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Cisplatin-induced activation of mitogen-activated protein kinases in ovarian carcinoma cells: inhibition of extracellular signal-regulated kinase activity increases sensitivity to cisplatin.
Persons DL, Yazlovitskaya EM, Cui W, Pelling JC
(1999) Clin Cancer Res 5: 1007-14
MeSH Terms: Adenocarcinoma, Antineoplastic Agents, Calcium-Calmodulin-Dependent Protein Kinases, Cisplatin, Cycloheximide, DNA Adducts, DNA Damage, DNA, Neoplasm, Enzyme Activation, Enzyme Induction, Enzyme Inhibitors, Female, Flavonoids, Gene Expression Regulation, Neoplastic, Humans, JNK Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Neoplasm Proteins, Ovarian Neoplasms, Protein Synthesis Inhibitors, Signal Transduction, Tumor Cells, Cultured, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added November 16, 2017
Cisplatin treatment activates multiple signal transduction pathways, which can lead to several cellular responses including cell cycle arrest, DNA repair, survival, or apoptosis. We investigated the response of the mitogen-activated protein kinases, extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun-N-terminal kinase 1 (JNK1), and p38, to cisplatin treatment in the ovarian carcinoma cell line SK-OV-3. Cisplatin caused a late and prolonged induction in a dose-dependent manner of both ERK1/2 and JNK1 activity. ERK1/2 and JNK1 activities continued to increase in magnitude up to 24 h following initiation of cisplatin treatment. In contrast, cisplatin treatment had no effect on p38 activity. Transplatin failed to induce either ERK1/2 or JNK1 at 24 h, which suggests that the activation of these kinases was dependent on cisplatin-specific DNA damage. Treatment with cycloheximide resulted in inhibition of cisplatin-induced ERK1/2 activation, demonstrating that ERK1/2 activity induced by cisplatin was dependent on de novo protein synthesis. Furthermore, inhibition of cisplatin-induced ERK1/2 activity by PD 98059 caused enhanced cisplatin cytotoxicity. Similar enhanced cytotoxic effects of cisplatin were also observed following treatment with PD 98059 in the ovarian carcinoma cell line UCI 101. These observations indicate that ERK1/2 activation induced by cisplatin partially protects cells from cisplatin cytotoxicity. Continued investigation into the mechanism by which the ERK pathway and other signal transduction pathways modulate the response to cisplatin may be helpful in the development of new strategies for improving the therapeutic use of platinum drugs.
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25 MeSH Terms
Association of apoptosis with the inhibition of extracellular signal-regulated protein kinase activity in the tumor necrosis factor alpha-resistant ovarian carcinoma cell line UCI 101.
Yazlovitskaya EM, Pelling JC, Persons DL
(1999) Mol Carcinog 25: 14-20
MeSH Terms: Adenocarcinoma, Apoptosis, Blotting, Western, Calcium-Calmodulin-Dependent Protein Kinases, Cell Division, Cell Survival, DNA Fragmentation, Dose-Response Relationship, Drug, Enzyme Activation, Enzyme Inhibitors, Female, Flavonoids, Humans, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 1, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Ovarian Neoplasms, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Signal Transduction, Time Factors, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha
Show Abstract · Added November 16, 2017
Tumor necrosis factor-alpha (TNF alpha) can function as both an autocrine and a paracrine growth factor and may therefore play a role in ovarian tumor progression. TNF alpha initiates multiple cellular responses, many of which are mediated through the mitogen-activated protein kinase pathways, which transduce signals from the TNF alpha receptors through the cytoplasm to the nucleus, resulting in regulation of gene expression. We examined the role of c-jun N-terminal kinase 1 (JNK1) and extracellular signal-regulated protein kinase (ERK) 1 and 2 in the cellular growth response to TNF alpha in the ovarian carcinoma cell line UCI 101. JNK1 activity was increased to a maximum level ninefold above the basal level after 10-20 min of treatment with 10 ng/mL TNF alpha. A maximum threefold induction of ERK1/2 activity was observed after 1 min of treatment. At concentrations up to 100 ng/mL, TNF alpha had neither a stimulatory nor an inhibitory effect on growth of UCI 101 cells. However, inhibition of TNF alpha-induced ERK1/2 activity by the MAP/ERK kinase 1 inhibitor PD 98059 resulted in 60% inhibition of cell growth in TNF alpha-treated UCI 101 cells. This decrease in cell growth was accompanied by apoptosis, as demonstrated by the presence of a 180-bp DNA ladder. Thus, the inhibition of TNF alpha-induced ERK1/2 activity was associated with induction of apoptosis in the TNF alpha-resistant cell line UCI 101. Inhibition of TNF alpha-induced ERK1/2 activity was accompanied by a subsequent transient increase in TNF alpha-induced JNK1 activity. The significance of this increase with respect to apoptosis induction remains to be determined. These findings demonstrated that ERK1/2 activity can modulate cellular sensitivity to TNF alpha and suggested that the balance between the levels of ERK1/2 and JNK1 activation may be critical in the cellular growth response to TNF alpha.
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26 MeSH Terms
Extracellular signal-regulated kinase activates topoisomerase IIalpha through a mechanism independent of phosphorylation.
Shapiro PS, Whalen AM, Tolwinski NS, Wilsbacher J, Froelich-Ammon SJ, Garcia M, Osheroff N, Ahn NG
(1999) Mol Cell Biol 19: 3551-60
MeSH Terms: Animals, Antigens, Neoplasm, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Cell Nucleus, Chromatin, DNA Topoisomerases, Type II, DNA, Superhelical, DNA-Binding Proteins, Dimerization, Drosophila, Enzyme Activation, Isoenzymes, MAP Kinase Kinase 1, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase Kinases, Mutation, Phosphoproteins, Phosphorylation, Precipitin Tests, Protein Binding, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Transfection
Show Abstract · Added March 5, 2014
The mitogen-activated protein (MAP) kinases, extracellular signal-related kinase 1 (ERK1) and ERK2, regulate cellular responses by mediating extracellular growth signals toward cytoplasmic and nuclear targets. A potential target for ERK is topoisomerase IIalpha, which becomes highly phosphorylated during mitosis and is required for several aspects of nucleic acid metabolism, including chromosome condensation and daughter chromosome separation. In this study, we demonstrated interactions between ERK2 and topoisomerase IIalpha proteins by coimmunoprecipitation from mixtures of purified enzymes and from nuclear extracts. In vitro, diphosphorylated active ERK2 phosphorylated topoisomerase IIalpha and enhanced its specific activity by sevenfold, as measured by DNA relaxation assays, whereas unphosphorylated ERK2 had no effect. However, activation of topoisomerase II was also observed with diphosphorylated inactive mutant ERK2, suggesting a mechanism of activation that depends on the phosphorylation state of ERK2 but not on its kinase activity. Nevertheless, activation of ERK by transient transfection of constitutively active mutant MAP kinase kinase 1 (MKK1) enhanced endogenous topoisomerase II activity by fourfold. Our findings indicate that ERK regulates topoisomerase IIalpha in vitro and in vivo, suggesting a potential target for the MKK/ERK pathway in the modulation of chromatin reorganization events during mitosis and in other phases of the cell cycle.
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24 MeSH Terms
Phosphorylation of mitogen-activated protein kinase in cultured rat cortical glia by stimulation of metabotropic glutamate receptors.
Peavy RD, Conn PJ
(1998) J Neurochem 71: 603-12
MeSH Terms: Animals, Calcium-Calmodulin-Dependent Protein Kinases, Cells, Cultured, Cerebral Cortex, Cycloleucine, Enzyme Inhibitors, Excitatory Amino Acid Antagonists, Flavonoids, Glycine, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase Kinases, Neuroglia, Neuroprotective Agents, Phosphorylation, Protein Kinase C, Protein Kinase Inhibitors, Protein Kinases, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate, Resorcinols, Tyrosine
Show Abstract · Added February 19, 2015
Activation of metabotropic glutamate receptors (mGluRs) in glia results in significant physiological effects for both the glia and the neighboring neurons; but in many cases, the mGluR subtypes and signal transduction mechanisms mediating these effects have not been determined. In this study, we report that mGluR activation in primary cultures of rat cortical glia results in tyrosine phosphorylation of several proteins, including p44/p42 mitogen-activated protein kinases, also referred to as extracellular signal-regulated kinases (ERK1/2). Incubation of glial cultures with the general mGluR agonist 1-aminocyclopentane-1S,3R-dicarboxylate and the mGluR group I-selective agonists (RS)-3,5-dihydroxyphenylglycine (DHPG) and L-quisqualate resulted in increased tyrosine phosphorylation of ERK1/2. The group II-selective agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine and group III-selective agonist L(+)-2-amino-4-phosphonobutyric acid had no effect on tyrosine phosphorylation. DHPG-induced ERK1/2 phosphorylation could be inhibited by an antagonist that acts at group I or group II mGluRs but not by antagonists for group II and group III mGluRs. Protein kinase C (PKC) activators also induced ERK1/2 phosphorylation, but the PKC inhibitor bisindolylmaleimide I did not inhibit DHPG-induced ERK1/2 phosphorylation at a concentration that inhibited the response to phorbol 12,13-dibutyrate. These data suggest that mGluR activation of ERK1/2 in cultured glia is mediated by group I mGluRs and that this effect is independent of PKC activation. Furthermore, immunoblots with antibodies against various mGluR subtypes show expression of mGluR5, but no other mGluRs in our cultures. Taken together, these results suggest that mGluR5 stimulation results in tyrosine phosphorylation of ERK1/2 and other glial proteins.
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22 MeSH Terms
Helicobacter pylori culture supernatant interferes with epidermal growth factor-activated signal transduction in human gastric KATO III cells.
Pai R, Wyle FA, Cover TL, Itani RM, Domek MJ, Tarnawski AS
(1998) Am J Pathol 152: 1617-24
MeSH Terms: Blotting, Northern, Blotting, Western, Calcium-Calmodulin-Dependent Protein Kinases, Culture Media, Conditioned, Epidermal Growth Factor, ErbB Receptors, Gastric Mucosa, Helicobacter pylori, Humans, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Phosphorylation, Proto-Oncogene Proteins c-fos, RNA, Messenger, Signal Transduction, Tumor Cells, Cultured, Up-Regulation
Show Abstract · Added March 5, 2014
The mechanisms by which Helicobacter pylori infection leads to gastroduodenal ulceration remain poorly understood. Previous studies have shown that H. pylori vacuolating cytotoxin (VacA) inhibits proliferation of gastric epithelial cells, which suggests that H pylori may interfere with gastric mucosal repair mechanisms. In this study, we investigated the effects of H. pylori broth culture supernatants on epidermal growth factor (EGF)-mediated signal transduction pathways in a gastric carcinoma cell line (KATO III). Exposure of these cells to EGF resulted in increased expression and phosphorylation of the EGF receptor (EGF-R), increased ERK2 activity and phosphorylation, and increased c-fos protein levels. Preincubation of cells with broth culture supernatant from VacA (+) H. pylori strain 60190 inhibited the capacity of EGF to induce each of these effects. In contrast, preincubation of cells with broth culture supernatant from an isogenic VacA-mutant strain (H. pylori 60190-v1) failed to inhibit the effects of EGF. These results suggest that the H. pylori vacuolating cytotoxin interferes with EGF-activated signal transduction pathways, which are known to be essential for cell proliferation and ulcer healing.
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18 MeSH Terms
Estradiol-induced phosphorylation of serine 118 in the estrogen receptor is independent of p42/p44 mitogen-activated protein kinase.
Joel PB, Traish AM, Lannigan DA
(1998) J Biol Chem 273: 13317-23
MeSH Terms: Animals, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Enzyme Activation, Epidermal Growth Factor, Estradiol, Humans, Mammary Glands, Animal, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Mutagenesis, Site-Directed, Phosphorylation, Receptors, Estrogen, Serine, Tetradecanoylphorbol Acetate
Show Abstract · Added January 20, 2015
Phosphorylation of Ser118 of human estrogen receptor alpha (ER) enhances ER-mediated transcription and is induced by hormone binding and by activation of the mitogen-activated protein kinase (MAPK) pathway. We discovered that phosphorylation of Ser118 reduces the electrophoretic mobility of the ER. Using this mobility shift as an assay, we determined the in vivo stoichiometry and kinetics of Ser118 phosphorylation in response to estradiol, ICI 182,780, epidermal growth factor (EGF), and phorbol 12-myristate 13-acetate (PMA). In human breast cancer MCF-7 cells, estradiol induced a steady state phosphorylation of Ser118 within 20 min with a stoichiometry of 0.67 mol of phosphate/mol of ER. Estradiol did not activate p42/p44 MAPK, and basal p42/p44 MAPK activity was not sufficient to account for phosphorylation of Ser118 in response to estradiol. In contrast, both EGF and PMA induced a rapid, transient phosphorylation of Ser118 with a stoichiometry of approximately 0. 25, and the onset of Ser118 phosphorylation correlated with the onset of p42/p44 MAPK activation by these agents. Either the EGF- or PMA-induced Ser118 phosphorylation could be inhibited without influencing estradiol-induced Ser118 phosphorylation. The data suggest that a kinase other than p42/p44 MAPK is involved in the estradiol-induced Ser118 phosphorylation. We propose that the hormone-induced change in ER conformation exposes Ser118 for phosphorylation by a constitutively active kinase.
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16 MeSH Terms
Tyrosine kinase cell signaling pathways of rat mesangial cells in 3-dimensional cultures: response to fetal bovine serum and platelet-derived growth factor-BB.
Zent R, Ailenberg M, Silverman M
(1998) Exp Cell Res 240: 134-43
MeSH Terms: Androstadienes, Animals, Anticoagulants, Becaplermin, Cattle, Cell Adhesion Molecules, Cells, Cultured, Cytoskeleton, Enzyme Inhibitors, Extracellular Matrix, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Gels, Glomerular Mesangium, Male, Mitogen-Activated Protein Kinase 1, Phosphorylation, Platelet-Derived Growth Factor, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-sis, Rats, Rats, Sprague-Dawley, Receptor, Insulin, Serum Albumin, Bovine, Signal Transduction, Wortmannin
Show Abstract · Added December 10, 2013
Cells grown in 3-dimensional collagen gels adopt a nonproliferative, contractile phenotype which is more characteristic of cells in vivo than cells grown in 2-dimensional culture. The floating collagen gel contraction assay is a well-defined system used to study cell-extracellular matrix interactions grown in 3-dimensional culture. Although the cell biology of this system is well defined, the cell signaling associated with gel contraction has not been well characterized. In this study we demonstrate that fetal bovine (FBS) and platelet-derived growth factor (PDGF)-induced mesangial cell-collagen gel contraction is associated with increased tyrosine phosphorylation of a number of proteins including focal adhesion kinase (FAK) and the 42-kDa isoform of MAPK (ERK2). FBS-induced gel contraction is not affected by the presence of the MEK inhibitor PD098059. Low concentrations of PDGF-BB (10 ng/ml) induce gel contraction; however, at higher PDGF-BB concentrations (80 ng/ml) gel contraction is not observed. PDGF-BB-induced gel contraction as well as tyrosine phosphorylation of FAK are inhibited in the presence of the PI-3 kinase inhibitor wortmanin. Minimal autophosphorylation of the PDGF-beta receptor is observed under 3-dimensional culture conditions following PDGF-BB stimulation; however, when mesangial cells grown in 2-dimensional culture are exposed to PDGF-BB, the PDGF-beta receptor was prominently phosphorylated. We conclude that induction of collagen gel contraction by FBS and PDGF-BB is associated with tyrosine kinase phosphorylation and that these responses differ substantially from what occurs in 2-dimensional cultures in the presence of the same agonists.
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26 MeSH Terms