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)

Tyrosine-specific phosphorylation of the epidermal growth factor (EGF) receptor in hormonally stimulated A431 cells is blocked by three chemically distinct classes of tumor promoters. Tumor-promoting esters of the diterpene phorbol (phorbol 12-myristate 13-acetate, beta-phorbol 12,13-dibutyrate, and beta-phorbol 12,13-didecanoate), indole alkaloids (teleocidin and lyngbyatoxin A), and polyacetates ( aplysiatoxin and debromoaplysiatoxin ) all inhibited EGF-stimulated phosphorylation of the receptor. Non-tumor-promoting analogs (beta-phorbol, alpha-phorbol 12,13-didecanoate, and hydrolyzed teleocidin) had no effect on the levels of receptor phosphorylation. The ED50 values of the inhibitory effect (0.1-3 ng/ml) reflected the relative tumor-promoting abilities of these compounds in vivo. None of the tumor promoters tested significantly decreased the overall specific binding of 125I-labeled EGF to A431 cells. Scatchard analysis, however, revealed two apparent EGF receptors in this cell type. The dose-responses for tumor-promoter inhibition of EGF receptor tyrosine phosphorylation and high-affinity EGF binding were similar, suggesting that the same initial event is responsible for both effects. This demonstrates a correlation between modulation of EGF receptor binding and phosphorylation of tyrosine by tumor promoters. The data suggest a possible role for protein kinase C, the putative cellular receptor for these tumor promoters, in the mechanism of action.
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PMID:Tumor promoters block tyrosine-specific phosphorylation of the epidermal growth factor receptor. 632 89

The derivation and properties of JB6 mouse epidermal clonal cell lines are reviewed and the conclusions that can be drawn from studies with the JB6 mouse epidermal system are summarized. Promoter induced mitogenic stimulation, epidermal growth factor (EGF) receptor binding and stimulated hexose transport are apparently not required for promotion of neoplastic transformation in JB6 cells by phorbol esters and other promoters. Phorbol ester receptor binding (or protein kinase C activation) and switched-off collagen synthesis may be required but definitive proof is not available. Decreased cell surface ganglioside GT synthesis, elevated superoxide, and one or more genes that determine promotion sensitivity appear to distinguish sensitive from resistant cells and to be required for promotion of neoplastic transformation in JB6 cells. The hypothesis is proposed that GT is a target for reactive oxygen elevated by 12-O-tetradecanoylphorbol-13-acetate (TPA) exposure and that GT oxidation produces decreased GT net synthesis which in turn leads to promotion of transformation. Finally evidence is presented suggesting the involvement of at least two genes in transformation of JB6 cells by TPA, one in induction, the other in maintenance of transformation.
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PMID:Membrane and genetic events in tumor promotion: studies with promoter resistant variants of JB6 cells. 639 88

Calphostin-C with perylenequinone structure is known to bind the regulatory domain of protein kinase C (PKC) and to inhibit kinase activity in vitro in a light-dependent fashion. We have found that calphostin-C induces substantial serine and threonine phosphorylation of the epidermal growth factor (EGF) receptor in a light-dependent fashion in the EGF receptor-hyperproducing squamous carcinoma cell line NA. Tryptic phospho-peptide mapping and phospho-amino acid analysis revealed that calphostin-C-enhanced phosphorylation was on threonine 669, serine 671, serine 1046/1047, and serine 1166. However, calphostin-C did not inhibit phosphorylation of the 80 K protein, a cytosolic major substrate of PKC (MARCKS). Staurosporine, a potent PKC inhibitor with affinity for the catalytic domain of PKC, inhibited phosphorylation of the 80 K protein and 12-O-tetradecanoyl-13-phorbol acetate induction of EGF receptor phosphorylation but did not inhibit the calphostin-C induction of the EGF receptor phosphorylation. These results suggest that the target of calphostin-C in vivo is different from that of staurosporine and thus calphostin-C in vivo does not inhibit PKC. Furthermore, calphostin-C enhanced the internalization of phosphorylated EGF receptor. Thus, calphostin-C apparently activates a novel signal transduction pathway which involves phosphorylation and internalization of the EGF receptor via light-dependent mechanism.
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PMID:Calphostin-C stimulates epidermal growth factor receptor phosphorylation and internalization via light-dependent mechanism. 750 75

We made an effort to identify a reliable source for obtaining large quantities of both free (PSA) and PSA-ACT complex for the preparation of the calibrator for the PSA assay. Using size exclusion chromatography, we found both free PSA and PSA-ACT complex in the conditioned cell medium of the LNCaP cell line, which was derived from a human metastatic adenocarcinoma of the prostate. An assay specific for PSA-ACT reacted only with the PSA-ACT complex from cells grown in serum-free medium, and not with the complex from the cell medium grown in 10% calf serum. We also found both free PSA and PSA-ACT complex in 15% of cytosols prepared from breast tumor tissues; the cytosol PSA concentrations ranged from 0.1 to 110 ng/ml. No correlation was found between cytosol PSA and concentrations of estrogen receptor, progestin receptor, epidermal growth factor receptor, cathepsin D, or the ectodomain of c-erbB-2 protein. Based on chromatographic characterizations and the slope of their dose-response curves, it appears that both free PSA and PSA-ACT complex found in the cytosols are similar to PSA complex from the cell medium and the serum of prostate cancer patients. Ectopic PSA was also detected in pooled sera from patients with breast, ovarian, pancreatic, and colon carcinoma. The PSA concentrations in these serum pools increased with the level of their dominant tumor marker. In any event, the LNCaP cell medium appears to be a reliable source for obtaining both free and ACT-complexed PSA of human tumor origin for the preparation of PSA assay calibrators.
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PMID:PSA immunoreactivity detected in LNCaP cell medium, breast tumor cytosol, and female serum. 756 42

GCF is a transcriptional regulator that was found to repress transcription of the epidermal growth factor (EGF) receptor and several other genes and is encoded by a 3-kb mRNA (R. Kageyama and I. Pastan, Cell, 59: 815-825, 1989; A. C. Johnson et al., J. Biol. Chem., 267: 1689-1694, 1992). To identify and characterize the GCF gene product at the cellular level, we have developed antibodies against a bacterially expressed GCF fusion protein. GCF antibodies recognize GCF present in extracts from human cells and causes a "supershift" of a protein DNA complex containing a GCF oligonucleotide binding site. The major form of GCF has a molecular weight of approximately M(r) 97,000, identical to that of GCF transiently expressed in CV1 cells by the vaccinia virus system. In addition, other less abundant species with slightly higher and lower apparent molecular weight are specifically recognized, suggesting extensive posttranslational modification. GCF is highly expressed in EGF receptor-negative human cell lines (HUT102, U266, and CA46) and in lower amounts in several EGF receptor-expressing cells (KB, A431, TMK, and HeLa). Cell fractionation studies indicate that GCF is predominantly localized in the nucleus. GCF is a stable protein with a relatively long half-life. In addition, GCF is a phosphoprotein, and the phosphorylated form is found to be associated with the nuclear compartment in both HUT102 and KB cells. Phosphorylation occurs on serine and threonine residues and is stimulated by okadaic acid, phorbol myristate acetate, and cyclic AMP, but not vanadate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biochemical characterization of human GCF transcription factor in tumor cells. 766 24

The stimulation of both phospholipase A2 (PLA2) enzymic activity and the production of prostaglandin E2 (PGE2) by transforming growth factor-alpha (TGF-alpha) and Ca2+ ionophore A23187 in TEA3A1 rat thymic epithelial cells were studied. TGF-alpha by itself at various concentrations (5-200 ng/ml) had no effect on the stimulation of PGE2 production. A23187 (1 microgram/ml) by itself stimulated PGE2 production on average by 18-fold over the control. When TGF-alpha (50 ng/ml) was added to the cells in the presence of A23187, a synergistic stimulation (on average 45-fold) of PGE2 production was observed. Synergistic stimulation was also observed at the level of arachidonic acid released from phospholipid pools, suggesting the activation of PLA2 enzymic activity. We have found that this synergistic activation of PLA2 enzymic activity and subsequent stimulation of PGE2 production required the activation of epidermal growth factor (EGF) receptor tyrosine kinase and Ca2+ influx. This was shown by the fact that genistein, an inhibitor of tyrosine kinase, blocks the synergistic stimulation by TGF-alpha and A23187 and by the fact that the stimulation of PGE2 production by TGF-alpha and A23187 is dependent on the culture-medium Ca2+ concentrations. The requirement for Ca2+ influx instead of intracellular mobilization of Ca2+ was shown by the fact that PGE2 production was not stimulated when cells were treated with TGF-alpha and thapsigargin. Moreover, the synergistic stimulation of PGE2 production by TGF-alpha and A23187 was not affected in protein kinase C down-modulated cells. In addition, the synergistic stimulation was not observed in cells treated with either phorbol 12-myristate 13-acetate (PMA) and TGF-alpha or PMA and A23187, and in cells treated with TGF-alpha and thapsigargin. The requirement for the activation of receptor tyrosine kinase seems to be specific to the EGF receptor, since a synergistic stimulation of PGE2 production was not observed when cells are treated with either insulin-like growth factor-I or fibroblast growth factor-I in the presence of A23187.
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PMID:Activation of phospholipase A2 and stimulation of prostaglandin E2 production by transforming growth factor-alpha in rat thymic epithelial cells requires influx of calcium. 768 26

Previous reports have shown that the epidermal growth factor (EGF) receptor is associated with the detergent-insoluble actin cytoskeleton. To assess how this association can influence receptor function, EGF-stimulated protein-tyrosine kinase activity was examined in the detergent-soluble and -insoluble (cytoskeletal) fractions of human A431 epidermoid carcinoma cells. EGF receptor extraction was optimal using 0.15% Triton X-100, and higher detergent concentrations did not significantly increase the amount of solubilized receptor as assessed by immunoblotting. Normalization of EGF-stimulated tyrosine kinase activity on the basis of receptor mass revealed that the specific activity of the cytoskeletal (0.15% Triton-insoluble) fraction is nearly 3-fold greater than that of the soluble receptor when using angiotensin II as the peptide substrate. The increased specific activity of the Triton-insoluble receptor suggests that interaction with the cytoskeleton can facilitate maximal kinase activity. This hypothesis is supported by the observation that, when compared with the soluble EGF receptor, the receptor in the cytoskeletal fraction demonstrates a 15-fold more favorable apparent Michaelis-Menten constant for ATP and a 4-fold more favorable Michaelis-Menten constant for angiotensin II. Although the cytoskeletal EGF receptor seems to represent less than 10% of the total receptor mass in cells not exposed to EGF, these data indicate that it comprises a highly active receptor pool. To examine the regulation of receptor association with the detergent-insoluble fraction, A431 cells were treated at 37 C with EGF for up to 5 h, or with the phorbol ester 12-phorbol 12-myristate 13-acetate for 1 h, and total receptor mass and distribution were determined. In these studies, total immunodetectable receptor decreased significantly after 20 min of EGF administration, whereas the population of Triton-insoluble receptors increased within 40 min to greater than four times that observed before EGF addition and remained at that level for the full 5 h of EGF treatment. Conversely, 12-phorbol 12-myristate 13-acetate treatment, which is known to down-regulate high affinity EGF binding, had little effect on receptor association with the cytoskeletal fraction. In sum, these data indicate the presence of a highly active subpopulation of cytoskeletally associated EGF receptors that can be up-regulated during long-term (5 h) ligand exposure.
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PMID:Modulation of epidermal growth factor receptor interaction with the detergent-insoluble cytoskeleton and its effects on receptor tyrosine kinase activity. 772 Jun 69

Interleukin (IL) 1 alpha induced the up-regulation of cell-surfac-expressed epidermal growth factor (EGF) receptor on both MDA-MB-468 and BT-20 breast cancer cell lines. IL-1 beta and tumor necrosis factor alpha (TNF-alpha) increased the EGF receptor surface expression only on BT-20 breast carcinoma cells. 12-O-tetradecanoylphorbol 13-acetate (TPA) induced up-regulation of EGF receptor on MDA-MB-468 cells, and a marginal but significant increase was determined in BT-20 cells and in interferon gamma (IFN-gamma)-treated MDA-MB-468 cells. CD15 (Lewisx) antigen was down-regulated on MDA-MB-468 cells by TNF-alpha, TPA, IL-1 alpha, as well as by IFN-gamma and all-trans-retinoic acid. 1,25(OH)2-vitamin D3 up-regulated the CD15 antigen surface expression on MDA-MB-468 cells.
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PMID:Modulation of EGF receptor and CD15 (Lewisx) antigen on the cell surface of breast carcinoma cell lines induced by cytokines, retinoic acid, 12-O-tetradecanoylphorbol 13-acetate and 1,25(OH)2-vitamin D3. 790 17

It has previously been shown that, in the estrogen-receptor-positive breast-tumor cell lines T47D and ZR75.1, the erbB-2 protein and mRNA content are controlled negatively and positively by, respectively, estrogens and anti-estrogens. Since estrogens have a positive effect on cell proliferation, while anti-estrogens inhibit cell growth, the results suggested that there may be an inverse correlation between growth and erbB-2 expression. We have now examined this matter further. The effect of various growth-modulatory agents including estrogen (E2), progesterone (Pg), retinoic acid (RA), epidermal growth factor (EGF), insulin (Ins), prolactin (Prl), 12-O-tetradecanolyl-phorbol-13-acetate (TPA) and dibutyryl-3':5'-cyclic-AMP (cAMP) on c-erbB-2 promoter activity, RNA and protein expression have been examined. The growth stimulators E2 and EGF both reduced the level of erbB-2 protein. However, while E2 clearly repressed erbB-2 transcription, in the case of EGF, neither mRNA nor transcription were decreased. Of the agents which inhibit the growth of T47D and ZR75.1 cells--Pg, Prl, cAMP, RA and TPA--only Pg and cAMP caused an increase in the erbB-2 protein level. Pg and cAMP positively influenced c-erbB-2 promoter activity and RNA amount. TPA and RA also increased promoter activity but neither erbB-2 mRNA nor protein level was enhanced. The erbB-2 protein expression in cultures of T47D and ZR75.1 cells at different densities was also analyzed. Both the level of erbB-2 protein and c-erbB-2 promoter activity rose markedly in confluent cultures, suggesting a transcriptional mechanism of control. In conclusion, the data suggest that the effects of various agents on erbB-2 expression are complex and cannot be explained simply as reflecting the growth state of the cells.
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PMID:erbB-2 expression in estrogen-receptor-positive breast-tumor cells is regulated by growth-modulatory reagents. 790 79

The aim of the study was to determine the binding characteristics of the epidermal growth factor (EGF) receptor in isolated human endometrial glands and stromal cells in culture. Stromal cells and glands were obtained from endometrial tissue by collagenase dispersion followed by sieve filtration. They were plated into 24-well multiwell plates in Ham's F10 medium supplemented with 5% fetal calf serum and used at 70-80% confluence. Scatchard analysis revealed a single class of high-affinity binding sites in both cell types with apparent dissociation constants of 1.17 +/- 0.6 (n = 15) and 1.20 +/- 0.3 (n = 8) nmol 1-1 for stromal cells and glands, respectively. The concentration of receptors was higher in stromal cells than in glands, 719 +/- 377 (n = 16) and 310 +/- 177 (n = 8) fmol mg-1 protein, respectively. Epidermal growth factor labelled with 125I was displaced from the receptor by EGF and transforming growth factor alpha, but not insulin, insulin-like growth factor, fibroblast growth factor, or platelet-derived growth factor. Binding was shown to be dependent on time and temperature. Downregulation of the receptor was demonstrated by preincubating cells with 5 nmol EGF I-1, which reduced receptor concentrations by 75%. 12-O-Tetradecanoylphorbol-13-acetate decreased the affinity of the receptor for EGF changing the dissociation constant from 1.8 to 3.9 nmol l-1. A suitable system for investigating the regulation of this receptor in human endometrium was established.
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PMID:Characterization of epidermal growth factor receptor in human endometrial cells in culture. 793 77


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