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

In the present study, we describe that ginsenoside-Rg1 (G-Rg1) stimulates the proliferation of cultured human hepatoma SK-HEP-1 cells. The incorporation of [3H] thymidine into DNA was increased in the cells in response to G-Rg1. The stimulatory effect of G-Rg1 on DNA synthesis in SK-HEP-1 cells require newly synthesized proteins, since cycloheximide blocked the DNA synthetic activity stimulated with G-Rg1. Thus, we examined whether G-Rg1 induces the intracellular protein levels of regulatory proteins for cell cycle progression using immunoblottings. The results from immunoblottings showed that G-Rg1 induced the levels of cyclin E and cdk2 proteins in the cells. Furthermore, the results from immuno-complex kinase assays for cyclin E-dependent kinase showed that G-Rg1 up-regulates the kinase activity in a dose-dependent manner. These results suggest that G-Rg1 stimulates cell-growth of SK-HEP-1 cells by inducing the intracellular levels of cyclin E/cdk2 complex, which in turn up-regulates cyclin E-dependent kinase activity.
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PMID:Ginsenoside-Rg1 positively regulates cyclin E-dependent kinase activity in human hepatoma SK-HEP-1 cells. 882 5

The mechanism of action by which ginsenoside-Rh2 (G-Rh2) suppresses the proliferation of SK-HEP-1 cells is reported. The results from flow cytometric analyses show that G-Rh2 arrested the cell cycle at the G1/S transition phase. The cyclin E-dependent kinase activity which had been immunoprecipitated with cyclin E-specific antibody was down-regulated in the cells in response to G-Rh2. The IC50 value required to down-regulate the kinase activity by 50% was approximately 0.75 microM. Immunoblotting analyses show that G-Rh2 selectively induced the expression of p27kip1 in a dose-dependent manner whereas it had no effect on the levels of cyclin E, cdk2, and p21WAF1. In addition, our data show that G-Rh2 reduced the protein levels of cdc25A at doses higher than 10 microM. Collectively, these data suggest that ginsenoside-Rh2 arrests the cell cycle at the G1/S transition phase by selectively inducing protein expression of p27Kip1 and, as a consequence, down-regulating cyclin E-dependent kinase activity.
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PMID:Ginsenoside-Rh2 blocks the cell cycle of SK-HEP-1 cells at the G1/S boundary by selectively inducing the protein expression of p27kip1. 901 1

In the present study, we show that aloesin, which is a low molecular weight ingredients present in Aloe vera, stimulates the proliferation of cultured human hepatoma SK-HEP-1 cells. The incorporation of [3H] thymidine into DNA in the cell cultures was significantly increased at a dose of 10 microM aloesin. The aloesin-induced DNA synthesis appears to require newly synthesized proteins because cycloheximide treatment blocked the DNA synthesis evoked by this compound. We then examined whether this compound increases the intracellular levels of cell cycle regulators by immunoblotting. The data showed that aloesin increased the levels of cyclin E, CDK2, and CDC25A in SK-HEP-1 cells. In addition, immuno-complex kinase assays showed that aloesin up-regulated the enzyme activity of cyclin E/CDK2 kinase in a dose-dependent manner. Collectively, these results suggest that aloesin stimulates the proliferation of SK-HEP-1 cells by inducing the intracellular levels of cyclin E/CDK2 kinase complex and CDC25A, which, together, result in the up-regulation of cyclin E-dependent kinase activity.
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PMID:Aloesin up-regulates cyclin E/CDK2 kinase activity via inducing the protein levels of cyclin E, CDK2, and CDC25A in SK-HEP-1 cells. 906 68

In the present study, we report that ginsenoside-Rg5 (G-Rg5), a newly discovered diol-containing ginsenoside, blocks the cell cycle of human hepatoma SK-HEP-1 cells via the down-regulation of cyclin E-dependent kinase activity. The results from flow cytometric analyses show that G-Rg5 arrests the cell cycle of SK-HEP-1 cells at the Gl/S transition phase. The cyclin E-dependent kinase activity that has been immunoprecipitated with cyclin E-specific antibody is down-regulated in response to G-Rg5. The results from immunoblottings show that the down-regulation of cyclin E-dependent kinase activity is related to increased protein levels of p21Cip/WAF1 and to decreased protein levels of cyclin E, CDK2, and CDC25A. Collectively, these data suggest that G-Rg5 blocks cell cycle of SK-HEP-1 cells at the Gl/S transition phase by down-regulating cyclin E-dependent kinase activity and that the down-regulation of cyclin E-dependent kinase activity is caused mainly by induced CDK2 inhibitor, p21Cip/WAF1 and decreased levels of cyclin E.
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PMID:Ginsenoside-Rg5 suppresses cyclin E-dependent protein kinase activity via up-regulating p21Cip/WAF1 and down-regulating cyclin E in SK-HEP-1 cells. 913 50

In situ duct carcinoma (DCIS) is a heterogeneous group of lesions which has recently been subdivided into three types: well-differentiated (type I), intermediately differentiated (type II) and poorly differentiated (type III) DCIS. Fourteen cases of DCIS and 11 of DCIS with minimal invasion were analysed for mRNA levels of beta-actin, EGFR, c-cerbB2, MTS1, k-ras, RB, BRCA1, cyclin E, and c-myc genes. A microdissection technique was used on paraffin-embedded tissue. A statistically significantly higher expression of cyclin E oncogene and MTS1 tumor suppressor gene was seen in type III DCIS than in the other types, while no significant differences in the mRNA expression patterns of the other genes were observed. These data are consistent with the fact that poorly differentiated DCIS is a readily recognizable class of tumours that have a particularly aggressive behaviour and probably unique histogenesis.
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PMID:Molecular characterization of intraductal breast carcinomas. 950 54

We have previously reported that certain tyrphostins which block EGF-R phosphorylation in cell-free systems fail to do so in intact cells. Nevertheless, we found that this family of tyrphostins inhibits both EGF- and calf serum-induced cell growth and DNA synthesis [Osherov, N.A., Gazit, C., Gilon, and Levitzki, A. (1993). Selective inhibition of the EGF and HER2/Neu receptors by Tyrphostins. J. Biol. Chem. 268, 11134-11142.] Now we show that these tyrphostins exert their inhibitory activity even when added at a time when the cells have already passed their restriction point and receptor activation is no longer necessary. AG555 and AG556 arrest 85% of the cells at late G1, whereas AG490 and AG494 cause cells to arrest at late G1 and during S phase. No arrest occurs during G2 or M phase. Further analysis revealed that these tyrphostins act by inhibiting the activation of the enzyme Cdk2 without affecting its levels or its intrinsic kinase activity. Furthermore, they do not alter the association of Cdk2 to cyclin E or cyclin A or to the inhibitory proteins p21 and p27. These compounds also have no effect on the activating phosphorylation of Cdk2 by Cdk2 activating kinase (CAK) and no effect on the catalytic domain of cdc25 phosphatase. These compounds lead to the accumulation of phosphorylated Cdk2 on tyrosine 15 which is most probably the cause for its inhibition leading to cell cycle arrest at G1/S. A structure-activity relationship study defines a very precise pharmacophore, suggesting a unique molecular target not yet identified and which is most probably involved in the regulation of the tyrosine-phosphorylated state of Cdk2. These compounds represent a new class of cell proliferation blockers whose target is Cdk2 activation.
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PMID:Inhibition of Cdk2 activation by selected tyrphostins causes cell cycle arrest at late G1 and S phase. 963 76

A new cancer cell line (KKP) was established from an ascitic effusion of an advanced gastric adenocarcinoma, intestinal type. The line has been maintained in continuous monolayer culture with a doubling time of 48 hours for more than 2 years. KKP cells, whose ultrastructural features are presented, showed an aneuploid DNA content, a modal number of 53 chromosomes, and the presence of one double minute chromosome. The karyotype showed trisomies of chromosomes 7, 12, 13, and 14, tetrasomy of chromosome 18, a reciprocal translocation [t(1;20)(q21;p11.2)], and a [t(4;?)] rearrangement. No amplification or rearrangements were evident in the c-MYC, c-ERB B2, H-RAS, INT-2, HST-1, c-MOS, and K-RAS genes, whereas somatic rearrangements were present in the sequences corresponding to c-MET and cyclin E genes by Southern blotting analysis. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis of P53 and RB genes did not reveal alterations or point mutations in the SSCP pattern of conformers. The chemosensitivity pattern assay of the KKP cell line indicated that it was sensitive to cisplatin, etoposide, and doxorubicin and resistant to 4'-hydroperoxycyclophosphamide. The clinical history of the patient from whom the cell line was derived is reported and compared with the results observed in the cell line in vitro. High levels of the tumor-associated antigens CEA (carcinoembryonic antigen) and CA19-9 were evident in the KKP cytosol, whereas the KKP spent culture medium maintained the same low levels of CEA and CA 19-9 found in the patient's serum. This new cell line may represent a useful tool for studying the biology of gastric cancer and for planning new therapeutic approaches.
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PMID:Molecular genetics and in vitro sensitivity of a new human cell line, KKP, from a gastric adenocarcinoma. 968 29

AIDS-associated Kaposi's sarcoma (KS) cell, a key element for development of KS lesions, proliferates in response to external cytokines, such as oncostatin M, the soluble IL-6R-IL-6 complex, TNF-alpha, and IL-1beta. In addition, the KS cell-produced basic fibroblast growth factor (bFGF) was reported to function as an autocrine growth factor. However, little is known of the exact roles of these external growth factors and endogenous bFGF on proliferation of KS cells, and underlying intracellular events have remained to be defined. We obtained evidence that anti-bFGF Ab abolished growth of KS cells by preventing S phase entry of the cell cycle, even in the presence of the external growth factors. Blockade of the FGF action profoundly inhibited cyclin E expression and cyclin-dependent kinase-2 (CDK2) activity, but not D-type cyclin expression and CDK4 activity. Exogenously added acidic FGF (aFGF), which generated a rapid tyrosine phosphorylation of FGFR1 and FGFR2 on KS cells, reversed the inhibitory effects of anti-bFGF Ab. Thus, FGF actions are essential for cyclin E-CDK2 activity and S phase entry. We also observed that the presence of external growth factors markedly induced cyclin E-CDK2 activity and S phase entrance, while the addition of aFGF or bFGF alone was insufficient to induce these responses. All this evidence shows that integration of the activities of external growth factors and endogenous bFGF is required for full activation of cyclin E-CDK2 activity and KS cell proliferation.
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PMID:Endogenous basic fibroblast growth factor is essential for cyclin E-CDK2 activity in multiple external cytokine-induced proliferation of AIDS-associated Kaposi's sarcoma cells: dual control of AIDS-associated Kaposi's sarcoma cell growth and cyclin E-CDK2 activity by endogenous and external signals. 971 33

Adherent cells assemble fibronectin into a fibrillar matrix on their apical surface. The fibril formation is initiated by fibronectin binding to the integrins alpha5 beta1 and alphav beta3, and is completed by a process that includes fibronectin self-assembly. We found that a 76- amino acid fragment of fibronectin (III1-C) that forms one of the self-assembly sites caused disassembly of preformed fibronectin matrix without affecting cell adhesion. Treating attached fibroblasts or endothelial cells with III1-C inhibited cell migration and proliferation. Rho-dependent stress fiber formation and Rho-dependent focal contact protein phosphorylation were also inhibited, whereas Cdc42 was activated, leading to actin polymerization into filopodia. ACK (activated Cdc42-binding kinase) and p38 MAPK (mitogen-activated protein kinase), two downstream effectors of Cdc42, were activated, whereas PAK (p21-activated kinase) and JNK/SAPK (c-Jun NH2-terminal kinase/ stress-activated protein kinase) were inhibited. III1-C treatment also modulated activation of JNK and ERK (extracellular signal-regulated kinases) in response to growth factors, and reduced the activity of the cyclin E-cdk2 complex. These results indicate that the absence of fibronectin matrix causes activation of Cdc42, and that fibronectin matrix is required for Rho activation and cell cycle progression.
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PMID:Fibronectin matrix regulates activation of RHO and CDC42 GTPases and cell cycle progression. 976 37

During late stages of breast cancer progression, tumors frequently acquire steroid hormone resistance with concurrent amplification of growth factor receptors; this alteration predicts a poor prognosis. We show here that following treatment with the progestin, R5020, breast cancer cells undergo a "biochemical shift" in the regulation of epidermal growth factor (EGF)-stimulated signaling pathways: R5020 potentiates the effects of EGF by up-regulating EGFR, c-ErbB2 and c-ErbB3 receptors, and by enhancing EGF-stimulated tyrosine phosphorylation of signaling molecules known to associate with activated type I receptors. Independently of EGF, R5020 increases Stat5 protein levels, association of Stat5 with phosphotyrosine-containing proteins, and tyrosine phosphorylation of JAK2 and Shc. Furthermore, progestins "prime" breast cancer cells for growth signals by potentiating EGF-stimulated p42/p44 mitogen-activated protein kinase (MAPK), p38 MAP kinase, and JNK activities. Although the levels of cyclin D1, cyclin E, and p21(WAF1), are up-regulated by R5020 alone, they are synergistically up-regulated by EGF in the presence of R5020. Up-regulation of cell cycle proteins by EGF is blocked by inhibition of p42/p44 MAPK only in the presence of R5020, supporting a shift in the regulation of these cell cycle mediators from MAPK-independent to MAPK-dependent pathways. In summary, progesterone selectively increases the sensitivity of key kinase cascades to growth factors, thereby priming cells for stimulation by latent growth signals. These data support a model in which breast cancer cell growth switches from steroid hormone to growth factor dependence.
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PMID:Convergence of progesterone and epidermal growth factor signaling in breast cancer. Potentiation of mitogen-activated protein kinase pathways. 981 39


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