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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) increases protein synthesis and induces hypertrophy in renal tubular epithelial cells (Senthil, D., Choudhury, G. G., McLaurin, C., and Kasinath, B. S. (2003) Kidney Int. 64, 468-479). We examined the role of Erk1/2 MAP kinase in protein synthesis induced by VEGF. VEGF stimulated Erk phosphorylation that was required for induction of protein synthesis. VEGF-induced Erk activation was not dependent on phosphoinositide (PI) 3-kinase activation but required sequential phosphorylation of type 2 VEGF receptor, PLCgamma and c-Src, as demonstrated by inhibitors SU1498, U73122, and PP1, respectively. c-Src phosphorylation was inhibited by U73122, indicating it was downstream of phospholipase (PL)Cgamma. Studies with PP1/2 showed that phosphorylation of c-Src was required for tyrosine phosphorylation of Raf-1, an upstream regulator of Erk. VEGF also stimulated phosphorylation of Pyk-2; VEGF-induced phosphorylation of Pyk2, c-Src and Raf-1 could be abolished by BAPTA/AM, demonstrating requirement for induction of intracellular calcium currents. We examined the downstream events following the phosphorylation of Erk. VEGF stimulated phosphorylation of Mnk1 and eIF4E and induced Mnk1 to shift from the cytoplasm to the nucleus upon phosphorylation. VEGF-induced phosphorylation of Mnk1 and eIF4E required phosphorylation of PLCgamma, c-Src, and Erk. Expression of dominant negative Mnk1 abrogated eIF4E phosphorylation and protein synthesis induced by VEGF. VEGF-stimulated protein synthesis could be blocked by inhibition of PLCgamma by a chemical inhibitor or expression of a dominant negative construct. Our data demonstrate that VEGF-stimulated protein synthesis is Erk-dependent and requires the activation of VEGF receptor 2, PLCgamma, c-Src, Raf, and Erk pathway. VEGF also stimulates Erk-dependent phosphorylation of Mnk1 and eIF4E, crucial events in the initiation phase of protein translation.
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PMID:Phospholipase Cgamma-Erk Axis in vascular endothelial growth factor-induced eukaryotic initiation factor 4E phosphorylation and protein synthesis in renal epithelial cells. 1591 58

Rapamycin and its derivatives are promising therapeutic agents with both immunosuppressant and anti-tumor properties. These rapamycin actions are mediated through the specific inhibition of the mTOR protein kinase. mTOR serves as part of an evolutionarily conserved signaling pathway that controls the cell cycle in response to changing nutrient levels. The mTOR signaling network contains a number of tumor suppressor genes including PTEN, LKB1, TSC1, and TSC2, and a number of proto-oncogenes including PI3K, Akt, and eIF4E, and mTOR signaling is constitutively activated in many tumor types. These observations point to mTOR as an ideal target for anti-cancer agents and suggest that rapamycin is such an agent. In fact, early preclinical and clinical studies indicate that rapamycin derivatives have efficacy as anti-tumor agents both alone, and when combined with other modes of therapy. Rapamycin appears to inhibit tumor growth by halting tumor cell proliferation, inducing tumor cell apoptosis, and suppressing tumor angiogenesis. Rapamycin immunosuppressant actions result from the inhibition of T and B cell proliferation through the same mechanisms that rapamycin blocks cancer cell proliferation. Therefore, one might think that rapamycin-induced immunosuppression would be detrimental to the use of rapamycin as an anti-cancer agent. To the contrary, rapamycin decreases the frequency of tumor formation that occurs in organ transplant experiments when combined with the widely used immunosuppressant cyclosporine compared with the tumor incidence observed when cyclosporine is used alone. The available evidence indicates that with respect to tumor growth, rapamycin anti-cancer activities are dominant over rapamycin immunosuppressant effects.
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PMID:Rapamycin: an anti-cancer immunosuppressant? 1603 68

Deoxynivalenol (DNV) is the most frequently encountered trichothecene in grain-based foods, and is able to produce toxic effects resulting in various diseases in farm and laboratory animals. The molecular mechanisms that control this mycotoxin mediated effects in porcine endometrial cells are far from being completely understood. Recent results show that DNV inhibits protein synthesis in actively proliferating tissues. Therefore, the present study investigated the effects of this mycotoxin on a cellular level in an in vivo and in vitro system. The abundance and phosphorylation state (activity) of the cell cycle dependent kinases MAPk and Akt (PKB) and their potential targets eIF-4E (eukaryotic initiation factor 4E) and 4E-BP1 (4E binding protein, eIF4E repressor protein) were examined. In previous investigations it was found that these factors are involved in initiation of mRNA translation. The results show that DNV in vitro strongly reduce the abundance of p38 MAPk, protein kinase Akt and the alpha- and beta-4E-BP1 bands. The phosphorylation state of these proteins was obviously not modulated. In contrast, the eIF4E phosphorylation was strongly reduced in DNV treated cells. In summary, our in vitro results let assume that DNV potentially influences gene expression, but this work does not present a direct proof that DNV alters processes, which are involved in the initiation of mRNA translation. Surprisingly in vivo, an influence of DNV feeding on the investigated molecular events could not be demonstrated.
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PMID:In vitro and in vivo effects of deoxynivalenol (DNV) on regulators of cap dependent translation control in porcine endometrium. 1609 39

The aim of this review is to describe the role of hepatitis C proteins, non-structural protein 5A and envelope protein E2, in resistance to interferon alpha. These proteins contain interferon induced-protein kinase R binding domains. The binding renders the kinase inactive; therefore the phosphorylation of translation factor eIF2 is inhibited. The studies indicate that phosphorylation of eIF4E is also inhibited. As a result, with the sufficient pool of active eIF2 in infected cell, synthesis of viral proteins proceeds while cap- and cap binding factors-, among them eIF4E, -dependent synthesis of host proteins is diminished. It seems this process is one of the molecular mechanisms responsible for the resistance of hepatitis C virus to interferon, persistence in infected cell and the resultant difficulties in treatment of infected individuals.
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PMID:[The mechanisms of hepatitis C virus resistance to interferon]. 1620 38

The poly(A)-binding protein (PABP) is an important regulator of mRNA translation and stability. The cellular level of PABP is controlled by regulating its mRNA translation by a feedback mechanism. The important aspect of this mechanism is that PABP binds to an adenosine-rich cis-element at the 5'-untranslated region of its own mRNA and inhibits its translation. To assess the importance of controlling the PABP level, we studied the effect of PABP overexpression on the transcription profile using the microarray technique. In PABP-overexpressing cells, 19 mRNAs showed a reduction in cellular levels due to reduced mRNA stability, and one showed an increase due to increased mRNA stability. Among these mRNAs, the MKK-2 mRNA encodes the protein kinase activator of ERK1/2 kinase, which is involved in the phosphorylation of eukaryotic initiation factor (eIF) 4E. As a result, mRNA translation may be regulated by the cellular level of MKK-2. In this study, we show that the abundance of the MKK-2 polypeptide is reduced in PABP-overexpressing cells. In these cells, the levels of phosphorylated PABP, eIF4E, and ERK2 are also reduced. Treatment of HeLa cells with the MKK-2 inhibitor U0126 reduced PABP phosphorylation, suggesting that the phosphorylation of PABP is mediated by the MKK-2/ERK signaling pathway. Thus, a novel signaling pathway involving MKK-2 and ERK1/2 may down-regulate the activity of PABP and eIF4E by controlling their phosphorylation and compensates for the effect of excess cellular PABP.
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PMID:Reduced stability of mitogen-activated protein kinase kinase-2 mRNA and phosphorylation of poly(A)-binding protein (PABP) in cells overexpressing PABP. 1633 85

The present study examined the effects of an acute bout of treadmill exercise on signalling through the extracellular signal-regulated kinase (ERK)1/2 and mammalian target of rapamycin (mTOR) pathways to regulatory mechanisms involved in mRNA translation in mouse gastrocnemius muscle. Briefly, C57BL/6 male mice were run at 26 m min(-1) on a treadmill for periods of 10, 20 or 30 min, then the gastrocnemius was rapidly removed and analysed for phosphorylation and/or association of protein components of signalling pathways and mRNA translation regulatory mechanisms. Repression of global mRNA translation was suggested by disaggregation of polysomes into free ribosomes, which occurred by 10 min and was sustained throughout the time course. Exercise repressed the mTOR signalling pathway, as shown by dephosphorylation of the eukaryotic initiation factor (eIF)4E-binding protein-1 (4E-BP1), enhanced association of the regulatory-associated protein of mTOR with mTOR, and increased assembly of the tuberin-hamartin complex. In contrast, exercise caused no change in phosphorylation of either Akt/PKB or tuberin. Upstream of mTOR, exercise was associated with an increase in cAMP, protein kinase A activity, and AMP-activated protein kinase phosphorylation. Simultaneously, exercise caused a rapid and sustained activation of the MEK1/2-ERK1/2-p90RSK pathway, resulting in increased phosphorylation of downstream targets including eIF4E and the ribosomal protein (rp)S6 on S235/S236. Overall, the data are consistent with exercise-induced repression of mTOR signalling and global rates of mRNA translation, accompanied perhaps by up-regulated translation of selected mRNAs through regulatory mechanisms such as eIF4E and rpS6 phosphorylation, mediated by activation of the ERK1/2 pathway.
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PMID:Exercise-induced alterations in extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin (mTOR) signalling to regulatory mechanisms of mRNA translation in mouse muscle. 1660 Sep 96

Protein expression in the heart is altered following periods of myocardial ischemia. The changes in protein expression are associated with increased cell size that can be maladaptive. There is little information regarding the regulation of protein expression through the process of mRNA translation during ischemia and reperfusion in the heart. Therefore, the purpose of this study was to identify changes in signaling pathways and downstream regulatory mechanisms of mRNA translation in an in vivo model of myocardial ischemia and reperfusion. Hearts were collected from rats whose left main coronary arteries had either been occluded for 25 min or reversibly occluded for 25 min and subsequently reperfused for 15 min. Following reperfusion, both the phosphoinositide 3-kinase and mitogen-activated protein kinase pathways were activated, as evidenced by increased phosphorylation of Akt (PKB), extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase. Activation of Akt stimulated signaling through the protein kinase mammalian target of rapamycin, as evidenced by increased phosphorylation of two of its effectors, the ribosomal protein S6 kinase and the eukaryotic initiation factor eIF4E binding protein 1. Ischemia and reperfusion also resulted in increased phosphorylation of eIF2 and eIF2B. These changes in protein phosphorylation suggest that control of mRNA translation following ischemia and reperfusion is modulated through a number of signaling pathways and regulatory mechanisms.
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PMID:Activation of signaling pathways and regulatory mechanisms of mRNA translation following myocardial ischemia-reperfusion. 1669 Jul 84

Activation of the tumour suppressor protein p53 rapidly inhibits protein synthesis. This is associated with dephosphorylation and cleavage of initiation factor eIF4GI and the eIF4E-binding protein 4E-BP1. When the activation of p53 is reversed within 16 h 4E-BP1 becomes rephosphorylated, the level of intact eIF4GI slowly increases and protein synthesis gradually recovers. The recovery of protein synthesis is partially blocked by rapamycin and wortmannin but not by the protein kinase inhibitors PD98059 and CGP74514A. Both rapamycin and wortmannin, but not PD98059 or CGP74514A, delay the reappearance of eIF4GI. In contrast, full-length 4E-BP1 rapidly becomes rephosphorylated and this process is partially inhibited by rapamycin, PD98059 and CGP74514A. Thus, activation of p53 results in the inhibition of distinct rapamycin- and wortmannin-sensitive pathways that target eIF4GI, and rapamycin-sensitive and -insensitive pathways that target 4E-BP1. Following inactivation of p53 the gradual recovery is determined largely by the kinetics of restoration of eIF4GI rather than by the rephosphorylation of full-length 4E-BP1. These findings suggest that the ability of cells to rephosphorylate 4E-BP1, resynthesise eIF4GI and restore the rate of protein synthesis after inactivation of p53 is an important aspect of recovery following the relief of physiological stress.
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PMID:Regulation of translation factors eIF4GI and 4E-BP1 during recovery of protein synthesis from inhibition by p53. 1699 Aug 47

The dimorphic transition of yeast to the hyphal form is regulated by the mitogen-activated protein kinase and cyclic AMP-dependent protein kinase A pathways in Saccharomyces cerevisiae. Signaling pathway-responsive transcription factors such as Ste12, Tec1, and Flo8 are known to mediate filamentation-specific transcription. We were interested in investigating the translational regulation of specific mRNAs during the yeast-to-hyphal-form transition. Using polyribosome fractionation and RT-PCR analysis, we identified STE12, GPA2, and CLN1 as translation regulation target genes during filamentous growth. The transcript levels for these genes did not change, but their mRNAs were preferentially associated with polyribosomes during the hyphal transition. The intracellular levels of Ste12, Gpa2, and Cln1 proteins increased under hyphal-growth conditions. The increase in Ste12 protein level was partially blocked by mutations in the CAF20 and DHH1 genes, which encode an eIF4E inhibitor and a decapping activator, respectively. In addition, the caf20 and dhh1 mutations resulted in defects in filamentous growth. The filamentation defects caused by caf20 and dhh1 mutations were suppressed by STE12 overexpression. These results suggest that Caf20 and Dhh1 control yeast filamentation by regulating STE12 translation.
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PMID:Identification of translational regulation target genes during filamentous growth in Saccharomyces cerevisiae: regulatory role of Caf20 and Dhh1. 1704 Nov 86

Angiogenesis and signaling through the RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinomas (HCC). Sorafenib (BAY 43-9006, Nexavar) is a multikinase inhibitor with activity against Raf kinase and several receptor tyrosine kinases, including vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. In this study, we investigated the in vitro effects of sorafenib on PLC/PRF/5 and HepG2 HCC cells and the in vivo antitumor efficacy and mechanism of action on PLC/PRF/5 human tumor xenografts in severe combined immunodeficient mice. Sorafenib inhibited the phosphorylation of MEK and ERK and down-regulated cyclin D1 levels in these two cell lines. Sorafenib also reduced the phosphorylation level of eIF4E and down-regulated the antiapoptotic protein Mcl-1 in a MEK/ERK-independent manner. Consistent with the effects on both MEK/ERK-dependent and MEK/ERK-independent signaling pathways, sorafenib inhibited proliferation and induced apoptosis in both HCC cell lines. In the PLC/PRF/5 xenograft model, sorafenib tosylate dosed at 10 mg/kg inhibited tumor growth by 49%. At 30 mg/kg, sorafenib tosylate produced complete tumor growth inhibition. A dose of 100 mg/kg produced partial tumor regressions in 50% of the mice. In mechanism of action studies, sorafenib inhibited the phosphorylation of both ERK and eIF4E, reduced the microvessel area (assessed by CD34 immunohistochemistry), and induced tumor cell apoptosis (assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling) in PLC/PRF/5 tumor xenografts. These results suggest that the antitumor activity of sorafenib in HCC models may be attributed to inhibition of tumor angiogenesis (VEGFR and PDGFR) and direct effects on tumor cell proliferation/survival (Raf kinase signaling-dependent and signaling-independent mechanisms).
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PMID:Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. 1717 82


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