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)

We have previously reported that apigenin inhibits the growth of thyroid cancer cells by attenuating epidermal growth factor receptor (EGF-R) tyrosine phosphorylation and phosphorylation of ERK mitogen-activated protein (MAP) kinase. In this study, we assessed the growth inhibitory effect of apigenin on MCF-7 breast carcinoma cells that express two key cell cycle regulators, wild-type p53 and the retinoblastoma tumor suppressor protein (Rb), and MDA-MB-468 breast carcinoma cells that are mutant for p53 and Rb negative. We found that apigenin potently inhibited growth of both MCF-7 and MDA-MB-468 breast carcinoma cells. The approximate IC50 values determined after 3 days incubation, were 7.8 micrograms/ml for MCF-7 cells, and 8.9 micrograms/ml for MDA-MB-468 cells, respectively. Because the cell cycle studies using FACS showed that both MCF-7 and MDA-MB-468 cells were arrested in G2/M phase after apigenin treatment, we studied the effects of apigenin on cell cycle regulatory molecules. We observed that G2/M arrest by apigenin involved a significant decrease in cyclin B1 and CDK1 protein levels, resulting in a marked inhibition of CDK1 kinase activity. Apigenin reduced the protein levels of CDK4, cyclins D1 and A, but did not affect cyclin E, CDK2 and CDK6 protein expression. In MCF-7 cells, apigenin markedly reduced Rb phosphorylation after 12 h. We also found that apigenin treatment resulted in a dose- and time-dependent inhibition of ERK MAP kinase phosphorylation and activation in MDA-MB-468 cells. These results suggest that apigenin is a promising antibreast cancer agent and its growth inhibitory effects are mediated by targeting different signal transduction pathways in MCF-7 and MDA-MB-468 breast carcinoma cells.
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PMID:Apigenin inhibits growth and induces G2/M arrest by modulating cyclin-CDK regulators and ERK MAP kinase activation in breast carcinoma cells. 1129 71

Fibroblast growth factor (FGF) and its receptor (FGFR) are thought to be negative regulators of chondrocytic growth, as exemplified by achondroplasia and related chondrodysplasias, which are caused by constitutively active mutations in FGFR3. To understand the growth-inhibitory mechanisms of FGF, we analyzed the effects of FGF2 on cell cycle-regulating molecules in chondrocytes. FGF2 dramatically inhibited proliferation of rat chondrosarcoma (RCS) cells and arrested their cell cycle at the G(1) phase. FGF2 increased p21 expression in RCS cells, which assembled with the cyclin E-Cdk2 complexes, although the expression of neither cyclin E nor Cdk2 increased. In addition, the kinase activity of immunoprecipitated cyclin E or Cdk2, assessed with retinoblastoma protein (pRb) as substrate, was dramatically reduced by FGF-2. Moreover, FGF2 shifted pRb to its underphosphorylated, active form in RCS cells. FGF2 not only induced p21 protein expression in proliferating chondrocytes in mouse fetal limbs cultured in vitro but also decreased their proliferation as assessed by the expression of histone H4 mRNA, a marker for cells in S phase. Furthermore, inhibitory effects of FGF2 on chondrocytic proliferation were partially reduced in p21-null limbs, compared with those in wild-type limbs in vitro. Taken together, FGF's growth inhibitory effects of chondrocytes appear to be mediated at least partially through p21 induction and the subsequent inactivation of cyclin E-Cdk2 and activation of pRb.
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PMID:Fibroblast growth factor inhibits chondrocytic growth through induction of p21 and subsequent inactivation of cyclin E-Cdk2. 1138 71

Viral DNA replication is generally dependent upon circumventing host cell cycle control to force S phase entry in an otherwise quiescent cell. Here we describe novel attributes of the cyclin encoded by Human Herpesvirus 8 (K cyclin) that enable it to subvert the quiescent state. K cyclin is most similar to the mammalian D-type cyclins in primary sequence but displays properties more akin to those of cyclin E. K cyclin (like cyclin E) can autonomously couple with its cognate cdk subunit and localize to the nucleus. D-type cyclins require mitogen stimulated accessory factors (such as p21(Cip1) and p27(Kip1)) to facilitate both of these processes. A striking difference between K cyclin and mammalian cyclins is that K cyclin binding to cdk6 can substantially activate the catalytic activity of the complex without the requirement for cyclin H/cdk7 phosphorylation of the cdk T-loop; this phosphorylation is obligatory for endogenous cyclin/cdk activity. However, K cyclin/cdk6 complexes are not totally immune from cell cycle control since CAK phosphorylation is necessary for complete activation. Thus, CAK phosphorylated K cyclin/cdk6 targets multiple sites in the retinoblastoma protein (pRb) whereas the unphosphorylated complex targets a single site. The restricted substrate specificity of the non-CAK phosphorylated K cyclin/cdk6 complex is insufficient to enable K cyclin-mediated S phase entry. Thus, the viral K cyclin is reliant upon endogenous CAK activity to subvert the quiescent state.
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PMID:Novel properties of the cyclin encoded by Human Herpesvirus 8 that facilitate exit from quiescence. 1142 81

Hepatocyte growth factor (HGF) induces growth stimulation of a variety of cell types, but it also induces growth inhibition of several types of tumor cell lines. The molecular mechanism of the HGF-induced growth inhibition of tumor cells remains obscure. We have investigated the intracellular signaling pathway involved in the antiproliferative effect of HGF on the human hepatocellular carcinoma cell line HepG2. HGF induced strong activation of ERK in HepG2 cells. Although the serum-dependent proliferation of HepG2 cells was inhibited by the MEK inhibitor PD98059 in a dose-dependent manner, 10 microM PD98059 reduced the HGF-induced strong activation of ERK to a weak activation; and as a result, the proliferation inhibited by HGF was completely restored. Above or below this specific concentration, the restoration was incomplete. Expression of constitutively activated Ha-Ras, which induces strong activation of ERK, led to the proliferation inhibition of HepG2 cells, as was observed in HGF-treated HepG2 cells. This inhibition was suppressed by the MEK inhibitor. Furthermore, HGF treatment and expression of constitutively activated Ha-Ras changed the hyperphosphorylated form of the retinoblastoma tumor suppressor gene product pRb to the hypophosphorylated form. This change was inhibited by the same concentration of MEK inhibitor needed to suppress the proliferation inhibition. These results suggest that ERK activity is required for both the stimulation and inhibition of proliferation of HepG2 cells; that the level of ERK activity determines the opposing proliferation responses; and that HGF-induced proliferation inhibition is caused by cell cycle arrest, which results from pRb being maintained in its active hypophosphorylated form via a high-intensity ERK signal in HepG2 cells.
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PMID:High intensity ERK signal mediates hepatocyte growth factor-induced proliferation inhibition of the human hepatocellular carcinoma cell line HepG2. 1153 45

Vitamin E-succinate (VES) induced HL-60 human leukemia cells to undergo apoptosis. Treatment with VES induced membrane translocation of Fas; cleavages of caspase-3, PARP, and lamin B; hypophosphorylation of retinoblastoma protein; and increase of p21(WAF1) protein level. During the induction of apoptosis, activity of PKC was gradually increased with downregulation of VES-induced ERK activity and accompanied by activation of caspase-3. Inhibition of PKC by GF109203X blocked VES-mediated membrane translocation of PKC-alpha and cleavage of caspase-3 cascade, resulting in prevention of VES-induced apoptosis. On the contrary, PKC activation by cotreatment with LPC or thapsigargin and VES synergistically increased VES-mediated apoptosis. However, inhibition of ERK activity by PD98059 showed no significant effect on VES-induced PKC activity and apoptosis. Taken together, our data suggest that VES induces activation of PKC and PKC-dependent hypophosphorylation of retinoblastoma protein, which results in induction of apoptosis, and that VES-induced early activation of ERK and ERK-dependent induction of p21(WAF1) are not required for apoptosis.
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PMID:Activation of PKC but not of ERK is required for vitamin E-succinate-induced apoptosis of HL-60 cells. 1168 77

Synucleins are small, highly conserved proteins in vertebrates, especially abundant in neurons and typically enriched in presynaptic terminals. alpha-Synuclein protein and a fragment of it, called NAC, have been found in association with pathological lesions of neurodegenerative diseases. Recently, mutations in a alpha-synuclein gene have been reported in families susceptible to an inherited form of Parkinson's diseases. In addition, alpha-synuclein has been implicated in the pathophysiology of other neurodegenerative diseases, including Alzheimer's disease and multiple system atrophy. Far less is known about other members of the synuclein family, beta- and gamma-synucleins. gamma-synuclein is up-regulated in several types of cancer and may affect the integrity of the neurofilament network, while its bovine ortholog, synoretin, activates the Elk-1 signal transduction pathway. In this paper, we present data about the localization and properties of human and bovine gamma-synuclein in several neuronal and non-neuronal cell cultures derived from ocular tissues. We show that gamma-synuclein is present in the perinuclear area and is localized to centrosomes in several types of human interphase cells and in bovine retinal pigment epithelium. In mitotic cells, gamma-synuclein staining is localized to the poles of the spindle. Further, overexpression of synoretin in retinoblastoma cells up-regulates MAPK and Elk-1. These results support the view that gamma-synuclein is a centrosome protein that may be involved in signal transduction pathways.
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PMID:Gamma synuclein: subcellular localization in neuronal and non-neuronal cells and effect on signal transduction. 1174 66

The retinoblastoma (Rb) tumor suppressor controls cellular proliferation, survival, and differentiation and is functionally inactivated by mutations or hyperphosphorylation in most human cancers. Although activation of endogenous Rb is thought to provide an effective approach to suppress cell proliferation, long-term inhibition of apoptosis by active Rb may have detrimental consequences in vivo. To directly test these paradigms, we targeted phosphorylation-resistant constitutively active Rb alleles, Rb Delta Ks, to the mouse mammary gland. Pubescent transgenic females displayed reduced ductal elongation and cell proliferation at the endbuds. Post-puberty transgenic mice exhibited precocious cellular differentiation and beta-casein expression and extended survival of the mammary epithelium with a moderate but specific effect on the expression of E2F1, IGF1R alpha, and phospho-protein kinase B/AKT. Remarkably, approximately 30% Rb Delta K transgenic females developed focal hyperplastic nodules, and approximately 7% exhibited full-blown mammary adenocarcinomas within 15 mo. Expression of the Rb Delta K transgene in these mammary tumors was reduced greatly. Our results suggest that transient activation of Rb induces cancer by extending cell survival and that the dual effects of Rb on cell proliferation and apoptosis impose an inherent caveat to the use of the Rb pathway for long-term cancer therapy.
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PMID:Activation of retinoblastoma protein in mammary gland leads to ductal growth suppression, precocious differentiation, and adenocarcinoma. 1177 37

Novel classes of drug that interfere with the signalling of the small G-protein Ras, the so-called Ras antagonists, are showing much promise as novel anti-cancer agents. In this study, we demonstrate that the novel Ras antagonist farnesylthiosalicylic acid (FTS) inhibits the growth of Colo 853 melanoma cells through a combination of cytostatic and pro-apoptotic effects. Furthermore, these phenomena are seen under conditions of cell attachment and in the presence of serum. Treatment of Colo 853 cells with FTS led to time-dependent inhibition of constitutive Akt, retinoblastoma protein (pRB) and ERK activity, with a concurrent loss of Akt expression. Inhibition of Akt and ERK activity induces apoptosis in other human cancer cell lines. Here it is demonstrated that inhibition of Akt, or ERK and Akt in combination, leads to cell cycle arrest but not apoptosis in melanoma cells. FTS treatment was also found to upregulate activity of the stress-activated p38 MAP kinase. Inhibition of p38 MAP kinase, using the selective inhibitor SB 203580, followed by FTS treatment, significantly increased the proportion of apoptotic cells after 72 hr, possibly suggesting a modulatory role for p38 MAP kinase in FTS-induced melanoma cell apoptosis.
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PMID:Farnesyl thiosalicylic acid inhibits the growth of melanoma cells through a combination of cytostatic and pro-apoptotic effects. 1192 Jun 10

The adhesion molecule CEACAM1 (CD66a, BGP, C-CAM) is not only involved in maintaining normal tissue architecture, but also acts as a tumor suppressor in several experimental systems where loss of CEACAM1 expression results in enhanced tumor-cell growth and tumorigenicity. In order to further analyze the role of CEACAM1 in the development of breast cancer, we performed Western-blot analysis and immunohistochemistry with highly specific monoclonal antibodies in a cohort of 68 mammary carcinomas which had also been analyzed for expression of cell-cycle regulatory proteins cyclin D1, cyclin E, p16, p21, p27, Rb, and Rb2, as well as for steroid hormone receptor status, Ki67, and HER2/neu immunoreactivity. High CEACAM1 protein expression as found using both methods correlated significantly with expression of the retinoblastoma proteins Rb (P=0.004 and 0.013) and Rb2/p130 (P=0.003 and 0.007). In addition, we found a weak association of CEACAM1 expression with p27 protein levels (P=0.087 and 0.039), but with none of the other analyzed parameters. These results indicate the possibility of a functional link between cell-adhesion molecules and cell-cycle regulation that might play an important role in the development of mammary carcinomas.
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PMID:Expression of the adhesion molecule CEACAM1 (CD66a, BGP, C-CAM) in breast cancer is associated with the expression of the tumor-suppressor genes Rb, Rb2, and p27. 1196 43

Neuroblastoma is a neural crest-derived tumor of childhood with a serious prognosis; only 20% of patients with stage 4 disease survive 5 years from diagnosis. Mechanisms involved in neuroblastoma development are unclear, but the engagement of many neuroblastoma-related gene(s) is suggested by specific chromosomal alterations. Most prominent among these is the amplification of the MYCN oncogene and the deletion of the 1p36 region. Other genetic aberrations have been discovered over the years such as deletions of 11q and 14q and gain of 17q. Although tumor aggressiveness greatly depends on the most frequent genetic abnormalities, to date no neuroblastoma-related gene has been discovered. Neuroblastoma usually occurs sporadically, but 1.5% of all diagnosed cases show familial recurrence with an autosomal dominant inheritance and incomplete penetrance. A comparison between hereditary and sporadic neuroblastomas led Knudson and Strong to gather that the two-hit hypothesis, proposed for retinoblastoma, could be applied to neuroblastoma. To determine if the 1p36 region harbors a predisposition gene for familial neuroblastoma, we carried out linkage analysis at 1p36 loci in two families with recurrent neuroblastoma. Similarly, we analyzed loci of chromosome 16, where a predisposition locus was recently mapped. We also analyzed markers located close to several candidate genes (RET, NF1, GDNF, GFRA1, EDNRB, and EDN3) involved to a different extent in other neurocristopathies. Our findings indicate that the candidate chromosomal regions and genes analyzed are not in linkage with neuroblastoma.
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PMID:Linkage analysis in families with recurrent neuroblastoma. 1209 31


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