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

In renal cells, hypertonicity induces genes for heat shock proteins (HSP70, alpha B-crystallin), as well as enzymes and transporters directly involved in the metabolism and transport of protective organic osmolytes. While heat shock proteins are induced by many stresses including osmotic stress, the induction of the osmolytes genes appears to be specific to osmotic stress. These two adaptive mechanisms allow kidney cells to survive and function in the hypertonic environment that exists on routine basis in kidney medulla. In mammalian cells, hypertonicity induces three mitogen-activated protein kinase pathways: ERK (extracellular regulated kinase), JNK (Jun N-terminal kinase), and p38. ERK activation by osmotic stress is a consistent finding in many cells, but it is not essential for transcriptional regulation of mRNA for transporter of organic osmolyte betaine. While the growth of yeast cells on NaCl-supplemented medium is dependent on HOG1 pathway, it is still unclear which pathway mediates the adaptation to osmotic stress in mammalian cells. Here, we show that inhibition of p38 kinase activity, using the specific inhibitor SB203580 (4-(fluorophenyl)-2-(4-methylsulfonyl-phenyl)-5-(4-pyridyl) imidazole), abolishes the hypertonicity-mediated induction of mRNAs for HSP70 and betaine transporter in Madin-Darby canine kidney cells. The inhibition is dose-dependent and correlates with the in situ activity of native p38 kinase, determined as MAPKAPK-2 activity in cell extracts. As reported previously, the activities of ERK-1 and -2 were not affected by SB203580, but surprisingly, inhibition of native p38 kinase activity correlates with up-regulation of native JNK-1 activity in osmotically stressed cells. p38 mRNA is induced by hypertonic stress and is attenuated with p38 kinase inhibition. We also find that thermal induction of HSP70 mRNA is not affected by p38 kinase inhibition. Such findings suggest that p38 kinase activity is essential for the induction of genes involved in the adaptation of mammalian cells to osmotic stress and that the increased activity of JNK-1 during p38 kinase inhibition is consistent with regulation of JNK-1 by p38 kinase in osmotically stressed cells. In addition, the transduction pathways mediating HSP70 mRNA induction by different stresses appear to be divergent; osmotic induction of HSP70 is p38 kinase-dependent, while thermal induction is not.
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PMID:p38 kinase activity is essential for osmotic induction of mRNAs for HSP70 and transporter for organic solute betaine in Madin-Darby canine kidney cells. 943 Jul 35

The MAP kinase (MAPK) JNK but not ERK is synergistically activated during costimulation of T cells. We examined how protein tyrosine kinases (PTKs) and GTPases differentially regulate JNK and ERK in T cells. While PTKs are not selective, small GTPases display distinct MAPK-activating functions. Whereas Ras activates ERK, Rac activates JNK. Rac cooperates with a Syk-generated signal to enhance JNK activation and appears to be at a nodal point for pathways emanating from CD28, calcineurin, and protein kinase C. AP-1- and NF-AT-dependent reporters are stimulated by Rac and Syk and are dependent on JNK. Unlike Syk, the PTK Lck activates JNK but does not cooperate with Rac, resulting in weak AP-1 and NF-AT activation. Therefore, signals generated by PTKs are functionally distinct and need to be integrated to induce transcriptional responses.
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PMID:Cooperation between Syk and Rac1 leads to synergistic JNK activation in T lymphocytes. 946 9

The T1 gene gives rise to two transcripts encoding a 62 kDa membrane-bound and a 37 kDa secreted protein with similarity to the type I IL-1 receptor. It is weakly expressed in proliferating but not in resting fibroblasts and is strongly induced during the entry of quiescent cells into the cell cycle. Here we show that the T1 gene is also transcriptionally activated in response to the treatment of fibroblasts with cycloheximide and anisomycin. These protein synthesis inhibitors are known to stimulate the JNK and p38/RK signal transduction pathways. We provide evidence that anisomycin triggers T1 gene induction through the stimulation of the p38/RK MAP kinase. This observation is in line with our finding that physiological activators of the p38/RK pathway, the proinflammatory cytokines IL-1 and TNFalpha, stimulate T1 gene expression efficiently. Growth factor mediated T1 gene induction is a delayed early event, requiring ongoing protein synthesis. In contrast, anisomycin induces T1 gene expression at concentrations which block translation completely. Thus, transcriptional induction of the T1 gene via the p38/RK pathway is an immediate early event not requiring de novo protein synthesis. The T1 gene is strongly induced by various mitogens in quiescent NIH3T3 fibroblasts but not in ras transformed NIH3T3 cells. In contrast, all of the three tested agent which activate the p38/RK pathway, IL-1, TNFalpha, and anisomycin led to strong T1 gene expression in normal and ras transformed NIH3T3 cells alike. Thus, the T1 gene can be induced through the activation of at least two MAP kinase pathways: signaling through the ERK pathway can occcur in normal but not in ras transformed NIH3T3 cells, whereas the signaling through the p38/RK pathway is not affected by ras transformation.
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PMID:Effects of ras transformation on the induction of the IL-1 receptor related T1 gene in response to mitogens, anisomycin, IL-1 and TNFalpha. 948 3

The mitogen-activated protein kinases ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase), and p38 phosphorylate and activate transcription factors that promote proliferative and inflammatory responses, whereas glucocorticoid receptor (GR) activation inhibits cell growth and inflammation. We demonstrate that JNK and ERK but not p38 phosphorylate GR in vitro primarily at Ser-246. Selective activation of either ERK or JNK in vivo inhibits GR-mediated transcriptional activation, which depends on receptor phosphorylation at Ser-246 by JNK but not ERK. Thus, JNK inhibits GR transcriptional activation by direct receptor phosphorylation, whereas ERK does so indirectly. We propose that phosphorylation of GR by JNK or of a GR cofactor by ERK provides mechanisms to ensure the rapid inhibition of GR-dependent gene expression when it conflicts with mitogenic or proinflammatory signals.
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PMID:Antagonism of glucocorticoid receptor transcriptional activation by the c-Jun N-terminal kinase. 948 36

Genotoxic stress triggers signalling pathways that either mediate cell killing or protection of affected cells. While induction of p53 is observed for most of the genotoxins, activation of MAPK/SAPK cascades is not a general response. The role of MAPK/SAPK activation on cell fate, seems to be dependent, in some systems, on the balanced response among both cascades. We have here examined the effect of cis and trans-DDP on the activation of ERK and JNK activities. While no significant induction of ERK was observed with the compounds, both of them are able to strongly activate JNK. Trans-DDP response is rapid and transient while the cis-DDP one is slow and persistent. In contrast with the observed nuclear translocation of JNK in response to U.V. light, none of the platinum compounds induces translocation, on the contrary, activation of JNK occurs in both the nuclear and cytoplasmic compartments. Inhibition of tyrosine phosphatases by orthovanadate pretreatment prolongs the time of JNK induction in response to both platinum compounds. The positive modulation of JNK activation correlates with an increase in toxicity that, for cis-DDP corresponds to a tenfold decrease in the IC50. A strong increase in MKP-1 levels was observed only in response to trans-DDP suggesting the involvement of this activity in the downregulation of JNK activity in response to this compound. Altogether the results suggest that the prolonged activation of JNK in response to cis-DDP contributes to cell death induction.
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PMID:Cisplatin induces a persistent activation of JNK that is related to cell death. 948 43

The Mas oncogene encodes a novel G-protein-coupled receptor that was identified originally as a transforming protein when overexpressed in NIH 3T3 cells. The mechanism and signaling pathways that mediate Mas transformation have not been determined. We observed that the foci of transformed NIH 3T3 cells caused by Mas were similar to those caused by activated Rho and Rac proteins. Therefore, we determined if Mas signaling and transformation are mediated through activation of a specific Rho family protein. First, we observed that, like activated Rac1, Mas cooperated with activated Raf and caused synergistic transformation of NIH 3T3 cells. Second, both Mas- and Rac1-transformed NIH 3T3 cells retained actin stress fibers and showed enhanced membrane ruffling. Third, like Rac, Mas induced lamellipodium formation in porcine aortic endothelial cells. Fourth, Mas and Rac1 strongly activated the JNK and p38, but not ERK, mitogen-activated protein kinases. Fifth, Mas and Rac1 stimulated transcription from common DNA promoter elements: NF-kappaB, serum response factor (SRF), Jun/ATF-2, and the cyclin D1 promoter. Finally, Mas transformation and some of Mas signaling (SRF and cyclin D1 but not NF-kappaB activation) were blocked by dominant negative Rac1. Taken together, these observations suggest that Mas transformation is mediated in part by activation of Rac-dependent signaling pathways. Thus, Rho family proteins are common mediators of transformation by a diverse variety of oncogene proteins that include Ras, Dbl family, and G-protein-coupled oncogene proteins.
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PMID:Mas oncogene signaling and transformation require the small GTP-binding protein Rac. 948 37

In the present study, we compared the ability of insulin to regulate SAPKs/JNKs and ERKs in CHO cells overexpressing human insulin receptors. We show that acute insulin treatment induced a time-dependent increase both in SAPK/JNK and ERK activity but with distinct kinetics. PI-3-kinase inhibition by wortmannin completely blocked insulin activation of SAPKs/JNKs, whereas it partially decreased ERK activation. Prolonged exposure to insulin caused a marked inhibition of SAPK/JNK activity while it induced a sustained activation of ERKs. Insulin inhibition of SAPKs/JNKs was partly due to decreased tyrosine phosphorylation of JNK2. These data indicate that insulin differentially regulates SAPKs/JNKs and ERKs. Moreover, they provide the first evidence that insulin exerts opposite effects on SAPK/JNK activity according to the time of cell treatment.
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PMID:Insulin differentially regulates SAPKs/JNKs and ERKs in CHO cells overexpressing human insulin receptors. 950 Oct 8

The activation of MAP kinase (MAPK) signal transduction pathways results in the phosphorylation of transcription factors by the terminal kinases in these cascades. Different pathways are activated by mitogenic and stress stimuli, which lead to the activation of distinct groups of target proteins. The ETS-domain transcription factor Elk-1 is a substrate for three distinct classes of MAPKs. Elk-1 contains a targeting domain, the D-domain, which is distinct from the phosphoacceptor motifs and is required for efficient phosphorylation and activation by the ERK MAPKs. In this study, we demonstrate that members of the JNK subfamily of MAPKs are also targeted to Elk-1 by this domain. Targeting via this domain is essential for the efficient and rapid phosphorylation and activation of Elk-1 both in vitro and in vivo. The ERK and JNK MAPKs use overlapping yet distinct determinants in the D-domain for targeting to Elk-1. In contrast, members of the p38 subfamily of MAPKs are not targeted to Elk-1 via this domain. Our data therefore demonstrate that different classes of MAPKs exhibit differential requirements for targeting to Elk-1.
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PMID:Differential targeting of MAP kinases to the ETS-domain transcription factor Elk-1. 950 Oct 95

The ovarian adenocarcinoma cell line HEY was used as an in vitro model to study the influence of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on epithelial tumours such as ovarian cancer. Serum-starved cells were treated with rhG-CSF in a time- and dose-dependent manner. Cell proliferation, measured as cell division and DNA synthesis, was stimulated about 40% by rhG-CSF. After harvesting, cells were examined for the presence of G-CSF receptor (FACS analysis and RT-PCR), as well as for expression of genes involved in mitogen signalling (ERKs, JNKs) and early gene expression (c-jun). rhG-CSF affected mitogen-activated pathways and was receptor-mediated if the G-CSF receptor was present. After rhG-CSF induction, Janus N-terminal kinases (JNK 1 and 2) were simultaneously increased in the cytosol, up to 30-fold as measured by Western blotting), whereas ERK 1 and 2 accumulated maximally by 2.5-fold 1 hr after rhG-CSF induction. c-Jun was up-regulated strongly by this cytokine at the translational level. Our data suggest that rhG-CSF affects genes involved in mitogen signalling and early gene expression in solid tumours. We also noted the presence of G-CSF receptor on ovarian cancer cell lines.
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PMID:rhG-CSF affects genes involved in mitogen signalling and early gene expression in the ovarian cancer cell line HEY. 950 29

Recent evidence suggests that branching pathways of sphingolipid metabolism may mediate either apoptotic or mitogenic responses depending on the cell type and the nature of the stimulus. While ceramide has been shown to be an important regulatory component of apoptosis induced by tumor necrosis factor alpha and the Fas ligand, sphingosine-1-phosphate (SPP), a further metabolite of ceramide, has been implicated as a second messenger in cellular proliferation and survival induced by platelet-derived growth factor, neuronal growth factor, and serum. SPP protects cells from apoptosis resulting from elevations of ceramide. Inflammatory cytokines stimulate sphingomyelinase, but not ceramidase, leading to accumulation of ceramide, whereas growth signals also stimulate ceramidase and sphingosine kinase leading to increased SPP levels. We propose that the dynamic balance between levels of sphingolipid metabolites, ceramide, and SPP and consequent regulation of different members of the mitogen-activated protein kinases (JNK versus ERK) family is an important factor that determines whether a cell survives or dies.
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PMID:Roles of sphingosine-1-phosphate in cell growth, differentiation, and death. 952 97


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