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)

Reactive oxygen species (ROS) are implicated in the pathogenesis of several proliferative diseases, including atherosclerosis and cancer. Eukaryotic translation initiation factor 4E (eIF4E) plays an important role in cell proliferation and differentiation. To gain insight into molecular mechanisms by which ROS influence the pathogenesis of these diseases, I have studied the effect of H(2)O(2), a ROS, on eIF4E phosphorylation. H(2)O(2) induced eIF4E phosphorylation in a dose- and time-dependent manner in growth-arrested smooth muscle cells (SMC). H(2)O(2)-induced eIF4E phosphorylation occurred on serine residues. PD098059, a specific inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase inhibited ERK activities but had no significant effect on eIF4E phosphorylation induced by H(2)O(2). Similarly, SB203580, a specific inhibitor of p38 MAPK, although inhibiting H(2)O(2)-induced p38 MAPK activity, had no effect on H(2)O(2)-induced eIF4E phosphorylation. Calphostin C, a specific inhibitor of protein kinase C, also had no effect on H(2)O(2)-induced eIF4E phosphorylation. In contrast, trifluoperazine, an antagonist of calcium/calmodulin kinases, completely blocked H(2)O(2)-induced eIF4E phosphorylation. In addition, intracellular and extracellular Ca(2+) chelators significantly inhibited H(2)O(2)-induced eIF4E phosphorylation. Despite its ability to induce eIF4E phosphorylation, H(2)O(2) had no significant effect on protein levels and new protein synthesis as compared with control. In contrast, it induced the expression of c-Fos, c-Jun, and HSP70 in a time-dependent manner in SMC. Together, these results suggest that H(2)O(2), a ROS and a cellular oxidant, induces eIF4E phosphorylation in a manner that is dependent on Ca(2+) and Ca(2+)/calmodulin kinases and independent of ERKs, p38 MAPK, and protein kinase C. These results also suggest that enhanced eIF4E phosphorylation by H(2)O(2) appears to be an important event in SMC in response to oxidant stress and that eIF4E phosphorylation may be associated with the translation of a small subset of mRNAs such as c-fos, c-jun, and HSP70 gene mRNAs, whose products may have a critical role in cell survival.
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PMID:Oxidant stress stimulates phosphorylation of eIF4E without an effect on global protein synthesis in smooth muscle cells. Lack of evidence for a role of H202 in angiotensin II-induced hypertrophy. 1082 72

The epidermal growth factor receptor (EGFR) was recently identified as a signal transducer of G protein-coupled receptors (GPCRs). In this study, we have examined the contribution of EGFR transactivation to the growth-promoting effect of GPCRs on vascular smooth muscle cells. Activation of the G(q)-coupled ANG II receptor or G(i)-coupled lysophosphatidic acid receptor resulted in increased tyrosine phosphorylation and activation of EGFR. Specific inhibition of EGFR kinase activity by tyrphostin AG-1478 or expression of a dominant-negative EGFR mutant abolished this response. Importantly, inhibition of EGFR function strongly attenuated the global stimulation of protein synthesis by GPCR agonists in vitro in cultured aortic smooth muscle cells and in vivo in the rat aorta and in small resistance arteries. The growth inhibition was associated with a marked reduction of extracellular signal-regulated kinase and phosphoinositide 3-kinase pathway activity and the resulting suppression of eukaryotic translation initiation factor 4E and 4E binding protein 1 phosphorylation. Our results demonstrate that EGFR transactivation is a physiologically relevant action of GPCRs linked to translational control and protein synthesis.
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PMID:EGF receptor transactivation is obligatory for protein synthesis stimulation by G protein-coupled receptors. 1210 54

Mnk1 and Mnk2 are protein kinases that are directly phosphorylated and activated by extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein (MAP) kinases and implicated in the regulation of protein synthesis through their phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) at Ser209. To investigate their physiological functions, we generated mice lacking the Mnk1 or Mnk2 gene or both; the resulting KO mice were viable, fertile, and developed normally. In embryonic fibroblasts prepared from Mnk1-Mnk2 DKO mice, eIF4E was not detectably phosphorylated at Ser209, even when the ERK and/or p38 MAP kinases were activated. Analysis of embryonic fibroblasts from single KO mice revealed that Mnk1 is responsible for the inducible phosphorylation of eIF4E in response to MAP kinase activation, whereas Mnk2 mainly contributes to eIF4E's basal, constitutive phosphorylation. Lipopolysaccharide (LPS)- or insulin-induced upregulation of eIF4E phosphorylation in the spleen, liver, or skeletal muscle was abolished in Mnk1(-/-) mice, whereas the basal eIF4E phosphorylation levels were decreased in Mnk2(-/-) mice. In Mnk1-Mnk2 DKO mice, no phosphorylated eIF4E was detected in any tissue studied, even after LPS or insulin injection. However, neither general protein synthesis nor cap-dependent translation, as assayed by a bicistronic reporter assay system, was affected in Mnk-deficient embryonic fibroblasts, despite the absence of phosphorylated eIF4E. Thus, Mnk1 and Mnk2 are exclusive eIF4E kinases both in cultured fibroblasts and adult tissues, and they regulate inducible and constitutive eIF4E phosphorylation, respectively. These results strongly suggest that eIF4E phosphorylation at Ser209 is not essential for cell growth during development.
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PMID:Mnk2 and Mnk1 are essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E but not for cell growth or development. 1525 22

Upon binding to the glycolipid receptor globotriaosylceramide, Shiga toxins (Stxs) undergo retrograde transport to reach ribosomes, cleave 28S rRNA, and inhibit protein synthesis. Stxs induce the ribotoxic stress response and cytokine and chemokine expression in some cell types. Signaling mechanisms necessary for cytokine expression in the face of toxin-mediated protein synthesis inhibition are not well characterized. Stxs may regulate cytokine expression via multiple mechanisms involving increased gene transcription, mRNA transcript stabilization, and/or increased translation initiation efficiency. We show that treatment of differentiated THP-1 cells with purified Stx1 resulted in prolonged activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) cascades, and lipopolysaccharides (LPS) rapidly triggered transient activation of JNK and p38 and prolonged activation of extracellular signal-regulated kinase cascades. Simultaneous treatment with Stx1 + LPS mediated prolonged p38 MAPK activation. Stx1 increased eukaryotic translation initiation factor 4E (eIF4E) activation by 4.3-fold within 4-6 h, and LPS or Stx1 + LPS treatment increased eIF4E activation by 7.8- and 11-fold, respectively, within 1 h. eIF4E activation required Stx1 enzymatic activity and was mediated by anisomycin, another ribotoxic stress inducer. A combination of MAPK inhibitors or a MAPK-interacting kinase 1 (Mnk1)-specific inhibitor blocked eIF4E activation by all stimulants. Mnk1 inhibition blocked the transient increase in total protein synthesis detected in Stx1-treated cells but failed to block long-term protein synthesis inhibition. The MAPK inhibitors or Mnk1 inhibitor blocked soluble interleukin (IL)-1beta and IL-8 production or release by 73-96%. These data suggest that Stxs may regulate cytokine expression in part through activation of MAPK cascades, activation of Mnk1, and phosphorylation of eIF4E.
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PMID:Shiga toxin 1-induced cytokine production is mediated by MAP kinase pathways and translation initiation factor eIF4E in the macrophage-like THP-1 cell line. 1630 26

c-Jun NH(2)-terminal kinases (JNK) are members of the mitogen-activated protein kinase family and have been implicated in the formation of several human tumors, especially gliomas. We have previously shown that a 55 kDa JNK isoform is constitutively active in 86% of human brain tumors and then showed that it is specifically a JNK2 isoform and likely to be either JNK2alpha2 or JNK2beta2. Notably, we found that only JNK2 isoforms possess intrinsic autophosphorylation activity and that JNK2alpha2 has the strongest activity. In the present study, we have further explored the contribution of JNK2 isoforms to brain tumor formation. Analysis of mRNA expression by reverse transcription-PCR revealed that JNK2alpha2 is expressed in 91% (10 of 11) of glioblastoma tumors, whereas JNK2beta2 is found in only 27% (3 of 11) of tumors. Both JNK2alpha2 and JNK2beta2 mRNAs are expressed in normal brain (3 of 3). Using an antibody specific for JNK2alpha isoforms, we verified that JNK2alpha2 protein is expressed in 88.2% (15 of 17) of glioblastomas, but, interestingly, no JNK2alpha2 protein was found in six normal brain samples. To evaluate biological function, we transfected U87MG cells with green fluorescent protein-tagged versions of JNK1alpha1, JNK2alpha2, and JNK2alpha2APF (a dominant-negative mutant), and derived cell lines with stable expression. Each cell line was evaluated for various tumorigenic variables including cellular growth, soft agar colony formation, and tumor formation in athymic nude mice. In each assay, JNK2alpha2 was found to be the most effective in promoting that phenotype. To identify effectors specifically affected by JNK2alpha2, we analyzed gene expression. Gene profiling showed several genes whose expression was specifically up-regulated by JNK2alpha2 but down-regulated by JNK2alpha2APF, among which eukaryotic translation initiation factor 4E (eIF4E) shows the greatest change. Because AKT acts on eIF4E, we also examined AKT activation. Unexpectedly, we found that JNK2alpha2 could specifically activate AKT. Our data provides evidence that JNK2alpha2 is the major active JNK isoform and is involved in the promotion of proliferation and growth of human glioblastoma tumors through specific activation of AKT and overexpression of eIF4E.
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PMID:c-Jun NH(2)-terminal kinase 2alpha2 promotes the tumorigenicity of human glioblastoma cells. 1704 65

In an attempt to identify molecules that clearly reflect the oncogenic role of cell signaling pathways in human tumors, we propose a concept we term "funnel factor", a factor where several oncogenic signals converge and drive the proliferative signal downstream. In studies done in various tumor types, the expression of key cell signaling factors, including Her1 and Her2 growth factor receptors, as well as the RAS-RAF-mitogen-activated protein kinase and the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathways was correlated with the associated clinicopathologic characteristics of these tumors. The downstream factors p70, S6, 4E-binding protein 1 (4E-BP1), and eukaryotic translation initiation factor 4E, which play a critical role in the control of protein synthesis, survival, and cell growth, were also analyzed. We found that phosphorylated 4E-BP1 (p-4E-BP1) expression in breast, ovary, and prostate tumors is associated with malignant progression and an adverse prognosis regardless of the upstream oncogenic alterations. Thus, p-4E-BP1 seems to act as a funnel factor for an essential oncogenic capability of tumor cells, self-sufficiency in growth signals, and could be a highly relevant molecular marker of malignant potential. Further investigation into this concept may identify additional funnel factors in the oncogenic pathways and provide potential therapeutic targets.
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PMID:4E-binding protein 1: a key molecular "funnel factor" in human cancer with clinical implications. 1769 57

The ERK MAPK signalling pathway is a highly conserved kinase cascade linking transmembrane receptors to downstream effector mechanisms. To investigate the function of ERK in neurons, a constitutively active form of MEK1 (caMEK1) was conditionally expressed in the murine brain, which resulted in ERK activation and caused spontaneous epileptic seizures. ERK activation stimulated phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) and augmented NMDA receptor 2B (NR2B) protein levels. Pharmacological inhibition of NR2B function impaired synaptic facilitation in area cornus ammonicus region 3 (CA3) in acute hippocampal slices derived from caMEK1-expressing mice and abrogated epilepsy in vivo. In addition, expression of caMEK1 caused phosphorylation of the transcription factor, cAMP response element-binding protein (CREB) and increased transcription of ephrinB2. EphrinB2 overexpression resulted in increased NR2B tyrosine phosphorylation, which was essential for caMEK1-induced epilepsy in vivo, since conditional inactivation of ephrinB2 greatly reduced seizure frequency in caMEK1 transgenic mice. Therefore, our study identifies a mechanism of epileptogenesis that links MAP kinase to Eph/Ephrin and NMDA receptor signalling.
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PMID:ERK activation causes epilepsy by stimulating NMDA receptor activity. 1797 14

The p75(NTR) acts as a tumor suppressor in the prostate, but its expression is lost as prostate cancer progresses and is minimal in established prostate cancer cell lines such as PC-3, DU-145, and LNCaP. Previously, we showed that treatment with R-flurbiprofen or ibuprofen induced p75(NTR) expression in PC-3 and DU-145 cells leading to p75(NTR)-mediated decreased survival. Here, we investigate the mechanism by which these drugs induce p75(NTR) expression. We show that the observed increase in p75(NTR) protein due to R-flurbiprofen and ibuprofen treatment was accompanied by an increase in p75(NTR) mRNA, and this increase in mRNA was the result of increased mRNA stability and not by an up-regulation of transcription. In addition, we show that treatment with R-flurbiprofen or ibuprofen led to sustained activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Furthermore, inhibition of the p38 MAPK pathway with the p38 MAPK-specific inhibitor SB202190 or by small interfering RNA (siRNA) knockdown of p38 MAPK protein prevented induction of p75(NTR) by R-flurbiprofen and ibuprofen. We also observed that siRNA knockdown of MAPK-activated protein kinase (MK)-2 and MK3, the kinases downstream of p38 MAPK that are responsible for the mRNA stabilizing effects of the p38 MAPK pathway, also prevented an induction of p75(NTR) by R-flurbiprofen and ibuprofen. Finally, we identify the RNA stabilizing protein HuR and the posttranscriptional regulator eukaryotic translation initiation factor 4E as two possible mechanisms by which the p38 MAPK pathway may increase p75(NTR) expression. Collectively, the data suggest that R-flurbiprofen and ibuprofen induce p75(NTR) expression by increased mRNA stability that is mediated through the p38 MAPK pathway.
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PMID:The p38 MAPK pathway mediates aryl propionic acid induced messenger rna stability of p75 NTR in prostate cancer cells. 1805 68

The eukaryotic translation initiation factor 4E (eIF-4E) is essential for cap-dependent protein translation. However, the role of eIF-4E phosphorylation in protein translation is still unclear. In this study, the function of eIF-4E phosphorylation in the formation of the translational initiation complex eIF-4F following DNA damage was investigated. Our results show that etoposide treatment caused a rapid increase in eIF-4E phosphorylation. The addition of CGP57380, a specific inhibitor of the eIF-4E kinase Mnk, not only inhibited eIF-4E phosphorylation but also resulted in reduced interaction between eIF-4E and eIF-4G. Furthermore, neither the p38 MAPK inhibitor nor the ERK inhibitor caused significant inhibition in eIF-4E phosphorylation induced by etoposide. However, a JNK-specific inhibitor, SP600125, strongly suppressed etoposide-induced eIF-4E phosphorylation. Our results provide the first evidence indicating that phosphorylation of eIF-4E by Mnk, possibly mediated by JNK or JNK-like kinases, is critical for formation of the translational initiation complex eIF-4F following DNA damage.
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PMID:Phosphorylation of eIF-4E positively regulates formation of the eIF-4F translation initiation complex following DNA damage. 1816 62

Eukaryotic translation initiation factor 4E (eIF4E) is a rate-limiting factor for cap-dependent protein synthesis and is regulated by PI3 kinase/mTOR and mitogen-activated protein kinase (MAPK)/Mnk signaling pathways. Recent studies have shown that Mnk-mediated eIF4E phosphorylation is absolutely required for eIF4E's oncogenic function. Overexpression of eIF4E has been reported in many types of cancers; however, the expression of phosphorylated eIF4E (p-eIF4E) in human cancer tissues, particularly solid tumor tissues, has not been reported. The current study focused on evaluating p-eIF4E expression patterns in the tumor tissues obtained from patients with a variety of malignancies. Using three different tissue microarrays consisting of a total of 380 cases of human cancers and 146 cases of adjacent normal tissues, we detected p-eIF4E positive staining in 63.4% (241/380) of cancers, but only in 30.1% (44/146) of adjacent normal tissues. Thus, p-eIF4E expression is significantly higher in cancers than in adjacent normal tissues (p < 0.001). In general, there was no major difference in p-eIF4E staining between cancers with and without lymph node metastasis. In certain types of maligancies such as lung, gastric and colorectal cancers, p-eIF4E staining was significantly higher in the early stage (T1) than in the late stage (T3) disease (p < 0.05). Collectively, these findings suggest that p-eIF4E may play a critical role in cancer development, particularly early stages of tumorigenesis and support p-eIF4E as a good cancer therapeutic target.
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PMID:Phosphorylated eukaryotic translation initiation factor 4 (eIF4E) is elevated in human cancer tissues. 1948 68


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