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)

Embryonic stem cells are immortalized cells whose proliferation rate is comparable to that of carcinogenic cells. To study the expression of embryonic stem cell genes in primary cells, genetic screening was performed by infecting mouse embryonic fibroblasts (MEFs) with a cDNA library from embryonic stem cells. Cold-inducible RNA-binding protein (CIRP) was identified due to its ability to bypass replicative senescence in primary cells. CIRP enhanced extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation, and treatment with an MEK inhibitor decreased the proliferation caused by CIRP. In contrast to CIRP upregulation, CIRP downregulation decreased cell proliferation and resulted in inhibition of phosphorylated ERK1/2 inhibition. This is the first evidence that ERK1/2 activation, through the same mechanism as that described for a Val12 mutant K-ras to induce premature senescence, is able to bypass senescence in the absence of p16(INK4a), p21(WAF1), and p19(ARF) upregulation. Moreover, these results show that CIRP functions by stimulating general protein synthesis with the involvement of the S6 and 4E-BP1 proteins. The overall effect is an increase in kinase activity of the cyclin D1-CDK4 complex, which is in accordance with the proliferative capacity of CIRP MEFs. Interestingly, CIRP mRNA and protein were upregulated in a subgroup of cancer patients, a finding that may be of relevance for cancer research.
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PMID:Cold-inducible RNA-binding protein bypasses replicative senescence in primary cells through extracellular signal-regulated kinase 1 and 2 activation. 1915 77

The effect of anthrax infection on phosphoprotein signaling was studied in human small airway lung epithelial cells exposed to B. anthracis spores of the plasmidless dSterne strain in comparison with the Sterne strain containing the toxigenic plasmid (pXO1). The differential regulation of phosphorylation was found in the mitogen-activated protein kinase cascade (ERK, p38, and P90RSK), the PI3K cascade (AKT, GSK-3alpha/beta), and downstream in the case of the proapoptotic BAD and the transcription factor STAT3. Both strains stimulate phosphorylation of CREB and inhibit phosphorylation of 4E-BP1 required for activation of cap-dependent translation. Downregulation of the survival AKT phosphorylation by the Sterne strain inhibits the process of Ca(2+)-dependent homophilic interaction of E-cadherin (EC) upon formation or repair of cell-cell contacts. Both lethal and edema toxins produced by the Sterne strain inhibit the AKT phosphorylation induced during the EC-mediated signaling. Activity of ERK1/2 and p38 inhibitors indicates that inhibition of AKT phosphorylation takes place through the ERK1/2-PI3K crosstalk. In Sterne spore-challenged mice, a specific inhibitor of PI3K/AKT, wortmannin, accelerates the lethal outcome, and reduction of AKT phosphorylation in the circulating blood cells coincides with the death of animals. We conclude that the PI3K/AKT pathway controlling the integrity of epithelium plays an important survival role in anthrax infection.
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PMID:Anthrax infection inhibits the AKT signaling involved in the E-cadherin-mediated adhesion of lung epithelial cells. 1941 48

In the oncogenic process, cell growth control plays a crucial role, and growth factor receptors and their signaling pathways are known to be altered in endometrial cancer, mostly in type I carcinomas. Two main pathways are involved in transmitting the proliferative signal from the membrane receptors to the nucleus: phosphatydil-inositol-3-kinase-protein kinase B-mammalian target of rapamycin and RAS-RAF-ERK pathways. A final effector of these signaling cascades is the cap-dependent mRNA translation initiation complex, which is negatively regulated by 4E-BP1. The aim of our work was to study the relative importance of the factors involved in these pathways and to see their correlation with the clinicopathologic features of the tumors and their prognosis. We studied 120 endometrial carcinomas, including 93 type I and 27 type II carcinomas, and 18 control cases. Tissue microarrays were constructed and immunohistochemistry was performed for HER2, p53, and the phosphorylated forms of protein kinase B, extracellular signal-regulated kinase, and 4E-BP1. HER2 was overexpressed in 11% of carcinomas but not in control cases, and 30% of carcinomas showed activation of protein kinase B and extracellular signal-regulated kinase, mostly in type II carcinomas. The phosphorylated form of 4E-BP1 was found to be cytoplasmic in 31% of cases, and in 63% of cases it showed nuclear expression; the latter was only found in carcinomas. p53 positivity was found in type II and in grade 3 type I carcinomas. This nuclear expression of phospho-4E-BP1 and HER2 overexpression were the only characteristics with prognostic significance. The activation of the signaling pathways that control cell growth is a common event in endometrial carcinomas. 4E-BP1 is a downstream effector of these pathways whose activation status correlates with aggressive phenotypes and prognosis. This factor can reflect the activity of these pathways, regardless of the upstream molecular alterations, and, therefore, it can be a hallmark of the transmission of the oncogenic signal to the nucleus.
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PMID:Cell signaling in endometrial carcinoma: phosphorylated 4E-binding protein-1 expression in endometrial cancer correlates with aggressive tumors and prognosis. 1942 47

Insulin-like growth factor-1 (IGF-1) interacts with the Type I receptor to activate two main signaling pathways, the mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) and the phosphatidylinositol 3-kinase (PI3K)-Akt cascades, which mediate proliferation or survival of oligodendrocyte (OL) progenitors (OLPs). In other cellular systems, mammalian target of rapamycin (mTOR) and the p70 S6 kinase are downstream effectors that phosphorylate translation initiation factors (e.g. eIF-4E), their regulators (e.g. 4E-binding protein 1, 4E-BP1) and ribosomal protein S6 (S6). The aim of this study was to determine whether these pathways are involved in IGF-1-stimulated protein synthesis, important for growth and differentiation of OLs. Rat cultured OLPs were treated with IGF-1 with or without inhibitors of PI3K (LY294002 or Wortmannin), mTOR (rapamycin), MEK (PD98059), and Akt (III or IV), as well as an adenovirus encoding a dominant negative form of Akt. Protein synthesis, as assessed by [(35)S]-methionine incorporation, was stimulated by IGF-1 and required the upstream activation of PI3K, Akt, mTOR and MEK/ERK. Concordant with the experiments using protein kinase inhibitors, western blotting revealed that IGF-1 stimulates phosphorylation of Akt, mTOR, ERK, S6 and 4E-BP1. Activation of S6 and inactivation of 4E-BP1, necessary for protein synthesis to take place, were dependent on the upstream activation of PI3K and mTOR. Finally, IGF-1 consistently stimulated protein synthesis through mTOR in differentiating OLPs but mRNA transcription was not required at day 4, indicating a differential role of IGF-1 throughout OL development.
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PMID:IGF-1-stimulated protein synthesis in oligodendrocyte progenitors requires PI3K/mTOR/Akt and MEK/ERK pathways. 1945 43

Elevated testosterone concentrations induce cardiac hypertrophy but the molecular mechanisms are poorly understood. Anabolic properties of testosterone involve an increase in protein synthesis. The mammalian target of rapamycin complex 1 (mTORC1) pathway is a major regulator of cell growth, but the relationship between testosterone action and mTORC1 in cardiac cells remains unknown. Here, we investigated whether the hypertrophic effects of testosterone are mediated by mTORC1 signaling in cultured cardiomyocytes. Testosterone increases the phosphorylation of mTOR and its downstream targets 40S ribosomal protein S6 kinase 1 (S6K1; also known as RPS6KB1) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). The S6K1 phosphorylation induced by testosterone was blocked by rapamycin and small interfering RNA to mTOR. Moreover, the hormone increased both extracellular-regulated kinase (ERK1/2) and protein kinase B (Akt) phosphorylation. ERK1/2 inhibitor PD98059 blocked the testosterone-induced S6K1 phosphorylation, whereas Akt inhibition (Akt-inhibitor-X) had no effect. Testosterone-induced ERK1/2 and S6K1 phosphorylation increases were blocked by either 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid-acetoxymethylester or by inhibitors of inositol 1,4,5-trisphosphate (IP(3)) pathway: U-73122 and 2-aminoethyl diphenylborate. Finally, cardiomyocyte hypertrophy was evaluated by, the expression of beta-myosin heavy chain, alpha-skeletal actin, cell size, and amino acid incorporation. Testosterone increased all four parameters and the increase being blocked by mTOR inhibition. Our findings suggest that testosterone activates the mTORC1/S6K1 axis through IP(3)/Ca(2+) and MEK/ERK1/2 to induce cardiomyocyte hypertrophy.
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PMID:Testosterone induces cardiomyocyte hypertrophy through mammalian target of rapamycin complex 1 pathway. 1947 60

Regulation of gene expression at the translational level is particularly essential during developmental periods, when transcription is impaired. According to the closed-loop model of translational initiation, we have analyzed components of the 5 -mRNA cap-binding complex eIF4F (eIF4E, eIF4G, eIF4A), the eIF4E repressor 4E-BP1, and 3 -mRNA poly-(A) tail-associated proteins (PABP1 and 3, PAIP1 and 2, CPEB1, Maskin) during in vitro maturation of bovine oocytes and early embryonic development up to the 16-cell stage. Furthermore, we have elucidated the activity of distinct kinases which are potentially involved in their phosphorylation. Major phosphorylation of specific target sequences of PKA, PKB, PKC, CDKs, ATM/ATR, and MAPK were observed in M II stage oocytes. Furthermore, main changes in the abundance and/or phosphorylation of distinct mRNA-binding factors occur at the transition from M II stage oocytes to 2-cell embryos. In conclusion, the results indicate that, at the transition from oocyte to embryonic development, translational initiation is regulated by striking differences in the abundance and/or phosphorylation of 5 -end and 3 -end mRNA associated factors, mainly the poly-(A) bindings proteins PABP1 and 3, their repressor PAIP2 and a Maskin-like protein with distinct eIF4E-binding properties which prevents eIF4E/cap binding and eIF4F formation in vitro. Nevertheless, from the M II stage to 16-cell embryos a substantial amount of eIF4E and, to a lesser extent, of eIF4G was precipitated by (7)m-GTP-Separose indicating eIF4F complex formation. Therefore, it is likely that in general the reduction in PABP1 and 3 abundance represses overall translation during early embryonic development.
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PMID:Analysis of mRNA associated factors during bovine oocyte maturation and early embryonic development. 1969 62

Ionizing radiation (IR) is a physiologically important stress to which cells respond by the activation of multiple signaling pathways. Using a panel of immortalized and transformed breast epithelial cell lines, we demonstrate that IR regulation of protein synthesis occurs in nontransformed cells and is lost with transformation. In nontransformed cells, IR rapidly activates the MAP kinases ERK1/2, resulting in an early transient increase in cap-dependent mRNA translation that involves mTOR and is radioprotective, enhancing the translation of a subset of mRNAs encoding proteins involved in DNA repair and cell survival. Following a transient increase in translation, IR-sensitive (nontransformed) cells inhibit cap-dependent protein synthesis through a mechanism that involves activation of p53, induction of Sestrin 1 and 2 genes, and stimulation of AMP kinase, inhibiting mTOR and hypophosphorylating 4E-BP1. IR is shown to block proteasome-mediated decay of 4E-BP1, increasing its abundance and the sequestration of eIF4E. The IR signal that impairs mTOR-dependent protein synthesis at late times is assembly of the DNA damage response machinery, consisting of Mre11, Rad50, and NBS1 (MRN); activation of the MRN complex kinase ATM; and p53. These results link genotoxic signaling from the DNA damage response complex to the control of protein synthesis.
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PMID:Regulation of protein synthesis by ionizing radiation. 1970 5

We have previously reported the synergistic cytotoxic effects of Docetaxel (TXT) and S-1 in gastric cancer in vitro and in vivo, and the combination regimen is now under phase III clinical trail. In this study, to elucidate whether the rapamycin, the inhibitor of the mTOR (mammalian target of rapamaycin), can enhance the potentiation of TXT and 5-fluorouracil (5-Fu) in gastric carcinoma cells. Rapamycin inhibited the growth of TMK-1, MKN-28, MKN-45 and MKN-74 cell lines by MTT assay, and it demonstrated the cytostatic effects as G1 arrest shown by flowcytometry. However, the cytotoxic effects of 5-Fu, TXT and cisplatin were enhanced by 2 to 4 times with the concomitant administration of rapamycin. To clarify the mechanism of the potentiation, the expression changes of the enzymes relating DNA metabolism and cell growth signal transduction pathways were examined by western blot analysis. Interestingly, the expression of thymidilate synthase was markedly decreased by the administration of rapamycin in TMK-1 cells in a time- and dose-dependent manner. Moreover, rapamycin decreased the phosphorylation of 4E-BP1, the phosphorylation of ERK1/2 and enhanced the phosphorylation of c-Jun NH2-terminal kinase, and the activation of caspase of apoptotic pathways in combination with TXT. These results strongly indicate that the mTOR inhibitor can enhance the potentiation of TXT and 5-Fu or S-1 and can serve as a new therapeutic tool for advanced and recurrent gastric cancer patients.
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PMID:Rapamycin enhances chemotherapy-induced cytotoxicity by inhibiting the expressions of TS and ERK in gastric cancer cells. 1985 12

Exercise stimulates muscle protein fractional synthesis rate (FSR), but the importance of contractile intensity and whether it interplays with feeding is not understood. This was investigated following two distinct resistance exercise (RE) contraction intensities using an intrasubject design in the fasted (n = 10) and fed (n = 10) states. RE consisted of 10 sets of knee extensions. One leg worked against light load (LL) at 16% of one-repetition maximum (1RM), the other leg against heavy load (HL) at 70% 1RM, with intensities equalized for total lifted load. Males were infused with [(13)C]leucine, and vastus lateralis biopsies were obtained bilaterally at rest as well as 0.5, 3, and 5.5 h after RE. Western blots were run on muscle lysates and phosphospecific antibodies used to detect phosphorylation status of targets involved in regulation of FSR. The intramuscular collagen FSR was evenly increased following LL- and HL-RE and was not affected by feeding. Myofibrillar FSR was unaffected by LL-RE, whereas HL-RE resulted in a delayed improvement (0.14 +/- 0.02%/h, P < 0.05). Myofibrillar FSR was increased at rest by feeding (P < 0.05) and remained elevated late in the postexercise period compared with the fasting condition. The Rp-s6k-4E-binding protein-1 (BP1) and the mitogen-activated protein kinase (MAPk) pathways were activated by the HL intensity and were suggested to be responsible for regulating myofibrillar FSR in response to adequate contractile activity. Feeding predominantly affected Rp-s6k and eukaryotic elongation factor 2 phosphorylations in correspondence with the observed changes in myofibrillar FSR, whereas 4E-BP1 remained to respond only to the HL contraction intensity. Thus the study design allows us to conclude that the MAPk- and mammalian target of rapamycin-dependent signaling responds to contractile activity, whereas elongation mainly was found to respond to feeding. Furthermore, although functionally linked, the contractile and the supportive matrix structures upregulate their protein synthesis rate quite differently in response to feeding and contractile activity and intensity.
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PMID:Contraction intensity and feeding affect collagen and myofibrillar protein synthesis rates differently in human skeletal muscle. 1990 66

The serine/threonine Pim kinases are up-regulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre-T-LBL/T-ALL) being highly sensitive. Incubation of pre-T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27(Kip1), apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phospho-p70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre-T-LBL cells. In immunodeficient mice carrying subcutaneous pre-T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre-T-LBL.
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PMID:A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma. 1996 90


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