. In this study, we examined the activation of ERK in 79 human acute leukemia samples and attempted to find factors contributing to constitutive ERK activation. First, we showed that ERK and MEK were constitutively activated in acute leukemias by in vitro kinase assay and immunoblot analysis. However, in only one half of the studied samples, the pattern of ERK activation was similar to that of MEK activation. Next, by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblot analysis, we showed hyperexpression of ERK in a majority of acute leukemias. In 17 of 26 cases (65.4%) analyzed by immunoblot, the pattern of ERK expression was similar to that of ERK activation. The fact of constitutive activation of ERK in acute leukemias suggested to us the possibility of an abnormal downregulation mechanism of ERK. Therefore, we examined PAC1, a specific ERK phosphatase predominantly expressed in hematopoietic tissue and known to be upregulated at the transcription level in response to ERK activation. Interestingly, in our study, PAC1 gene expression in acute leukemias showing constitutive ERK activation was significantly lower than that in unstimulated, normal bone marrow (BM) samples showing minimal or no ERK activation (P =.002). Also, a significant correlation was observed between PAC1 downregulation and phosphorylation of ERK in acute leukemias (P =.002). Finally, by further analysis of 26 cases, we showed that a complementary role of MEK activation, ERK hyperexpression, and PAC1 downregulation could contribute to determining the constitutive activation of ERK in acute leukemia. Our results suggest that ERK is constitutively activated in a majority of acute leukemias, and in addition to the activation of MEK, the hyperexpression of ERK and downregulation of PAC1 also contribute to constitutive ERK activation in acute leukemias.
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PMID:Constitutive activation of extracellular signal-regulated kinase in human acute leukemias: combined role of activation of MEK, hyperexpression of extracellular signal-regulated kinase, and downregulation of a phosphatase, PAC1. 1033 98

The signal transduction pathways regulating smooth-muscle gene expression and production of cytokines in response to proinflammatory mediators are undefined. Cultured human bronchial smooth-muscle cells were treated for 20 h with a cytokine cocktail containing interleukin (IL)-1beta, tumor necrosis factor-alpha, and interferon-gamma. A complementary DNA expression array containing 588 genes was used to follow cytokine-stimulated gene expression. The expression and secretion of the cytokines IL-1beta, IL-6, and IL-8 significantly increased after 20 h of stimulation as measured by relative reverse transcriptase/ polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blotting techniques. Expression of IL-6 and IL-8 was sensitive to SB203580, the specific inhibitor of p38 mitogen-activated protein (MAP) kinase and PD98059, an inhibitor of MAP kinase kinase. Expression of IL-1beta was sensitive only to PD98059. Together, these results demonstrate that the p38 and extracellular signal-regulated protein kinase MAP kinase pathways are required for proinflammatory mediator- induced cytokine expression in airway myocytes. The generation of chemokines and cytokines in airway smooth muscle also provides evidence that smooth-muscle cells have the ability to contribute to the inflammatory response.
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PMID:Mitogen-activated protein kinases regulate cytokine gene expression in human airway myocytes. 1087 57

The bronchial epithelium is a potential source of growth factors that could mediate airway fibrosis during the progression of diseases such as asthma and chronic bronchitis. We report that conditioned medium (CM) from normal human bronchial epithelial cells (NHBECs) contains mitogenic activity for human lung fibroblasts that is blocked by the epidermal growth factor receptor (EGF-R) tyrosine kinase inhibitor AG1478 and by neutralizing antibodies raised against heparin-binding epidermal growth factor-like growth factor (HB-EGF). Neutralizing antibodies against other EGF-R ligands (EGF and transforming growth factor-alpha) or other antibodies against growth factors (platelet-derived growth factors, insulin-like growth factor-1) had no affect on the mitogenic activity of NHBEC-CM. HB-EGF messenger RNA (mRNA) expression in NHBEC was detected by reverse transcriptase/polymerase chain reaction and Northern blot analysis. HB-EGF protein was detected by enzyme-linked immunosorbent assay. Vanadium pentoxide (V2O5), a fibrogenic metal associated with occupational asthma, caused a several-fold increase in HB-EGF mRNA expression and protein, whereas the inert metal titanium dioxide had no effect on HB-EGF expression. V2O5-induced HB-EGF mRNA expression was inhibited by the EGF-R tyrosine kinase inhibitor AG1478, the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580, and the MAP kinase kinase inhibitor PD98059. Finally, HB-EGF induced the production of fibroblast growth factor (FGF)-2 by human lung fibroblasts and anti-FGF-2 antibody partially blocked the mitogenic activity of NHBEC-CM on fibroblasts. These data suggest that HB-EGF is a fibroblast mitogen produced by NHBECs and that induction of an FGF-2 autocrine loop in fibroblasts by HB-EGF accounts for part of this mitogenic activity.
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PMID:Vanadium stimulates human bronchial epithelial cells to produce heparin-binding epidermal growth factor-like growth factor: a mitogen for lung fibroblasts. 1115 45

We investigated the mechanisms of parathyroid hormone-related peptide (PTHrP)-mediated effects on osteogenic cells in primary rat bone marrow cell (BMC) cultures. We first demonstrated by reverse transcriptase-polymerase chain reaction and immunocytochemistry that BMCs express the type I parathyroid hormone/PTHrP receptor. Treatment with PTHrP increased osteogenic cell proliferation as determined by [(3)H]thymidine and bromodeoxyuridine incorporation and augmented osteogenic colonies. Immunocytochemistry and Western blotting revealed no direct effect on expression of the osteoblast markers, type I collagen, bone sialoprotein, and osteocalcin, indicating that PTHrP did not directly stimulate differentiation in this system. PTHrP increased mitogen-activated protein kinase (MAPK) activity in BMC and MAPK activity, and PTHrP-induced osteogenic cell proliferation could be blocked by the MEK inhibitor PD-098059. PTHrP also increased Ras activity in BMC. Although wortmannin and H8, inhibitors of phosphoinositol 3-kinase and protein kinase A, respectively, did not block PTHrP-stimulated Ras or MAPK activity, chelerythrin chloride, a known protein kinase C inhibitor, did block these PTHrP actions as well as PTHrP-induced osteogenic cell proliferation. These results demonstrate that PTHrP stimulates osteogenic cell proliferation in rat marrow mesenchymal progenitor cells through protein kinase C-dependent activation of the Ras and MAPK signaling pathway.
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PMID:Parathyroid hormone-related peptide stimulates osteogenic cell proliferation through protein kinase C activation of the Ras/mitogen-activated protein kinase signaling pathway. 1140 23

Pulmonary fibrosis is a progressive disorder characterized by the loss of alveolar architecture through epithelial and endothelial cell apoptosis and fibroblast proliferation. Recent studies showed that angiotensin-converting enzyme (ACE) activity is increased in fibrotic tissues, and ACE inhibitors administered in vivo ameliorate fibrosis, suggesting that ACE may play a critical role. However, the regulation of ACE expression is not well understood. In the present study, we demonstrate that bleomycin, a chemotherapeutic agent which induces pulmonary fibrosis in animals and humans, increases gene expression of ACE. Treatment of primary bovine pulmonary artery endothelial cells with 0.1 to 1.0 microg/ml bleomycin increased ACE enzymatic activity and ACE mRNA, as monitored by hippuryl-L-histidyl-L-leucine assay and competitive quantitative reverse transcriptase polymerase chain reaction (RT-PCR), respectively. Luciferase reporter constructs showed that upregulation of ACE transcription by bleomycin is mediated through element(s) in the 97-bp ACE promoter. Bleomycin activated p42/p44 mitogen-activated protein kinase (MAPK) and induced nuclear translocation and activation of the early growth response (Egr)-1 transcription factor, a factor previously shown to positively regulate ACE expression. The MAPK kinase1/2 (MEK1/2) inhibitor U0126 blocked MAPK and Egr-1 activation by bleomycin, suggesting that Egr-1 activation is MAPK dependent. These data provide the first evidence that bleomycin activates ACE gene expression through the MAPK pathway and Egr-1.
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PMID:Bleomycin upregulates gene expression of angiotensin-converting enzyme via mitogen-activated protein kinase and early growth response 1 transcription factor. 1171 4

The effects of prostaglandin (PG) E(1) on NO neurotoxicity were examined using rat cultured spinal neurons. Rat cultured spinal neurons exposed to the NO donor, 2,2'-(hydroxynitrosohydrazono) bis-ethanamine (NOC18), showed neurotoxic effects that were accompanied by apoptotic nuclear change, free radical generation, a reduction in glutathione, and mitochondrial dysfunction. PGE(1), at concentrations of 1-100 nM, protected cultured spinal neurons from NO toxicity by reversing the oxidative and pro-apoptotic properties elicited by NOC18 exposure. The administration of PGE(1) increased the intracellular cyclic AMP (cAMP) levels in cultured spinal neurons. In addition, reverse transcriptase-polymerase chain reaction (RT-PCR) analysis confirmed the existence of EP4, a cAMP-elevating PGE receptor, in cultured spinal neurons. The protective effects of PGE(1) against NO neurotoxicity was partially blocked by an inhibitor of MEK [the mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) kinase], suggesting that the MAPK/ERK pathway may play a significant role in the activity of PGE(1). PGE(1) up-regulated the expression of the anti-apoptotic protein, Bcl-2, as determined by Western blot analysis. PGE(1) also induced the expression of thioredoxin in cultured spinal neurons. Our data indicate that PGE(1) exerts a protective action against NO neurotoxicity in cultured spinal neurons, and suggests a therapeutic potential of PGE(1) against spinal cord disease, such as amyotrophic lateral sclerosis.
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PMID:Prostaglandin E1 protects cultured spinal neurons against the effects of nitric oxide toxicity. 1198 30

Aminoglycoside antibiotics (AGAs) are nephrotoxic, with most of the damage confined to the proximal tubule, but the mechanism for cellular toxicity is not clear. It has been previously shown that the extracellular-calcium sensing receptor (CaR) is expressed in intact rat proximal tubule and can be stimulated by the AGA neomycin. To investigate whether CaR could contribute to AGA-induced nephrotoxicity, the acute responses to various AGAs in the proximal tubule-derived opossum kidney (OK) cell line were examined. The presence in OK cells of CaR-related transcripts and protein was demonstrated by northern analyses, reverse transcriptase-PCR, immunocytochemistry, and immunoblotting. OK cells responded to elevated extracellular calcium (Ca(2+)(o)) and neomycin but also to gentamicin and tobramycin with an increase in cytosolic [Ca(2+)]. Ca(2+)(o), neomycin, and gentamicin also activated the extracellular signal-regulated kinases, ERK1 and ERK2. Neomycin-induced ERK activation was both dose- and time-dependent and was attenuated by inhibitors of phosphatidylinositol 3-kinase, phosphatidylinositol bisphosphate (PIP(2))-specific phospholipase C, and MEK1, but not of protein kinase C. Thus, proximal tubular OK cells express a CaR that mediates Ca(2+)(i) mobilization and PIP(2)-PLC-dependent ERK activation in response to AGAs and thus could play a role in AGA-induced nephrotoxicity.
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PMID:Aminoglycosides increase intracellular calcium levels and ERK activity in proximal tubular OK cells expressing the extracellular calcium-sensing receptor. 1203 77

Interleukin 1beta(IL-1beta), a proinflammatory cytokine, is related with inflammatory diseases and it up-regulates MUC2 gene expression and mucin secretion. This study was designed to investigate the signal transduction pathway of the IL-1beta-mediated MUC2 gene expression and mucin secretion in human airway epithelial cells. In cultured human airway NCI-H292 epithelial cells, the steady state of the mRNA level of MUC2 gene expression and mucin secretion induced by IL-1beta were determined by reverse transcriptase-polymerase chain reaction (RT-PCR), enzyme immunoassay, and immunoblot analysis. To observe the signal pathway of the IL-1beta-mediated MUC2 gene expression and mucin secretion, we used several specific inhibitors. PD98059 (MEK/ERK inhibitor) suppressed IL-1beta-mediated MUC2 gene expression and mucin secretion, while SB203580 (p38 inhibitor) did not. Ro31-8220 (PKC inhibitor) inhibited IL-1beta-mediated MUC2 gene expression and mucin secretion. It inhibited ERK phosphorylation, but did not inhibit p38 phosphorylation. LY294002 (PI3K inhibitor) also suppressed MUC2 expression, but did not inhibit any MAPKs phosphorylation. These results suggest that the IL-1beta-mediated MUC2 gene expression and mucin secretion in NCI-H292 cells are regulated through activation of the PKC-MEK/ERK pathway, and that PI3K is also involved in the IL-1beta-mediated MUC2 gene expression and mucin secretion.
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PMID:Interleukin-1beta induces MUC2 gene expression and mucin secretion via activation of PKC-MEK/ERK, and PI3K in human airway epithelial cells. 1248 99

Chlamydiae are obligate intracellular bacterial parasites that infect eukaryotic cells and live their entire life cycle within a cytoplasmic vacuole or inclusion. We have employed cDNA microarray and conventional biological approaches to study the pathogen-host cell interaction during C. pneumoniae infection of eukaryotic cells. Two host cell signaling pathways, MEK/ERK and PI 3-kinase/Akt, were activated within 5 and 20 minutes, respectively, following infection with chlamydiae. Pharmacological inhibition of these pathways blocked invasion of HEp2 cells indicating that activation of these pathways was required for infection. Rho family GTPase activity was essential for invasion, since the pan-Rho GTPase inhibitor, compactin, blocked infection of HEp2 cells. cDNA microarrays and reverse transcriptase PCR were used to study host cell and chlamydial gene expression during the replication cycle. Analysis of host cell gene expression following infection with C. pneumoniae indicated that genes coding for cytokines, growth factors, and signaling molecules were upregulated, as early as 2 hours postinfection. Analysis of chlamydial gene expression indicated a temporal regulation of transcription with distinct early-, mid-, and late-cycle classes of RNA transcripts. Newly discovered genes encoding three Ser/Thr protein kinases and one protein phosphatase were upregulated 6-12 hours postinfection. One protein kinase, designated CpnPK1, was first detected at 12 hours postinfection, accumulated in the inclusion throughout the replication cycle, and may be a type III effector molecule. An increased understanding of chlamydial host cell interactions, in particular the role of various chlamydial proteins in infection and identification of essential virulence factors should provide novel targets for the development of new antimicrobials.
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PMID:Chlamydiae host cell interactions revealed using DNA microarrays. 1253 65


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