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)

Normal tissues, primary tumors, and metastases of mammary and salivary glands and oral/laryngeal mucosa have been analyzed with Northern-blots employing 32P-labeled RNA probes for the expression of the neu oncogene. Neu oncogene expression of a mRNA species of 4.6 kilobases was found in all normal salivary (five) and mammary glands (four) as well as in two normal or inflamed samples of tongue mucosa. This expression was regarded as baseline activity of the neu gene for the respective tissues and was used as standard for the evaluation of benign and malignant tumors. None of 14 squamous cell carcinomas of the oral and laryngeal mucosa showed enhanced neu transcription level. Five fibroadenomas, one benign variant of phylloid tumor, one carcinosarcoma, and one of two proliferative fibrocystic diseases of the breast showed lacking or normal baseline expression of the neu oncogene, as did one monomorphous cystadenolymphoma of the parotid gland. In contrast, four parotid pleomorphic adenomas and one salivary gland adenocarcinoma showed enhanced neu expression. For mammary adenocarcinomas, increased neu oncogene expression concerned ten of 34 cases--all being variants of ductal carcinomas--and all metastases analyzed (six) deriving from three primaries. One adenoid cystic carcinoma also showed enhanced neu expression. Neu overexpression may reflect accidents of genomic reconstitutional events occurring regularly within the differentiation pathway of epithelial/myoepithelial cells. This assumption was supported by further immunohistochemical analysis which showed stainings of myoepithelial and myoepithelia-like cell populations in tumors, especially pleomorphic adenomas and adjacent normal-looking tissues.
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PMID:Comparative investigation of c-erbB2/neu expression in head and neck tumors and mammary cancer. 167 62

A partially agonistic monoclonal antibody, 4D5, known to bind to the extracellular domain of p185HER2 and shown to inhibit long term growth of p185HER2-overexpressing breast cancer cells, was used to study signal transduction and phosphotyrosyl protein substrates associated with this receptor. Normal breast epithelial cells and breast carcinoma cells expressing low levels of p185HER2 were not affected by 4D5. HER2/neu-overexpressing breast cancer cells (BT-474 and SK-Br-3) exposed to 4D5 exhibited rapid phosphorylation of both p185HER2 and an associated 56-kDa phosphotyrosyl protein (ptyr56). Paralleling the 4D5- stimulated phosphorylation of p185HER2 and ptyr56 was a 5-10-fold induction of c-fos mRNA and phosphatidylinositol 4-kinase activity and a 2-fold induction of inositol 1,4,5-trisphosphate 3'-kinase activity. The increased phosphatidylinositol 4-kinase activity immunoprecipitated with p185HER2 and also co-eluted with ptyr56 from an antiphosphotyrosine immunoaffinity column. These results indicate that short term (less than 6 h) 4D5 activation of p185HER2 in overexpressing breast cancer cells produces agonistic-like signaling typical of homologous tyrosine kinase growth factor receptors such as epidermal growth factor receptor. The data also suggest that ptyr56 represents a novel phosphorylated substrate associated with 4D5-stimulated p185HER2.
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PMID:p185HER2 signal transduction in breast cancer cells. 167 43

The HER2 protooncogene encodes a growth factor receptor-like transmembrane protein tyrosine kinase (p185HER2) whose ligand remains to be fully characterized. The overexpression of p185HER2 is implicated in aggressive forms of breast and ovarian cancers. The role of p185HER2 in aggressive malignancy, as well as its cell surface localization, makes it an attractive target for therapeutic monoclonal antibodies. In this report we have studied the modulation of p185HER2 function with 2 monoclonal antibodies, termed 4D5 and 6E9, which bind the extracellular domain of p185HER2. 4D5 inhibited proliferation of p185HER2 overexpressing SK-BR-3 human breast carcinoma cells (ED50 of approximately 1 nM) but did not inhibit proliferation of cultured human breast carcinoma MCF7 cells, low expressors of p185HER2. Monoclonal antibody 6E9 does not inhibit the growth of either cell line. Antibody binding studies revealed 2 populations of p185HER2 molecules on SK-BR-3 cells: one of high abundance (approximately 2 x 10(6) sites/cell) recognized by 4D5 (Kd approximately 6 nM) and the other of low abundance (2 x 10(4) sites/cell) recognized by 6E9 (Kd approximately 0.1 nM). 4D5, in an agonistic manner, downregulated SK-BR-3 cell surface p185HER2, was internalized, and stimulated p185HER2 phosphorylation in intact cells. Phosphoamino acid analysis of p185HER2 derived from SK-BR-3 cells incubated with the 4D5 monoclonal antibody demonstrated increased tyrosine, serine and threonine phosphorylation. 4D5, on short term (5 min) exposure to SK-BR-3 cells, stimulated inositol lipid hydrolysis as evidenced by increased intracellular levels of inositol polyphosphates (InsP) and sn-1,2-diacylglycerol (sn-1,2-DAG). On longer (24 h) exposure to the cells, the antibody appeared to downregulate this signalling pathway since the intracellular levels of InsP and sn-1,2-DAG decreased by 30 to 40%. 6E9 did not inhibit SK-BR-3 cell proliferation, downregulate surface p185HER2, stimulate receptor phosphorylation, or stimulate the second messenger pathway. Despite these agonistic properties, 4D5 was an inhibitor of SK-BR-3 cell proliferation at all concentrations tested (0.7 to 70 pM). The data suggest that 4D5 is a partial or weak agonist and thus may inhibit cell proliferation by mimicking ligand-like receptor downregulation.
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PMID:Characterization of an anti-p185HER2 monoclonal antibody that stimulates receptor function and inhibits tumor cell growth. 168 87

Some human carcinoma cells constitutively produce granulocyte colony-stimulating factor (G-CSF) which stimulates the proliferation and differentiation of the progenitor cells of neutrophilic granulocytes. By introducing mouse G-CSF chromosomal gene or its promoter DNA into human carcinoma cell lines of CHU-2, SK-HEP-1, and U-87MG, it was shown that the constitutive expression of G-CSF in these carcinoma cells was due to the intrinsic activation of nuclear factors which work on the promoter region of the G-CSF gene. A series of 5' deletion mutants, linker scanning mutants, and internal deletion mutants was constructed in the promoter of mouse G-CSF gene and was introduced into human CHU-2 cells to analyze their promoter activities. These studies demonstrated that at least three regulatory elements in the promoter of the G-CSF gene are essential for the constitutive expression of G-CSF in CHU-2 cells. These elements include the consensus decanucleotide "GAGRTTCCA/CC" present on G-CSF, granulocyte/macrophage colony-stimulating factor, and interleukin 3 genes and the "ATTTGCAT" octamer transcription factor binding site. Some point mutations in these consensus sequences significantly diminished the promoter activity in CHU-2 cells.
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PMID:Multiple elements in the promoter of granulocyte colony-stimulating factor gene regulate its constitutive expression in human carcinoma cells. 169 Jul 17

Diagnosis- and/or prognosis-related alterations of (proto) oncogenes may be detected in neuroblastoma (N-myc), carcinoma of breast and ovary (HER2/neu), NHL (c-myc, bcl-2), CML (c-abl/bcr), and some other neoplasias. A wide variety of methods for the detection of gene alterations can be applied. The methods of detection have to be chosen according to the expected mechanisms of oncogene activation, the availability of adequately prepared tissue, and the technical standard of the laboratory. The sensitivity, specificity, and quantitation of morphological techniques (immunohistochemistry and in situ hybridization) is restricted and their results have to be interpreted most carefully. Whenever possible, at least two different techniques should be used, preferably on two different levels, i.e. RNA/DNA and protein. Furthermore, the combination of morphological and non morphological methods should be aspired.
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PMID:[Oncogenes and oncogene products--possibilities and significance of their detection]. 170 8

The ERBB2 (also called HER2, neu, and c-erbB-2) gene product, which encodes a growth factor receptor, was implicated in the malignancy of human adenocarcinomas. An antibody directed to the rat oncogenic receptor has been previously shown to have an antitumor effect in model systems. In an attempt to extend this observation to the protooncogenic human receptor and also to understand the underlying mechanism, we generated a panel of monoclonal antibodies specific to the extracellular portion of the ERBB2 protein. The effects of the antibodies on tumor growth were compared with their cellular and biochemical actions in vitro. Surprisingly, opposing in vivo effects were observed: although some antibodies almost completely inhibited the growth in athymic mice of transfected murine fibroblasts that overexpress Erbb-2, other antibodies either accelerated tumor growth or resulted in intermediate responses. When tested on cultured human breast carcinoma cells or ERBB2 transfectants, the tumor-stimulatory antibody was found to induce significant elevation of tyrosine phosphorylation of the ERBB2 protein. In contrast, only partial correlation was observed between the capacity to restrict tumor growth and the effects of the antibodies on receptor degradation and cellular proliferation in vitro. This suggests that the antitumor antibodies affect both receptor function and host-tumor interactions. Our results may help establish experimental criteria for the selection of specific antibodies for use either alone or in conjunction with other molecules as pharmacological antitumor agents.
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PMID:Mechanistic aspects of the opposing effects of monoclonal antibodies to the ERBB2 receptor on tumor growth. 171 84

The receptor for hepatocyte growth factor, also known as scatter factor (HGF/SF), has recently been identified as the 190-kDa heterodimeric tyrosine kinase encoded by the MET proto-oncogene (p190MET). The signaling pathway(s) triggered by HGF/SF are unknown. In A549 cells, a lung epithelial cell line, nanomolar concentrations of HGF/SF induced tyrosine phosphorylation of the p190MET receptor. The autophosphorylated receptor coprecipitated with phosphatidylinositol 3-kinase (PI 3-kinase) activity. In GTL16 cells, a cell line derived from a gastric carcinoma, the p190MET receptor, overexpressed and constitutively phosphorylated on tyrosine, coprecipitated with PI 3-kinase activity and with the 85-kDa PI 3-kinase subunit. In these cells activation of protein kinase C or the increase of intracellular [Ca2+] inhibits tyrosine phosphorylation of the p190MET receptor as well as the association with both PI 3-kinase activity and the 85-kDa subunit of the enzyme. In an in vitro assay, tyrosine phosphorylation of the immobilized p190MET receptor was required for binding of PI 3-kinase from cell lysates. These data strongly suggest that the signaling pathway activated by the HGF/SF receptor includes generation of D-3-phosphorylated inositol phospholipids.
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PMID:The tyrosine-phosphorylated hepatocyte growth factor/scatter factor receptor associates with phosphatidylinositol 3-kinase. 171 89

In the present investigation we show data from our studies of anaplastic human thyroid carcinoma cell lines. The cell lines employed in the study were HTh 7, HTh 74, C 643 and SW 1736, all derived from tumours diagnosed as anaplastic thyroid carcinomas. Northern blot analysis with four different thyroid specific cDNA probes showed a varying pattern of expression. Thyroglobulin mRNA was found in three of the carcinoma cell lines, although the signal was very weak compared to the expression in tissue from a toxic goitre, used as positive control. Interestingly, two of the cell lines expressed the receptor for thyrotropin, but none of them contained thyroperoxidase mRNA. Three of the cell lines expressed mRNA for receptors platelet-derived growth factor, PDGFR-alpha and/or PDGFR-beta type. Messenger RNA of a thyroid specific transcription factor, TTF-1, known to regulate the normal function of thyrocytes, was found in the toxic goitre but not in the anaplastic thyroid carcinoma cell lines. Lack of expression of TTF-1 might the immediate cause of the anaplastic phenotype, considering the possibility that TTF-1 functions as a master regulatory gene in thyroid cell differentiation.
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PMID:The molecular biology of the human anaplastic thyroid carcinoma cell. 172 28

Four human colon adenocarcinoma cell lines, SNU-C1, SNU-C4, SNU-C5, and NCI-H716, that are capable of proliferating autonomously in serum-free medium containing no added peptide growth factors were identified. All four cell lines show epidermal growth factor (EGF) receptors (EGFRs), express transforming growth factor alpha (TGF-alpha) messenger RNA, and release anti-TGF-alpha-immunoreactive molecules. The blocking anti-EGFR monoclonal antibody (mAb) 225 blocks autonomous proliferation of SNU-C1 and SNU-C4 cells. In both of these cell lines, the inhibitory effect of mAb 225 is reversible by the addition of EGF, TGF-alpha, or conditioned medium from any of the four cell lines. In contrast, autonomous proliferation of SNU-C5 and NCI-H716 cells is not inhibited by mAb 225 and is not affected by exogenous EGF, TGF-alpha, or conditioned medium. Together, these data confirm the previous finding that anti-EGFR antibodies can inhibit the proliferation of some carcinoma cell lines that coexpress TGF-alpha and EGFR. However, here it is shown that the mechanisms of autonomous proliferation of colon carcinoma cell lines are heterogeneous and not always sensitive to antibody disruption of TGF-alpha/EGFR autocrine interactions.
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PMID:Autonomous proliferation of colon cancer cells that coexpress transforming growth factor alpha and its receptor. Variable effects of receptor-blocking antibody. 173 18

The expression of EGFR was determined immunohistochemically in two groups of patients with glottic carcinoma, one that recurred after a full course of radiotherapy and one that did not. Using a 4-graded scale (-,+,++, ) 80% (12/15) of the recurrent carcinomas had a staining intensity and proportion of stained cells of ++ or more. The same figure for non-recurrent carcinomas was 39% (7/18). The difference is statistically significant (chi-squared with Yates' correction, P less than 0.05). The results indicate that an increased expression of EGFR may influence the rate of recurrence of glottic squamous cell carcinoma after radiotherapy.
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PMID:Expression of epidermal growth factor receptor in glottic carcinoma and its relation to recurrence after radiotherapy. 174 94


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