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)

Breast cancers frequently over-express a number of growth factor receptors. In addition, elevated src family kinase activity is present in a percentage of these neoplasms and has been implicated in signal transduction in these cells. Therefore, inhibiting tyrosine kinase activity is a potential approach for treating these tumors. Utilizing the SKBR3 and MCF-7 breast cancer cell lines, we evaluated the effects of broadly targeting growth factor receptor and cytoplasmic tyrosine kinases with tyrosine kinase inhibitors (herbimycin A and genistein) to inhibit proliferation. We also evaluated these inhibitor's effects on proteins that regulate ras function, which is a convergence point for signaling through both src family kinases and a number of growth factor receptors with tyrosine kinase activity (e.g., epidermal growth factor and erbB-2 receptors). We specifically evaluated whether these compounds affected 2 recently discovered proteins involved in controlling ras function: Shc, which is tyrosine-phosphorylated by src and activated growth factor receptors, and Grb-2, which mediates signal transduction from activated growth factor receptors through ras. We evaluated their effects on tyrosine phosphorylation of Shc, binding of Grb-2 to Shc and MAP kinase activity. Both cell lines were inhibited in a dose-dependent manner by each compound. This was accompanied by decreased Shc tyrosine phosphorylation, Shc's association with Grb-2 and MAP kinase activity. Thus, tyrosine kinase inhibitors can inhibit proliferation of breast cancer cells, accompanied by inhibition of signal transduction steps potentially mediated through ras. Tyrosine kinase inhibitors might, therefore, be useful for the treatment of breast cancer.
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PMID:Effects of tyrosine kinase inhibitors on the proliferation of human breast cancer cell lines and proteins important in the ras signaling pathway. 856 15

Rap1 small GTP-binding protein has the same amino acid sequence at its effector domain as that of Ras. Rap1 has been shown to antagonize the Ras functions, such as the Ras-induced transformation of NIH 3T3 cells and the Ras-induced activation of the c-Raf-1 protein kinase-dependent mitogen-activated protein (MAP) kinase cascade in Rat-1 cells, whereas we have shown that Rap1 as well as Ras stimulates DNA synthesis in Swiss 3T3 cells. We have established a cell-free assay system in which Ras activates bovine brain B-Raf protein kinase. Here we have used this assay system and examined the effect of Rap1 on the B-Raf activity to phosphorylate recombinant MAP kinase kinase (MEK). Recombinant Rap1B stimulated the activity of B-Raf, which was partially purified from bovine brain and immunoprecipitated by an anti-B-Raf antibody. The GTP-bound form was active, but the GDP-bound form was inactive. The fully post-translationally lipid-modified form was active, but the unmodified form was nearly inactive. The maximum B-Raf activity stimulated by Rap1B was nearly the same as that stimulated by Ki-Ras. Rap1B enhanced the Ki-Ras-stimulated B-Raf activity in an additive manner. These results indicate that not only Ras but also Rap1 is involved in the activation of the B-Raf-dependent MAP kinase cascade.
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PMID:Activation of brain B-Raf protein kinase by Rap1B small GTP-binding protein. 857 7

So far, treatment with anti-cancer agents has failed to achieve satisfactory results in hepatocellular carcinoma. In the process of hepatocarcinogenesis, ras has been shown to play a role. ras requires a farnesyl moiety for activation. It has been found that UCFI-C (manumycin), an antibiotic, inhibits farnesyl protein transferase, an enzyme that catalyzes farnesylation. Therefore, we investigated the effects of UCFI-C on cell growth, prenylation of cellular proteins including ras and Rapl, MAP kinase activity, activities of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and synthesis of cholesterol in a ras-activated human hepatoma cell line, Hep G2. Treatment with varying concentrations of UCF1-C(10-30 microM for 24 and 72 hr resulted in a time- and dose-dependent inhibition of cell numbers. 3H-Thymidine incorporation was also inhibited in a dose-dependent manner, with 50% inhibition after 44 hr being observed at a concentration of 17 microM. UCFI-C dose-dependently inhibited ras farnesylation and MAP kinase activity, but did not decrease Rap 1++ geranylgeranylation or prenylation of 21-to 26-kDa proteins. Neither the activities of 3-hydroxy-3-methylglutaryl-coenzyme A reductase nor cholesterol synthesis were inhibited. These results suggest that UCFI-C antagonizes the growth of Hep G2 via the suppression of ras farnesylation and could be a lead for the development of new anti-cancer agents blocking the function of oncogenic ras associated with human cancer, including hepatocellular carcinoma.
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PMID:Inhibition of cell growth of human hepatoma cell line (Hep G2) by a farnesyl protein transferase inhibitor: a preferential suppression of ras farnesylation. 859 13

Insulin, guanosine 5'-[gamma-thio]triphosphate (GTP[S] and phorbol 12-myristate 13-acetate (PMA) trigger the translocation of Gl UT4 (type 4 glucose transporter; insulin-sensitive glucose transporter) from an intracellular pool to the cell surface. We have developed a highly sensitive and quantitative method to detect GLUT4 immunologically on the surface of intact 3T3-L1 adipocytes and Chinese hamster ovary (CHO) cells, using c-myc epitope-tagged GLUT4 (GLUT4myc). We examined the roles of insulin, GTP[S] and PMA in the signalling pathways of GLUT4 translocation in the CHO cell system. Among small molecular GTP-binding proteins, ras, rab3D, rad and rho seem to be candidates as signal transmitters of insulin-stimulated GLUT4 translocation. Overexpression of wild-type H-ras and the dominant negative mutant H-rass17N in our cell system respectively enhanced and blocked insulin-stimulated activation of mitogen-activated protein kinase, but did not affect insulin-stimulated GLUT4 translocation. Overexpression of rab3D or rad in the cells did not affect GLUT4 translocation triggered by insulin, GTP[S] or PMA. Treatment with Botulinum C3 exoenzyme, a specific inhibitor of rho, had no effect on GLUT4 translocation induced by insulin, GTP[S] or PMA. Therefore these small molecular GTP-binding proteins are not likely to be involved in GLUT4 translocation. In addition, insulin, GTP[S] and PMA apparently stimulate GLUT4 translocation through independent pathways.
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PMID:Roles of insulin, guanosine 5'-[gamma-thio]triphosphate and phorbol 12-myristate 13-acetate in signalling pathways of GLUT4 translocation. 864 71

The refractoriness of prostate cancer to androgen suppression is the landmark of clinically aggressive disease. In this study, the androgen-dependent LNCaP prostate cancer cells were transfected with the mutated c-Ha-ras gene from the T24 human bladder cancer. The derivative clone overexpressing T24-ras (LNCaP(T24-ras)) proliferated in androgen-depleted medium and showed increased growth. Protein isoprenylation and p21ras farnesylation in LNCaP(T24-ras) cells were tested in the presence of phenylacetate to document a possible relationship with the drug-induced inhibition of cell proliferation. Phenylacetate is a differentiation inducer that down-regulates in vitro the expression of the myc oncogene and activates the human peroxisome proliferator-activated nuclear receptor involved in cell growth regulation. The drug inhibited protein isoprenylation and p21ras farnesylation in LNCaP(T24-ras) cells; IC50 values were 3.1 and 3.3 mM, respectively, compared with controls. The drug reduced the cellular levels of endogenous farnesyl-PP (mean IC50 = 3.5 mM) and inhibited activation of the p21ras downstream target, p42(MAPK)/ERK2. LNCaP(T24-ras) was more sensitive than the parental line to both growth inhibition (mean IC50 = 3.01 and 7.1 mM, respectively) and apoptosis by phenylacetate. Exogenous farnesyl- and geranylgeranyl-PP indeed reduced the effects of the drug on proliferation and apoptosis in LNCaP(T24-ras) cells. In conclusion, the inhibition of protein isoprenylation and p21ras farnesylation by phenylacetate resulted in increased chemosensitivity of the androgen-independent LNCaP(T24-ras) cells compared with LNCaP, and this effect might contribute to the pharmacological activity of the drug.
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PMID:Phenylacetate inhibits protein isoprenylation and growth of the androgen-independent LNCaP prostate cancer cells transfected with the T24 Ha-ras oncogene. 864 57

PAC-1, an early-response gene originally identified in activated T cells, encodes a dual-specificity mitogen-activated protein kinase phosphatase. Here we report on the regulation of PAC-1 expression in murine hemopoietic cells. PAC-1 mRNA levels rapidly increase in mitogen-stimulated lymphocytes, with the induced expression being transient in B cells but sustained in activated T cells. Transfection analysis of murine PAC-1 promoter-reporter constructs established that in T cells, sequences necessary for basal and induced transcription reside within a 200-bp region located immediately upstream of the transcription initiation sites. Basal transcription is regulated in part by an E-box element that binds a 53-kDa protein. PAC-1 transcription induced by phorbol myristate acetate stimulation and the expression of the v-ras or v-raf oncogene is mediated via the E-box motif and an AP-2-related site and coincides with increased binding activity of the constitutive 53-kDa E-box-binding protein and induced binding of AP-2. The ability of an interfering ERK-2 mutant to block phorbol myristate acetate and v-ras-dependent PAC-1 transcription indicates that mitogen-activated protein kinase activation is necessary for these stimuli to induce transcription of the PAC-1 gene in T cells.
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PMID:Activation of the mitogen-activated protein kinase pathway induces transcription of the PAC-1 phosphatase gene. 864 2

We and others recently generated mice with a targeted disruption of the insulin receptor substrate 1 (IRS-1) gene and demonstrated that they exhibited growth retardation and had resistance to the glucose-lowering effect of insulin. Insulin initiates its biological effects by activating at least two major signalling pathways, one involving phosphatidylinositol 3-kinase (PI3-kinase) and the other involving a ras/mitogen-activated protein kinase (MAP kinase) cascade. In this study, we investigated the roles of IRS-1 and IRS-2 in the biological action in the physiological target organs of insulin by comparing the effects of insulin in wild-type and IRS-1-deficient mice. In muscles from IRS-1-deficient mice, the responses to insulin-induced PI3-kinase activation, glucose transport, p70 S6 kinase and MAP kinase activation, mRNA translation, and protein synthesis were significantly impaired compared with those in wild-type mice. Insulin-induced protein synthesis was both wortmannin sensitive and insensitive in wild-type and IRS-1 deficient mice. However, in another target organ, the liver, the responses to insulin-induced PI3-kinase and MAP kinase activation were not significantly reduced. The amount of tyrosine-phosphorylated IRS-2 (in IRS-1-deficient mice) was roughly equal to that of IRS-1 (in wild-type mice) in the liver, whereas it only 20 to 30% of that of IRS-1 in the muscles. In conclusion, (i) IRS-1 plays central roles in two major biological actions of insulin in muscles, glucose transport and protein synthesis; (ii) the insulin resistance of IRS-1-deficient mice is mainly due to resistance in the muscles; and (iii) the degree of compensation for IRS-1 deficiency appears to be correlated with the amount of tyrosine-phosphorylated IRS-2 (in IRS-1-deficient mice) relative to that of IRS-1 (in wild-type mice).
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PMID:Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice. 864 19

We have studied the signaling pathways responsible for the monocytic and/or megakaryocytic differentiation of K562 cells. The results demonstrated that although the mitogen-activated protein kinase (MAPK) was activated during the phorbol myristate acetate (PMA)-induced monocytic and/or megakaryocytic differentiation of K562 cells, the overexpression of Ha-ras which can activate the MAPK did not induce the monocytic and/or megakaryocytic differentiation of K562 cells. Instead PMA-induced megakaryocytic differentiation of K562 cells was inhibited by the pretreatment of pyrrolidine dithiocarbamate, a specific nuclear factor kappaB (NF-kappaB) inhibitor. Taken together, these results suggest that the activation of NF-kappaB rather than that of MAPK might be involved in the PMA-induced megakaryocytic differentiation of K562 cells.
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PMID:Signaling mechanism of PMA-induced differentiation of K562 cells. 866 Mar 51

In cultured rat vascular smooth muscle cells, angiotensin II (Ang II) induced a rapid increase in mitogen-activated protein kinase (MAPK) activity through the Ang II type 1 receptor, which was insensitive to pertussis toxin but was abolished by the phospholipase C inhibitor, U73122. The Ang II-induced MAPK activation was not affected by the protein kinase C inhibitor, GF109203X, and was only partially impaired by pretreatment with a phorbol ester, whereas both treatments completely prevented MAPK activation by the phorbol ester. Intracellular Ca2+ chelation by TMB-8, but not extracellular Ca2+ chelation or inhibition of Ca2+ influx, abolished Ang II-induced MAPK activation. The calmodulin inhibitor, calmidazolium, and the tyrosine kinase inhibitor, genistein, completely blocked MAPK activation by Ang II as well as by the Ca2+ ionophore A23187. Ang II caused a rapid increase in the binding of GTP to p21(ras), and this was inhibited by genistein, TMB-8, and calmidazolium but not by pertussis toxin or GF109203X. These data suggest that Ang II-induced MAPK activation through the Ang II type 1 receptor could be mediated by p21(ras)activation through a currently unidentified tyrosine kinase that lies downstream of Gq-coupled Ca2+/calmodulin signals.
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PMID:Identification of an essential signaling cascade for mitogen-activated protein kinase activation by angiotensin II in cultured rat vascular smooth muscle cells. Possible requirement of Gq-mediated p21ras activation coupled to a Ca2+/calmodulin-sensitive tyrosine kinase. 866 12

We have recently purified a Ki-Ras- and Ha-Ras-dependent extracellular signal-regulated kinase kinase from bovine brain and identified it as B-Raf protein kinase complexed with 14-3-3 proteins (Yamamori, B., Kuroda, S., Shimizu, K., Fukui, K., Ohtsuka, T., and Takai, Y. (1995) J. Biol. Chem. 270, 11723-11726). Moreover, we found that Rap1B as well as Ki-Ras and Ha-Ras stimulate the B-Raf activity. Since B-Raf contains a cysteine-rich domain originally found in protein kinase C as a domain responsible for interaction with phosphatidylserine (PS) and diacylglycerol or 12-O-tetradecanoylphorbol-13-acetate, we have examined here the effect of these compounds on the Ki-Ras-, Ha-Ras-, and Rap1B-induced activation of bovine brain B-Raf. Bovine brain PS enhanced Ki-Ras-stimulated B-Raf activity. Phosphatidic acid was slightly active, but other phospholipids, such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol (PI), PI-4-monophosphate, PI-4,5-bisphosphate, and PI-3,4,5-trisphosphate, were inactive. However, none of the above phospholipids affected the Ha-Ras-stimulated B-Raf activity, whereas PI, PS, phosphatidylethanolamine, and phosphatidic acid inhibited the Rap1B-stimulated B-Raf activity. Phosphatidylcholine or PI-4-monophosphate did not show any effect on the Rap1B-stimulated B-Raf activity. Synthetic PS with two unsaturated fatty acids, such as 1,2-dioleoyl-PS or 1,2-dilinoleoyl-PS, showed the same effect toward the Ki-Ras- and Rap1B-stimulated B-Raf activities, but synthetic PS with two saturated fatty acids, such as 1, 2-distearoyl-PS, was inactive. 12-O-Tetradecanoylphorbol-13-acetate did not affect the stimulatory or inhibitory effect of PS on the Ki-Ras- and Rap1B-stimulated B-Raf activities, respectively. PS did not affect the Ki-Ras-, Ha-Ras-, or Rap1B-independent basal B-Raf activity or the mitogen-activated protein kinase kinase or extracellular signal-regulated kinase activity. These results indicate that various phospholipids differently affect Ki-Ras-, Ha-Ras, and Rap1B-induced B-Raf activation.
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PMID:Different effects of various phospholipids on Ki-Ras-, Ha-Ras-, and Rap1B-induced B-Raf activation. 866 12


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