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)

There is little information regarding the molecular mechanisms of hepatocarcinogenesis. We studied the p53 gene at the DNA, RNA, and protein level in seven human hepatocellular carcinoma (HCC)-derived cell lines; six of seven showed p53 abnormalities. By Southern blotting, the p53 gene was found to be partially deleted in Hep 3B and rearranged in SK-HEP-1 cells. Transcripts of the p53 gene were undetectable in Hep 3B as well as in FOCUS cells that had no apparent deletion or rearrangement of the p53 gene. Immunoprecipitation after [35S]methionine labeling of HCC cells demonstrated that p53 protein was absent in Hep 3B and FOCUS and reduced in concentration in PLC/PRF/5 cells. p53 synthesized by Mahlavu cells showed a slower migration on SDS/polyacrylamide gels suggesting it was an abnormal protein. In Huh7 cells, p53 protein had a prolonged half-life leading to its accumulation in the nuclei; increased levels of p53 protein were also found by immunoblotting. The p53 gene and its expression appeared to be unaltered in the hepatoblastoma-derived Hep G2 cell line. We found that the loss of p53 expression did not occur as a late in vitro event in the FOCUS cell line because p53 protein was also nondetectable at an early passage. We conclude that the loss of p53 expression or the presence of abnormal forms of the protein are frequently associated with HCC cell lines. These observations suggest that alterations in p53 may be important events in the transformation of hepatocytes to the malignant phenotype.
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PMID:Abnormal structure and expression of p53 gene in human hepatocellular carcinoma. 215 27

A new endothelial cell growth factor (f-ECGF) was partially purified from the cultured medium of human fibroblast cells of embryonic lungs. The partially purified f-ECGF induced neovascularization in rabbit cornea. It showed a selective growth stimulatory activity on the endothelial cells in vitro, whereas acidic- and basic-fibroblast growth factors (a- and b-FGFs) showed a broad spectrum of growth stimulation among tissues or cells. f-ECGF did not compete with the binding of a-FGF to the cell surface receptor in HEP-G2 hepatoblastoma cell lines. These results indicated that f-ECGF is a new endothelial cell growth factor distinct from a- and b-FGFs which are known to be potent endothelial cell growth factors.
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PMID:Characterization of a new endothelial cell growth factor (f-ECGF) partially purified from the supernatant of human fibroblast cells. 248 61

Insulin-like growth factors (IGF's) circulate in blood complexed to specific carrier proteins. The BRL 3A and BRL 3A2 rat liver cell lines secrete a 30,000-50,000 mol wt IGF carrier protein. Since the liver parenchymal cell is a likely source of IGF carrier protein synthesis, we have evaluated medium conditioned by three human hepatocellular carcinoma- or hepatoblastoma-derived cell lines for the presence of IGF carrier protein. The HEP G2 and the HEP 3B, but not the PLC/PRF/5, cell lines secrete a specific IGF carrier protein(s) into serum-free medium. This carrier protein is specific for IGF molecules. Multiplication-stimulating activity, IGF I, and IGF II were equipotent in competing for the binding of [125I]multiplication-stimulating activity to HEP G2 medium. The HEP G2 IGF carrier protein is trypsin sensitive, acid stabile, and does not contain a glycoprotein moiety. It has a molecular size of 30,000-50,000, as assessed by Sephadex G-200 gel filtration. These studies suggest that the HEP G2 cell line is a useful model to study the synthesis and secretion of human IGF carrier protein.
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PMID:Demonstration that a human hepatoma cell line produces a specific insulin-like growth factor carrier protein. 618 61

In the present studies, we demonstrate that heregulin is a potent and rapid activator of the serine/threonine kinase called Akt in the MCF-7 breast cancer cell line but not in 3 other breast cancer cell lines (T47D, HBL-100, and MDA-231). The extent of activation of Akt in the 4 cell lines correlated with the ability of heregulin to activate phosphatidylinositol 3-kinase and inhibition of the kinase blocked Akt activation. A monoclonal antibody to HER2 inhibited the ability of heregulin to activate Akt in the MCF-7 cells. BT474, a breast cancer cell line which overexpresses HER2, had high basal Akt enzymatic activity. This high basal activity was lowered when cells were pre-incubated with an anti-HER2 monoclonal antibody which is used to treat breast cancer patients. Our results indicate that heregulin is a potent activator of Akt and that overexpression of HER2 in breast cancers could also lead to activation of Akt.
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PMID:Heregulin regulation of Akt/protein kinase B in breast cancer cells. 1044 22

Previous reports have demonstrated that expression of insulin-like growth factor 2 (IGF2) is altered in hepatoblastoma. Using RNAase protection analysis (RPA), we examined the gene expression for IGF1, IGF2, IGF1R, M6P/IGF2R, IGFBP-1 and IGFBP-2 in a series of hepatoblastomas with corresponding normal liver from the same individuals. The results show that the expression of the IGF-axis members included in the present study are altered between tumour and normal, and indicate that the IGF-axis may be involved in hepatoblastoma development.
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PMID:Altered expression of members of the IGF-axis in hepatoblastomas. 1078 25

Carbocyclic oligopeptides containing of two, three or four aromatic rings with N,N-dimethylpropyl-1,3-diamine group as C-terminus fragment of compounds and 5-[bis(2-chloroethyl)amino]-2,4-dinitrobenzamide as N-terminal were synthesized. These lexitropsins present antitumour activity on the neoplastic cells hepatoblastoma HEP G2. These experiments were evaluated in hypoxic and oxygen conditions. Significant differences of activity in oxygen and hypoxic conditions were shown only in compound, N-(3-dimethylaminopropyl)-N'-([3-[5-bis(2-chlorethyl)amino]-2,4-dinitrobenzamide])-phenyl]urea dihydrochloride 1 (IC50 = 8545 nM in oxygen vs. IC50 = 710 nM in hypoxia). The rest of compounds (2-6) do not indicate differences of activity in oxygen and hypoxia.
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PMID:Synthesis and biological activity of carbocyclic lexitropsins with a bioreductive fragment. 1256 78

FosB is a member of the AP-1 family of transcription factors which represent important regulators of cell proliferation and differentiation. Based on prior results which indicated a role of FosB in breast cancer, we studied FosB protein and mRNA expression by immunohistochemistry and, partly, in situ hybridization in 68 mammary carcinomas and normal breast tissues. We found strong nuclear FosB immunoreactivity in epithelial cells of normal lobules and ducts, whereas carcinomas frequently showed loss of FosB expression (n = 8) or weak immunostaining (n = 24). Reduced FosB protein expression in tumors correlated with high grading (p = 0.005), negative estrogen and progesterone receptor status (p < 0.001), and strong HER2/neu expression (p = 0.025). Comparison with expression of seven cell-cycle regulators revealed an association of low/absent FosB staining with p16MTS1 overexpression (p = 0.005). RT-PCR showed expression of full-length FosB and the smaller splice variant FosB2 in most carcinomas and cell lines with and without FosB protein expression, indicating that both proteins are differentially regulated mainly at a post-transcriptional level. By sequence analysis of the coding region in four cell lines and 17 carcinomas we detected a mutation in HBL-100 cells. Our results indicate that high FosB expression might be necessary for normal proliferation and differentiation of mammary epithelial cells, and reduced FosB protein levels might be involved in dedifferentiation during breast tumorigenesis.
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PMID:FosB is highly expressed in normal mammary epithelia, but down-regulated in poorly differentiated breast carcinomas. 1260 26

Cylindrospermopsis raciborskii, a freshwater cyanobacterium of tropical origin, is not only increasingly found in (sub) tropical water bodies, but also in temperate regions. Since this species may produce potent toxins such as cylindrospermopsin (CYN) and paralytic shellfish poisons, its massive occurrence in water bodies used as drinking water sources or for recreation is of major concern. The proliferation of C. raciborskii in German water bodies has been documented for the past decade. We investigated the occurrence of CYN in field populations and isolates of C. raciborskii from two lakes, and assessed the toxicity of culture isolates using the mouse bioassay, primary rat hepatocytes and human derived cell lines. We show for the first time the occurrence of CYN in German water bodies. None of seven isolates of C. raciborskii contained CYN, however, all isolates were toxic to primary rat hepatocytes, human hepatoblastoma (HEP-G2) and human colon adenocarcinoma (CACO-2) cells. Methanolic extracts were more toxic than aqueous extracts. Three isolates tested in the mouse bioassay were toxic at a concentration of 800 mg kg(-1) showing liver and spleen damage and inflammation of the intestine. These results give strong evidence that the German isolates of C. raciborskii contain currently not identified or unknown toxins.
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PMID:Cylindrospermopsin occurrence in two German lakes and preliminary assessment of toxicity and toxin production of Cylindrospermopsis raciborskii (Cyanobacteria) isolates. 1455 84

Thrombopoietin (TPO), a cytokine that participates in the differentiation and maturation of megakaryocytes, is produced in the liver, but only limited information is available on the biological response of liver-derived cells to TPO. In this study, we investigated whether HepG2 cells express c-Mpl, the receptor for TPO, and whether TPO elicits biological responses and intracellular signaling in this cell type. Specific transcripts for c-Mpl were detected in HepG2 cells by RT-PCR, and expression of the protein was demonstrated by Western blot analysis and immunofluorescence. Exposure of HepG2 cells to TPO was associated with a dose-dependent increase in cell migration and chemoinvasion through Matrigel-coated filters. A checkerboard analysis showed that the effects of TPO on cell migration were dependent on both chemotaxis and chemokinesis. Exposure of HepG2 cells to TPO resulted in the activation of different members of the MAPK family, including ERK and JNK, as assessed using phosphorylation-specific antibodies and immune complex kinase assays. TPO also activated phosphatidylinositol 3-kinase (PI3K) and the downstream kinase Akt in a time-dependent manner. Finally, activation of c-Mpl was associated with increased activation of nuclear factor-kappaB. With the use of specific inhibitors, tyrosine phosphorylation and activation of PI3K were found to be required for the induction of migration in response to TPO. We conclude that TPO exerts biological actions on cultured hepatoblastoma cells via activation of c-Mpl and its downstream signaling.
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PMID:Thrombopoietin stimulates migration and activates multiple signaling pathways in hepatoblastoma cells. 1615 Aug 72

Inhibition of angiogenesis has become a major target in experimental cancer therapies. Vascular endothelial growth factor (VEGF) and its receptors are essential for breast cancer progression and relevant targets in experimental anti-angiogenesis. VEGF, produced by carcinoma cells, acts in a paracrine fashion on endothelial cells and displays autocrine activity on carcinoma cells. Breast cancer cells express VEGF-A, VEGF-B, VEGF-C and their receptors VEGFR-1 (Flt-1), VEGFR-2 (Flk-1/KDR) and neuropilin (NP-1/NP-2). VEGF-A triggers cellular signalling, an invasive phenotype of certain breast cancer cell lines and influences cell survival. However, such an autocrine VEGF/VEGFR signalling loop remains to be established. We demonstrate production of VEGF-A in cell lines MDA-MB-468, T47d, MCF-7, HBL-100 and in a primary breast cancer culture. Moreover, these cells showed baseline VEGFR-2 tyrosine-phosphorylation that could be enhanced by VEGF-A stimulation. In addition, VEGF-A leads to increased phosphorylation of ERK1/2 and Akt indicating that VEGF-A stimulation plays a crucial role in the regulation of cell growth, apoptosis, survival and differentiation. Moreover, we have established a novel breast cancer cell culture MW1 that expresses high levels of VEGF-A. We demonstrate that VEGFR-2 on the surface of breast cancer cells is functional and is capable of being stimulated by external VEGF-A. VEGF-A production by and VEGFR-2 activation on the surface of breast cancer cells indicates the presence of a distinct autocrine signalling loop that enables breast cancer cells to promote their own growth and survival by phosphorylation and activation of VEGFR-2. Moreover, this autocrine loop represents an attractive therapeutic target.
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PMID:Autocrine vascular endothelial growth factor signalling in breast cancer. Evidence from cell lines and primary breast cancer cultures in vitro. 1632 60


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