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

---

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

2,3-Dihydro-5-methyl-3-([morpholinyl]methyl)pyrollo(1,2,3-de)-1,4-benzoxazinyl]-[1-naphthaleny]methanone [WIN 55,212-2, (WIN)] is a synthetic cannabinoid that inhibits RKO, HT-29, and SW480 cell growth, induced apoptosis, and downregulated expression of survivin, cyclin D1, EGF receptor (EGFR), VEGF, and its receptor (VEGFR1). WIN also decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4, and this is consistent with the observed downregulation of the aforementioned Sp-regulated genes. In addition, we also observed by RNA interference (RNAi) that the oncogenic cap protein eIF4E was an Sp-regulated gene also downregulated by WIN in colon cancer cells. WIN-mediated repression of Sp proteins was not affected by cannabinoid receptor antagonists or by knockdown of the receptor but was attenuated by the phosphatase inhibitor sodium orthovanadate or by knockdown of protein phosphatase 2A (PP2A). WIN-mediated repression of Sp1, Sp3, and Sp4 was due to PP2A-dependent downregulation of microRNA-27a (miR-27a) and induction of miR-27a-regulated ZBTB10, which has previously been characterized as an "Sp repressor." The results show that the anticancer activity of WIN is due, in part, to PP2A-dependent disruption of miR-27a:ZBTB10 and ZBTB10-mediated repression of Sp transcription factors and Sp-regulated genes, including eIF4E.
...
PMID:The cannabinoid WIN 55,212-2 decreases specificity protein transcription factors and the oncogenic cap protein eIF4E in colon cancer cells. 2403 Jun 32

BANK1, an adaptor protein expressed in B cells, plays a little understood role in B cell signaling. Because BANK1 contains an N-terminal putative Toll/IL-1R receptor domain, we used mouse Bank1(-/-) splenic B cells to test whether BANK1 affects signaling induced by the TLR9 agonist CpG. Following CpG stimulation, BANK1 deficiency reduced p38 phosphorylation without affecting that of ERK or JNK and reduced IL-6 secretion. Bank1(-/-) B cells showed reduced phosphorylation of MNK1/2 and eIF4E, suggesting an effect on translation initiation, whereas Bank1(-/-) had no effect on IL-6 mRNA stability, thus suggesting that BANK1 has no effect on MK2 signaling. IL-6 secretion observed when CpG stimulation was combined with anti-CD40 was reduced in the absence of BANK1. Whereas in the presence of anti-CD40 stimulation CpG induced a stronger phosphorylation of AKT, mTOR, and 4E-BP1, Bank1(-/-) had no effect on phosphorylation of mTOR and 4E-BP1, and a weak effect on AKT, implying that BANK1 does not affect the release of eIF4E by phospho-4E-BP1. Taken together, these data establish a previously unrecognized role for BANK1 in CpG-induced responses by splenic B cells on p38 signaling and control of translation initiation of IL-6 via MNK1/2 and eIF4E.
...
PMID:BANK1 controls CpG-induced IL-6 secretion via a p38 and MNK1/2/eIF4E translation initiation pathway. 2422 80

Rocaglamides (= flavaglines) are potent natural anti-cancer phytochemicals that inhibit cancer growth at nanomolar concentrations by the following mechanisms: (1) inhibition of translation initiation via inhibition of phosphorylation of the mRNA cap-binding eukaryotic translation initiation factor eIF4E and stabilization of RNA-binding of the translation initiation factor eIF4A in the eIF4F complex; (2) blocking cell cycle progression by activation of the ATM/ATR-Chk1/Chk2 checkpoint pathway; (3) inactivation of the heat shock factor 1 (HSF1) leading to up-regulation of thioredoxin-interacting protein (TXNIP) and consequent reduction of glucose uptake and (4) induction of apoptosis through activation of the MAPK p38 and JNK and inhibition of the Ras-CRaf-MEK-ERK signaling pathway. Besides the anti-cancer activities, rocaglamides are also shown to protect primary cells from chemotherapy-induced cell death and alleviate inflammation- and drug-induced injury in neuronal tissues. This review will focus on the recently discovered molecular mechanisms of the actions of rocaglamides and highlights the benefits of using rocaglamides in cancer treatment.
...
PMID:Molecular mechanisms and anti-cancer aspects of the medicinal phytochemicals rocaglamides (=flavaglines). 2489 51

Breast cancers and most malignant tumors are composed of heterogeneous tumor cells both at genetic and morphological levels; intra-tumor heterogeneity can be one underlying cause of therapeutic resistance. Classical studies have focused on analyses of the relationship between primary tumors and metastatic dissemination, and on subclone evolution. However, it should be noted that tumor heterogeneity at the level of protein expression (proteomics) has not been yet studied in depth. The differences in protein expression also can play an important role in elucidating the relationship between intra-tumor heterogeneity and resistance to systemic therapy. In fact, in human tumors there is not always a homogeneous expression of many of the crucial factors involved in cell signaling, such as pMAPK, pAKt, pMTOR, even with constitutive oncogenic alterations upstream, such as HER2, PI3 K. Conversely, two of these factors, peIF4E and p4E-BP1, which are downstream, and control protein translation, show a diffuse and strong protein expression. In summary, most of cell signaling factors show a heterogeneous expression, regardless of oncogenic alterations. Tissue heterogeneity could be driven by local factors, including hypoxia. The fact that the phosphorylation of crucial proteins such as 4E-BP1 and eIF4E is observed homogeneously throughout most tumors and are druggable opens the chance to get real potential targets in cancer therapy.
...
PMID:The intra-tumor heterogeneity of cell signaling factors in breast cancer: p4E-BP1 and peIF4E are diffusely expressed and are real potential targets. 2506 May 67

Leucine has been shown to influence intestinal protein metabolism, cell proliferation and migration. Furthermore, our previous study demonstrated that branched-chain amino acids could modulate the intestinal amino acid and peptide transporters in vivo. As the possible mechanisms are still largely unknown, in the present work, we studied the transcriptional and translational regulation of leucine on amino acid transporter production in IPEC-J2 cells and the signaling pathways involved. Treatment of IPEC-J2 cells with 7.5 mM leucine enhanced the mRNA expression of the Na(+)-neutral AA exchanger 2 (ASCT2) and 4F2 heavy chain (4F2hc) and caused an increase in ASCT2 protein expression. Leucine also activated phosphorylation of 4E-BP1 and eIF4E through the phosphorylation of mTOR, Akt and ERK signaling pathways in IPEC-J2 cells. Pre-treatment of IPEC-J2 cells with inhibitors of mTOR and Akt (rapamycin and wortmannin) or an inhibitor of ERK (PD098059) for 30 min before leucine treatment attenuated the positive effect of leucine in enhancing the protein abundance of ASCT2. These results demonstrate that leucine could up-regulate the expression of the amino acid transporters (ASCT2) through transcriptional and translational regulation by ERK and PI3K/Akt/mTOR activation.
...
PMID:Leucine stimulates ASCT2 amino acid transporter expression in porcine jejunal epithelial cell line (IPEC-J2) through PI3K/Akt/mTOR and ERK signaling pathways. 2506 4

In BRAF(V600)-mutant tumours, most mechanisms of resistance to drugs that target the BRAF and/or MEK kinases rely on reactivation of the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal transduction pathway, on activation of the alternative, PI(3)K-AKT-mTOR, pathway (which is ERK independent) or on modulation of the caspase-dependent apoptotic cascade. All three pathways converge to regulate the formation of the eIF4F eukaryotic translation initiation complex, which binds to the 7-methylguanylate cap (m(7)G) at the 5' end of messenger RNA, thereby modulating the translation of specific mRNAs. Here we show that the persistent formation of the eIF4F complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, is associated with resistance to anti-BRAF, anti-MEK and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with one of three mechanisms: reactivation of MAPK signalling, persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 or increased pro-apoptotic BCL-2-modifying factor (BMF)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions shows that eIF4F complex formation is decreased in tumours that respond to anti-BRAF therapy and increased in resistant metastases compared to tumours before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergizes with inhibiting BRAF(V600) to kill the cancer cells. eIF4F not only appears to be an indicator of both innate and acquired resistance but also is a promising therapeutic target. Combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms arising in BRAF(V600)-mutant cancers.
...
PMID:eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies. 2522 Mar 42

The MAP kinase signal-integrating kinases or MAP kinase-interacting protein kinases (Mnks) are activated by signaling through the oncogenic MAP kinase (ERK) pathway. The best-known Mnk substrate is eukaryotic initiation factor eIF4E, the protein which binds the 5'-cap structure of eukaryotic mRNAs and helps to recruit ribosomes to them. eIF4E is a well-established proto-oncogene, whose expression or activation is associated with transformation and tumorigenesis. Mnks phosphorylate eIF4E at a single site. Increasing evidence implicates the Mnks and/or phosphorylation of eIF4E in cell transformation, tumorigenesis or tumor progression, in a growing range of settings. Mnks and/or the phosphorylation of eIF4E have been suggested to regulate the expression of proteins involved in cell cycle progression, cell survival and cell motility. Further work is needed to extend our understanding of the impact of the Mnks on gene expression, explore the biochemical mechanisms involved and evaluate the utility of targeting the Mnks in cancer therapy. This article is part of a Special Issue entitled: Translation and Cancer.
...
PMID:Mnks, eIF4E phosphorylation and cancer. 2545 May 20

The MAP kinase-interacting kinases (Mnk1 and Mnk2) are activated by ERK and are best known for phosphorylating the translation initiation factor eIF4E. Genetic knockout of the Mnks impaired the migration of embryonic fibroblasts both in two-dimensional wound-healing experiments and in three-dimensional migration assays. Furthermore, a novel and selective Mnk inhibitor, Mnk-I1, which potently blocks eIF4E phosphorylation, blocked the migration of fibroblasts and cancer cells, without exerting 'off-target' effects on other signalling pathways such as Erk. Mnk-I1 or genetic knockout of the Mnks decreased the expression of vimentin, a marker of mesenchymal cells, without affecting vimentin mRNA levels. Vimentin protein levels were much lower in Mnk1/2-knockout cells than in controls, although mRNA levels were similar. Our data suggest that the Mnks regulate the translation of the vimentin mRNA and the stability of the vimentin protein. Inhibition or genetic knockout of the Mnks increased the binding of eIF4E to the cytoplasmic FMRP-interacting protein 1 (CYFIP1), which binds the fragile-X mental retardation protein, FMRP, a translational repressor. Since FMRP binds mRNAs for proteins involved in metastasis, the Mnk-dependent release of CYFIP1 from eIF4E is expected to release the repression of translation of FMRP-bound mRNAs, potentially providing a molecular mechanism for the control of cell migration by the Mnks. As Mnk1/2 are not essential for viability, inhibition of the Mnks may be a useful approach to tackling cancer metastasis, a key process contributing to mortality in cancer patients.
...
PMID:The MAP kinase-interacting kinases regulate cell migration, vimentin expression and eIF4E/CYFIP1 binding. 2558 2

Although the MAP kinase-interacting kinases (MNKs) have been known for >15 years, their roles in the regulation of protein synthesis have remained obscure. Here, we explore the involvement of the MNKs in brain-derived neurotrophic factor (BDNF)-stimulated protein synthesis in cortical neurons from mice. Using a combination of pharmacological and genetic approaches, we show that BDNF-induced upregulation of protein synthesis requires MEK/ERK signaling and the downstream kinase, MNK1, which phosphorylates eukaryotic initiation factor (eIF) 4E. Translation initiation is mediated by the interaction of eIF4E with the m(7)GTP cap of mRNA and with eIF4G. The latter interaction is inhibited by the interactions of eIF4E with partner proteins, such as CYFIP1, which acts as a translational repressor. We find that BDNF induces the release of CYFIP1 from eIF4E, and that this depends on MNK1. Finally, using a novel combination of BONCAT and SILAC, we identify a subset of proteins whose synthesis is upregulated by BDNF signaling via MNK1 in neurons. Interestingly, this subset of MNK1-sensitive proteins is enriched for functions involved in neurotransmission and synaptic plasticity. Additionally, we find significant overlap between our subset of proteins whose synthesis is regulated by MNK1 and those encoded by known FMRP-binding mRNAs. Together, our data implicate MNK1 as a key component of BDNF-mediated translational regulation in neurons.
...
PMID:BDNF stimulation of protein synthesis in cortical neurons requires the MAP kinase-interacting kinase MNK1. 2560 15

Ligustrazine (TMP) has recently been used for the treatment of various cancers. However, its exact mechanisms of action, particularly the functions and the mechanisms of Ligustrazine in human hormone-refractory prostate cancer (HRPC), have not yet been extensively studied. Recently, our findings suggest that Ligustrazine dose- and time-dependently inhibits the growth of HRPC cells by reducing their proliferation and promoting apoptosis. Interestingly, the treatment of hormone-refractory prostate cancer (PC-3) cells with Ligustrazine results in a significant inhibition of the activation of mTOR and related downstream targets, which are critical for cell growth. Furthermore, pull-down assays with 7-methyl- GTP Sepharose 4B beads indicate that Ligustrazine reduces the available eIF4E for translation initiation. Accordingly, the results from the translation assay using a luciferase reporter system further demonstrate that Ligustrazine indeed inhibits cap-dependent translation. In addition, the transient overexpression of eIF4E or MNK1 prevents the Ligustrazine-induced inhibition of proliferation and confers significant protection against Ligustrazine-induced apoptosis. Therefore, the present study provides evidences that Ligustrazine may be a candidate for therapeutic reagent for the treatment of HRPC and certifies that Ligustrazine modulates the availability of eIF4E mainly through the mTOR and MEK/ERK signaling pathways to inhibit cap-dependent translation. Taken together, our results indicate that the inhibition of cap-dependent translation is likely an essential mechanism in Ligustrazine-induced apoptosis.
...
PMID:Ligustrazine Suppresses the Growth of HRPC Cells through the Inhibition of Cap- Dependent Translation Via Both the mTOR and the MEK/ERK Pathways. 2574 94


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---