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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three endothelin (ET) isopeptides have been identified: ET-1, ET-2 and ET-3. These have two well-established gross effects on the cardiac myocyte. They affect the contractile properties and they stimulate myocyte growth and myofibrillogenesis. There may be other effects that are less fully characterized (e.g. increased resistance apoptosis). The changes in myocyte biology are brought about by modulation of intracellular signaling pathways. ET-1 binds to the ET(A) receptor on the cell surface and stimulates hydrolysis of phosphatidylinositol 4', 5'-bisphosphate to diacylglycerol and inositol 1', 4', 5'-trisphosphate. Diacylglycerol remains in the plane of the membrane and this causes translocation of the delta- and epsilon-isoforms of protein kinase C (PKC) to that compartment, an event thought to be indicative of PKC activation. The next events (probably associated with PKC activation) are the activation of the small G-protein Ras and of the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade. Over a longer time course, two protein kinase cascades related to the ERK1/2 cascade, the c-Jun N-terminal kinase and p38-mitogen-activated protein kinase (p38-mitogen) cascades, also become activated. As the signals originating from the ET(A) receptor are transmitted through these protein kinase pathways, other signaling molecules become phosphorylated, thus changing their biological activity. Such molecules include nuclear transcription factors (e.g. GATA-4, c-Jun), protein kinases (e.g. 90-kDa ribosomal protein S6 kinase, MAPK-activated protein kinase 2), and ion exchangers/channels (e.g. the Na(+)/H(+) exchanger 1). These changes are responsible for the overall biological effects of ET isopeptides on the myocyte.
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PMID:An overview of endothelin signaling in the cardiac myocyte. 1287 73

The neurobiological underpinnings of mood modulation, molecular pathophysiology of manic-depressive illness, and therapeutic mechanism of mood stabilizers are largely unknown. The extracellular signal-regulated kinase (ERK) pathway is activated by neurotrophins and other neuroactive chemicals to produce their effects on neuronal differentiation, survival, regeneration, and structural and functional plasticity. We found that lithium and valproate, commonly used mood stabilizers for the treatment of manic-depressive illness, stimulated the ERK pathway in the rat hippocampus and frontal cortex. Both drugs increased the levels of activated phospho-ERK44/42, activated phospho-ribosomal protein S6 kinase-1 (RSK1) (a substrate of ERK), phospho-CREB (cAMP response element-binding protein) and phospho-B cell lymphoma protein-2 antagonist of cell death (substrates of RSK), and BDNF. Inhibiting the ERK pathway with the blood-brain barrier-penetrating mitogen-activated protein kinase (MAP kinase)/ERK kinase (MEK) kinase inhibitor SL327, but not with the nonblood-brain barrier-penetrating MEK inhibitor U0126, decreased immobility time and increased swimming time of rats in the forced-swim test. SL327, but not U0126, also increased locomotion time and distance traveled in a large open field. The behavioral changes in the open field were prevented with chronic lithium pretreatment. SL327-induced behavioral changes are qualitatively similar to the changes induced by amphetamine, a compound that induces relapse in remitted manic patients and mood elevation in normal subjects. These data suggest that the ERK pathway may mediate the antimanic effects of mood stabilizers.
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PMID:The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. 1291 64

It has been shown that the ethylating agent diethylsulphate (DES) induces centromere-containing micronuclei with kinetics suggesting that molecules other than DNA could be targets. In quiescent Chinese hamster fibroblasts CHEF/18, O6-alkylated bases inhibit ribosomal protein S6 kinase (S6K1), the terminal member of a kinase cascade responsible for an increased rate of protein synthesis, but not extracellular signal-activated kinases (ERK1/2) or terminal kinases of a second cascade which activates transcription. The inhibition correlates with the appearance of abnormal metaphases at the following mitosis, suggesting that alkylation of the nucleotide pool and inhibition of S6K1 could be one of the mechanisms leading to chromosome loss by alkylating agents. To clarify the role of protein kinases in chromosome loss induced by alkylating agents, we have studied the effects of DES and methylnitrosourea (MNU) on S6K1 and ERK1/2 activation by growth factors. The alkylating agents were studied in a battery of Chinese hamster fibroblasts (CHEF/18, CHO and ClB) with normal and mutated p53 to control for DNA damage-induced activation of p53, which could indirectly inhibit protein kinases. The role of repair in induction of micronuclei was studied in mismatch repair-proficient CHO and repair-deficient ClB cells. Our results indicate that DES induced micronuclei in a mismatch repair-independent manner, within 8 h of treatment, in agreement with a role for S6K1 inhibition in micronucleus formation. MNU induced centromere-containing micronuclei only in CHO cells, one cell cycle after treatment, without any detectable influences on either kinase cascade, suggesting a role for mismatch repair in chromosome loss.
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PMID:Diethylsulphate and methylnitrosourea affect different targets in Chinese hamster fibroblasts: possible mechanisms of aneuploidy induction by these agents. 1296 Apr 7

The cyclin-dependent kinase inhibitor p27Kip1 plays an important role in cell cycle regulation. The cyclin-dependent kinase-inhibitory activity of p27Kip1 is regulated by changes in its concentration and its subcellular localization. Several reports suggest that phosphorylation of p27Kip1 at serine 10, threonine 157, and threonine 187 regulate its localization. We have previously identified that carboxyl-terminal threonine 198 (Thr198) in p27Kip1 is a novel phosphorylation site and that Akt is associated with the phosphorylation at the site (Fujita, N., Sato, S., Katayama, K., and Tsuruo, T. (2002) J. Biol. Chem. 277, 28706-28713). We show herein that activation of the Ras/Raf/mitogen-activated protein kinase kinase (MAPK kinase/MEK) pathway also regulates phosphorylation of p27Kip1 at Thr198. MAPKs were not directly associated with p27Kip1 phosphorylation at Thr198, but the p90 ribosomal protein S6 kinases (RSKs) could bind to and directly phosphorylate p27Kip1 at Thr198 in a Ras/Raf/MEK-dependent manner. RSK-dependent phosphorylation promoted the p27Kip1 binding to 14-3-3 and its cytoplasmic localization. To prove the direct relationship between 14-3-3 binding and cytoplasmic localization, we constructed a p27Kip1-R18 fusion protein in which the R18 peptide was fused to the carboxyl-terminal region of p27Kip1. The R18 peptide is known to interact with 14-3-3 independent of phosphorylation. The p27Kip1-R18 distributed mainly in the cytosol, whereas mutant p27Kip1-R18 (p27Kip1-R18-K2) that had no 14-3-3 binding capability existed mainly in the nucleus. These results indicate that RSKs play a crucial role in cell cycle progression through translocation of p27Kip1, in addition to Akt, to the cytoplasm in a phosphorylation and 14-3-3 binding-dependent manner.
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PMID:Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization. 1450 89

Anthracyclines are commonly used chemotherapeutics, and in some models enhance p44/42-mitogen-activated protein kinase (MAPK) pathway signaling by effects on upstream kinases. To evaluate the impact of anthracyclines on p44/42-MAPK in breast cancer, A1N4-myc human mammary and BT-474 and MDA-MB-231 breast carcinoma cells were studied. Treatment with doxorubicin or epirubicin resulted in increased phospho-p44/42-MAPK levels in a time- and concentration-dependent manner. This was associated with p44/42 activation, as reflected by increased p90 ribosomal protein S6 kinase and Bad phosphorylation. Activation of p44/42 appeared to be antiapoptotic, since MAPK stimulation with epidermal growth factor or a dominant-positive p42 construct inhibited apoptosis. Modest activation of the upstream MAPK kinase MEK was noted under some conditions, but inhibition of MEK did not abolish p44/42 activation, suggesting a contribution from another mechanism. Anthracyclines were found to decrease expression of MAPK phosphatase-1 (MKP-1) both in vitro and in vivo. MKP-1 mRNA levels were decreased in anthracycline-treated cells, and transcription from the MKP-1 promoter was repressed. Inhibition of MKP-1 expression through the use of small interfering RNAs decreased the ability of anthracyclines to induce phospho-p44/42. Wild-type mouse embryo fibroblasts (MEFs) treated with doxorubicin showed increased phospho-p44/42-MAPK levels, but MEFs from MKP-1 heterozygous and homozygous knockout mice had blunted p44/42 activation. These studies support the ability of anthracyclines to activate antiapoptotic p44/42-MAPK phosphorylation in breast cancer, and indicate that this occurs in part through the novel mechanism of repression of MKP-1 transcription.
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PMID:Repression of mitogen-activated protein kinase (MAPK) phosphatase-1 by anthracyclines contributes to their antiapoptotic activation of p44/42-MAPK. 1455 75

Phosphatidylinositol 3'-kinase (PI3K) activity is required for Ras- mediated transformation of intestinal epithelial cells (IECs). The mammalian target of rapamycin (mTOR) and its downstream pathways control the translation of specific mRNAs that are required for cell proliferation and transformation. Here, we elucidated the roles of PI3K and mTOR in K-Ras-mediated transformation of IECs (IEC-6). Induction of K-Ras activated PI3K and mTOR in IECs. p70 ribosomal protein S6 kinase activity was induced by K-Ras in a PI3K- and mTOR-dependent manner. K-Ras did not significantly alter the phosphorylation of eukaryotic initiation factor 4E-binding protein 1. Treatment with either LY-294002 or rapamycin inhibited IEC proliferation and resulted in G(1) growth arrest. However, it was noted that inhibition of mTOR enhanced K-Ras-mediated morphological transformation and increased invasiveness of IECs in a mitogen-activated protein/extracellular signal-regulated kinase-dependent manner. Furthermore, inhibition of PI3K or mTOR impaired the growth of an array of colon cancer cells. Spindle transformation, reduced E-cadherin, and increased invasiveness were observed in LY-294002-treated Moser cells. Thus, our results suggest that K-Ras-mediated transformation of IECs involves activation of the PI3K/mTOR pathway. Inhibition of PI3K/mTOR activity leads to G(1) growth arrest of transformed IECs. On the other hand, inhibition of PI3K or mTOR may induce the epithelial to mesenchymal transdifferentiation of IECs under certain circumstances.
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PMID:Roles of phosphatidylinositol 3'-kinase and mammalian target of rapamycin/p70 ribosomal protein S6 kinase in K-Ras-mediated transformation of intestinal epithelial cells. 1472 29

Hydra regenerate throughout their life. We previously described early modulations in cAMP-response element-binding protein (CREB) DNA-binding activity during regeneration. We now show that the Ser-67 residue located in the P-box is a target for post-translational regulation. The antihydra CREB antiserum detected CREB-positive nuclei distributed in endoderm and ectoderm, whereas the phosphoSer133-CREB antibody detected phospho-CREB-positive nuclei exclusively in endodermal cells. During early regeneration, we observed a dramatic increase in the number of phospho-CREB-positive nuclei in head-regenerating tips, exceeding 80% of the endodermal cells. We identified among CREB-binding kinases the p80 kinase, which showed an enhanced activity and a hyperphosphorylated status during head but not foot regeneration. According to biochemical and immunological evidence, this p80 kinase belongs to the Ribosomal protein S6 kinase family. Exposure to the U0126 mitogen-activated protein kinase kinase inhibitor inhibited head but not foot regeneration, abolished CREB phosphorylation and activation of the early gene HyBra1 in head-regenerating tips. These data support a role for the mitogen-activated protein kinase/ribosomal protein S6 kinase/CREB pathway in hydra head organizer activity.
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PMID:Reactivation of developmental programs: the cAMP-response element-binding protein pathway is involved in hydra head regeneration. 1498 15

Epidermal growth factor receptor (EGFR) signaling has become an important target for drug development because EGFR signaling enhances tumor cell proliferation, migration, and invasion and inhibits apoptosis. However, the results of clinical trials using EGFR inhibitors in patients with solid tumors have been disappointing. Here, we report a protective effect of the EGFR inhibitors AG1478 and PD153035 against cell death induced by acute hypoxia, which contrasts with their proapoptotic effects under normoxia. Under hypoxic conditions, both agents reduced glucose consumption, delayed ATP depletion, and preserved the mitochondrial membrane potential. Exposure either to hypoxia or the EGFR inhibitors under normoxic conditions resulted in the dephosphorylation of ribosomal protein S6, a player in the energy and nutrient-sensing pathway governed by mammalian target-of-rapamycin (mTOR). Combined inhibition of phosphatidylinositol 3'-kinase (PI3K) and extracellular signal-regulated kinase-1/2 (ERK1/2) mimicked the protective effects of EGFR inhibition on hypoxia-induced cell death and protein S6 dephosphorylation. These results caution that therapies targeting EGFR signaling pathways can protect tumor cells from acute hypoxia.
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PMID:Inhibition of epidermal growth factor receptor signaling protects human malignant glioma cells from hypoxia-induced cell death. 1499 11

The aim of the study was to investigate the effect of resistance exercise alone or in combination with oral intake of branched-chain amino acids (BCAA) on phosphorylation of the 70-kDa S6 protein kinase (p70(S6k)) and mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK1/2), and p38 MAPK in skeletal muscle. Seven male subjects performed one session of quadriceps muscle resistance training (4 x 10 repetitions at 80% of one repetition maximum) on two occasions. In a randomized order, double-blind, crossover test, subjects ingested a solution of BCAA or placebo during and after exercise. Ingestion of BCAA increased plasma concentrations of isoleucine, leucine, and valine during exercise and throughout recovery after exercise (2 h postexercise), whereas no change was noted after the placebo trial. Resistance exercise led to a robust increase in p70(S6k) phosphorylation at Ser(424) and/or Thr(421), which persisted 1 and 2 h after exercise. BCAA ingestion further enhanced p70(S6k) phosphorylation 3.5-fold during recovery. p70(S6k) phosphorylation at Thr(389) was unaltered directly after resistance exercise. However, during recovery, Thr(389) phosphorylation was profoundly increased, but only during the BCAA trial. Furthermore, phosphorylation of the ribosomal protein S6 was also increased in the recovery period only during the BCAA trial. Exercise led to a marked increase in ERK1/2 and p38 MAPK phosphorylation, which was completely suppressed upon recovery and unaltered by BCAA. In conclusion, BCAA, ingested during and after resistance exercise, mediate signal transduction through p70(S6k) in skeletal muscle.
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PMID:Branched-chain amino acids increase p70S6k phosphorylation in human skeletal muscle after resistance exercise. 1499 84

Enduring forms of synaptic plasticity and memory require new protein synthesis, but little is known about the underlying regulatory mechanisms. Here, we investigate the role of MAPK signaling in these processes. Conditional expression of a dominant-negative form of MEK1 in the postnatal murine forebrain inhibited ERK activation and caused selective deficits in hippocampal memory retention and the translation-dependent, transcription-independent phase of hippocampal L-LTP. In hippocampal neurons, ERK inhibition blocked neuronal activity-induced translation as well as phosphorylation of the translation factors eIF4E, 4EBP1, and ribosomal protein S6. Correspondingly, protein synthesis and translation factor phosphorylation induced in control hippocampal slices by L-LTP-generating tetanization were significantly reduced in mutant slices. Translation factor phosphorylation induced in the control hippocampus by memory formation was similarly diminished in the mutant hippocampus. These results suggest a crucial role for translational control by MAPK signaling in long-lasting forms of synaptic plasticity and memory.
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PMID:Translational control by MAPK signaling in long-term synaptic plasticity and memory. 1501 80


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