Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CD45 antigen cluster identifies a family of transmembrane glycoprotein tyrosine phosphatases (PTPases) present on nearly all hemopoietic cells. Recent studies suggest that CD45 may play a role in the control of receptor mediated blood cell responses, and that expression of the CD45 gene varies during bone marrow cell maturation. However, relatively little is known of the mechanisms controlling CD45 expression and function. Here we show that the induction of granulocyte or monocyte differentiation of HL60 leukemia cells is accompanied by a rapid increase in CD45 antigen expression and CD45 PTPase activity. In contrast, other leukemia cell lines induced for monocyte/macrophage differentiation did not show increased CD45. Immunoprecipitation of radiolabelled CD45 glycoprotein from dimethyl sulphoxide (DMSO) treated HL60 cells indicated that the cells expressed 200 and 180 kD isoforms. Northern blots of steady-state RNA from HL60 cells showed a 4-11-fold increase in CD45 transcripts after DMSO treatment, but no alteration in the half-life of CD45 mRNA. Nuclear transcription assays showed that CD45 expression was controlled at the level of gene transcription. Namalwa Burkitt leukemia cells expressing the heterologous epidermal growth factor (EGF) receptor protein tyrosine kinase were used to assess the specificity of CD45 PTPase activity. Co-clustering of CD45 and the EGF receptor with specific monoclonal antibodies failed to alter the EGF stimulated tyrosine phosphorylation of the EGF receptor. These studies indicate that CD45 increases during myeloid maturation, and the expression of the CD45 gene is controlled at the level of gene transcription. Preliminary studies suggest that CD45 does not alter the protein tyrosine kinase activity of the EGF receptor in intact cells, suggesting substrate specificity in vivo.
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PMID:Regulation of CD45 expression in human leukemia cells. 185 Dec 41

The existence of an autocrine loop for self-stimulation of growth in malignant cells has been proposed for transforming growth factor-alpha (TGF alpha) and its receptor, the epidermal growth factor (EGF) receptor, in a variety of malignant cell types. Expression of both has been described in colon carcinoma. In order to investigate whether there is a correlation between TGF alpha and EGF receptor mRNA expression and differentiation, we studied the effects of differentiating agents on seven human colon carcinoma cell lines. All of the lines responded to the differentiating agents. In four of the seven lines there was increased EGF receptor mRNA two to five days after treatment with 2 mM sodium butyrate. In three of these lines TGF alpha mRNA and protein were also increased. In the one cell line treated with the differentiating agents DMF and DMSO, EGF receptor mRNA was also increased. [125I]-EGF binding to the cells was measured before and after treatment with butyrate. In two of three cell lines, increased EGF receptor mRNA was accompanied by a 2.4-fold increase in the number of binding sites per cell. In SW620 cells, no EGF receptor binding was detected before or after butyrate treatment. In the two cell lines in which butyrate increased EGF receptor binding, simultaneous treatment with EGF did not enhance growth. These data demonstrate increased expression of the TGF alpha/EGF receptor system after differentiation of colon carcinoma cell lines and suggest that their expression may be characteristic of a differentiated phenotype.
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PMID:Modulation of EGF receptor expression by differentiating agents in human colon carcinoma cell lines. 220 77

We have applied enzyme complementation technology to develop a screen for antagonists of the epidermal growth factor (EGF) receptor. Chimeric proteins containing two weakly complementing deletion mutants of Escherichia coli beta-galactosidase (beta-gal), each fused to the EGF receptor extracellular and transmembrane domains, have been stably expressed in C2C12 cells. In this cell line, formation of active beta-gal is dependent on agonist-stimulated dimerization of the EGF receptor. We have developed a homogenous 384-well assay protocol and have applied this to characterize the pharmacology of the receptor and to develop a high throughput screen (HTS) for EGF receptor antagonists. The assay is tolerant to DMSO concentrations of up to 2% and, across 21 passages in culture, exhibits an EC(50) for EGF of 5.4 +/- 3.6 ng/ml (n = 11) and a Z' of 0.55 +/- 0.13 (n = 11). A random set of 1,280 compounds was screened in duplicate at 11 microM to examine the robustness of enzyme complementation technology and to characterize the false-positive hit rate in the assay. Using a cutoff of 40% inhibition of EGF-promoted beta-gal activity, the hit rate on day 1 was 2.5% and on day 2 was 1.9%. After retesting the active compounds, the hit rate was reduced to 0.4%, of which one of the compounds was identified as a beta-gal inhibitor and the remainder appeared to be nonspecific inhibitors in the assay. This technology is amenable to automated screen workstations, there are highly sensitive chemiluminescent and fluorescent beta-gal assay reagents amenable to detection in miniaturized plate formats, and the assay benefits from a low false-positive hit rate. Enzyme complementation technology may have wide application within the HTS environment for the detection of modulators of receptor activation or inhibitors of protein-protein interactions in mammalian cells.
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PMID:Application of beta-galactosidase enzyme complementation technology as a high throughput screening format for antagonists of the epidermal growth factor receptor. 1178 58

Colonic carcinogenesis involves the progressive dysregulation of homeostatic mechanisms that control growth. The epidermal growth factor (EGF) receptor (EGFR) regulates colonocyte growth and differentiation and is overexpressed in many human colon cancers. A requirement for EGFR in colonic premalignancy, however, has not been shown. In the current study, we used a specific EGFR antagonist, gefitinib, to investigate this role of the receptor in azoxymethane colonic premalignancy. The azoxymethane model shares many clinical, histologic, and molecular features of human colon cancer. Mice received azoxymethane i.p. (5 mg/kg/wk) or saline for 6 weeks. Animals were also gavaged with gefitinib (10 mg/kg body weight) or vehicle (DMSO) thrice weekly for 18 weeks, a dose schedule that inhibited normal receptor activation by exogenous EGF. Compared with control colonocytes [bromodeoxyuridine (BrdUrd), 2.2+/-1.2%], azoxymethane significantly increased proliferation (BrdUrd, 12.6+/-2.8%), whereas gefitinib inhibited this hyperproliferation (BrdUrd, 6.2+/-4.0%; <0.005). Azoxymethane significantly induced pro-transforming growth factor-alpha (6.4+/-1.3-fold) and increased phospho-(active) EGFR (5.9+/-1.1-fold), phospho-(active) ErbB2 (2.3+/-0.2-fold), and phospho-(active) extracellular signal-regulated kinase (3.3+/-0.4-fold) in premalignant colonocytes. Gefitinib inhibited activations of these kinases by >75% (P<0.05). Gefitinib also significantly reduced the number of large aberrant crypt foci and decreased the incidence of colonic microadenomas from 75% to 33% (P<0.05). Gefitinib concomitantly decreased cell cycle-regulating cyclin D1 and prostanoid biosynthetic enzyme cyclooxygenase-2 in microadenomas, suggesting that these regulators are key targets of EGFR in colonic carcinogenesis. These results show for the first time that EGFR signaling is required for early stages of colonic carcinogenesis. Our findings suggest, moreover, that inhibitors of EGFR might be useful in chemopreventive strategies in individuals at increased risk for colonic malignancies.
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PMID:Epidermal growth factor receptor signaling is required for microadenoma formation in the mouse azoxymethane model of colonic carcinogenesis. 1723 95