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)

Multi-autocrine loops of the epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), platelet-derived growth factor (PDGF) and TGF beta system are expressed in human gastrointestinal carcinomas. In esophageal and gastric carcinomas, they evidently play an important role in tumor progression. Gastrin, one of the major gut hormones, may also act as an autocrine growth factor for gastric and colonic carcinomas. The HST1 and INT-2 genes, belonging to the fibroblast growth factor gene family, are coamplified in approximately 50% of primary tumors and in all the metastatic tumors of esophageal carcinoma. TGF alpha and EGF are the ligands of the tumor cells that overexpress EGF receptor in esophageal carcinomas. The synchronous expression of EGF and its receptor, as well as TGF alpha and ras p21, is evidently correlated with the depth of tumor invasion, metastasis and prognosis of gastric carcinomas. Amplification of c-erbB-2 and EGF receptor genes has been observed in many metastatic sites of gastric carcinomas regardless of histological type. In addition to TGF alpha and EGF, TGF beta and PDGF A chain produced by tumor cells may stimulate collagen synthesis not only by fibroblasts but also by tumor cells themselves, resulting in extensive progression and diffuse fibrosis of scirrhous gastric carcinomas. Moreover, TGF alpha or EGF and estrogen may also play a cooperative role in the development of scirrhous gastric carcinoma. In colorectal carcinoma, it has been shown that the accumulation of several alterations in ras genes and p53 genes is most important for the conversion of adenoma to carcinoma. Critical genetic changes, including activation of oncogenes, mutation and deletion of tumor suppressor genes and disturbances in transcriptional regulatory sequences, may bring about aberrant expression of growth factors and their receptors in gastrointestinal carcinomas. The understanding of the significance of EGF-related growth factors in tumor progression provides a framework for a biological approach to the therapy of human gastrointestinal carcinomas. 8-Cl-cAMP, which inhibits expression of oncogenes and TGF alpha, may be useful not only for cancer therapy but also for the study of cell differentiation.
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PMID:Growth factors and oncogenes in human gastrointestinal carcinomas. 215 13

The effects of 13-cis retinoic acid (RA) and dexamethasone on the levels of epidermal growth factor (EGF) receptor and fibroblast derived proteoglycan core protein (PG40) mRNAs were studied in human skin fibroblasts. The EGF receptor is involved in the regulation of cellular proliferation and the synthesis of matrix proteins, and proteoglycan 40 is important for cell attachment and interaction with collagen and fibronectin. 13-cis-RA at a concentration of 10(-7) M markedly reduced the levels of the EGF receptor and PG40 mRNAs, the decreases being 33 and 56%, respectively. Dexamethasone reduced these mRNAs markedly less. Simultaneous treatment of the fibroblasts with 13-cis-RA and dexamethasone resulted in similar decreases in EGF receptor and PG40 mRNAs as with 13-cis-RA alone. Surprisingly, the proliferation rate of the fibroblasts was increased in the presence of dexamethasone under conditions similar to those which caused slight decrease in the EGF receptor mRNA levels. This indicates that glucocorticoids also affect the cellular growth by mechanisms which do not involve EGF receptors.
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PMID:13-cis retinoic acid and dexamethasone modulate the gene expression of epidermal growth factor receptor and fibroblast proteoglycan 40 core protein in human skin fibroblasts. 257 17

By using a direct electron microscopic autoradiographical technique, we were able to demonstrate that the epidermal growth factor (EGF) receptor is asymmetrically located on polarized porcine thyroid follicle cells cultured on a collagen gel matrix. More than 80% of autoradiographical grains from [125I]EGF were associated with the basolateral cell surface compared to only about 2.5% at the apical cell margin. EGF stimulated growth only when the collagen gels were floating, indicating a basolateral location of functional EGF receptors. Preincubation with TSH or another stimulator of cAMP synthesis, forskolin, increased binding of [125I]EGF to the cells. Moreover, the subsequent mitogenic response to EGF was potentiated by such pretreatment. The results are in accordance with the hypothesis that TSH potentiates the response to EGF in the stimulation of thyroid growth.
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PMID:Location of epidermal growth factor receptors on porcine thyroid follicle cells and receptor regulation by thyrotropin. 300 89

Human recombinant transforming growth factor alpha (TGF alpha), which binds to the epidermal growth factor (EGF) receptor and causes several biological effects similar to those caused by EGF, was compared with murine EGF for its effects on a number of parameters of bone cell metabolism. TGF alpha stimulated bone resorption in two organ culture systems, the fetal rat long bone and neonatal mouse calvarial systems. TGF alpha stimulated bone resorption at concentrations as low as 0.1 ng/ml. TGF alpha effects on bone resorption in mouse calvariae were inhibited by indomethacin, suggesting that, like EGF, its effects were mediated by prostaglandin synthesis. TGF alpha had a different time course of action on bone resorption from that of EGF, causing more rapid release of previously incorporated 45Ca from bone cultures, suggesting that TGF alpha does not function on bone as a simple EGF analogue. TGF alpha also caused effects on osteoblast function resembling those of EGF. It inhibited alkaline phosphatase activity in cultured rat osteosarcoma cells with the osteoblast phenotype and inhibited collagen synthesis in fetal rat calvaria at concentrations of 1.0 ng/ml. The lowest concentration of TGF alpha (expressed as nanogram equivalents of EGF per ml) required to produce a response in all of the systems tested was about 1/10th of that needed for EGF to produce a similar effect. These results indicate that TGF alpha is a potent stimulator of bone resorption and inhibitor of bone formation as assessed by inhibition of collagen synthesis and alkaline phosphatase activity and are consistent with the hypothesis that TGF alpha may be responsible, at least in part, for the bone resorption associated with some tumors.
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PMID:Human recombinant transforming growth factor alpha stimulates bone resorption and inhibits formation in vitro. 348 99

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

Some human neoplasms show aberrant expression or overexpression of epidermal growth factor (EGF) receptor, and the degree of the receptor expression is correlated with the malignant phenotype in certain epithelial tumors including squamous carcinoma cells. Since phenotypic transformation of cells could involve quantitative and qualitative alteration of integrin function, the effects of EGF on cell-matrix interactions were studied using HSC-1 cells, a human squamous carcinoma cell line showing EGF receptor overexpression. The EGF-treated HSC-1 cells interacted with matrix proteins differently from the untreated cells, as shown by cell adhesion and phagokinetic track assays. Among fibronectin, laminin, fibrinogen, and type I collagen, fibronectin was the most efficient substratum to promote untreated HSC-1 cell adhesion and migration. Pretreatment of the cells with 50 ng/ml EGF for 18 h selectively increased the number of spread cells and the size of the individual cell migration area on type I collagen by 250 and 400%, respectively. The same pretreatment diminished cell adhesion and migration on other substrata so that the EGF treatment converted type I collagen as the most efficient substratum for cell adhesion and migration of the HSC-1 cells. ELISA and immunoprecipitation studies showed that EGF up-regulated the expression of alpha 2 beta 1 integrin collagen receptor in a time- and dose-dependent manner by stimulating biosynthesis of alpha 2 subunit, but did not up-regulate those of the alpha 3 beta 1, alpha 5 beta 1, or alpha v beta 3 integrins. These results suggest that EGF preferentially enhances HSC-1 cell interaction with type I collagen, leading to the enhanced cellular migratory activity on the substratum, as a result of selective up-regulation of alpha 2 beta 1 integrin expression.
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PMID:Epidermal growth factor enhancement of HSC-1 human cutaneous squamous carcinoma cell adhesion and migration on type I collagen involves selective up-regulation of alpha 2 beta 1 integrin expression. 752 89

The expression of collagen IV and tenascin was studied in a series of 219 salivary gland tumours with special emphasis on the prognostic significance of these extracellular matrix constituents. Continuous and uninterrupted staining of the basal membrane with collagen IV antibody was found in 62% (64/103) of the carcinomas and in 92% (107/116) of the benign tumours, the staining being weak and interrupted in 38% (39/103) and 8% (9/116) of cases, respectively. Weak immunoreactivity for collagen IV was significantly (p = 0.05) associated with recurrences of the malignant salivary gland tumours. Intense collagen IV staining of the basal membrane was more frequent (35.9%) in patients who were alive, as compared with that (19.4%) of the patients who died of salivary gland cancer (p = 0.03). Similarly, the intactness of the basal membrane was directly related to patient survival. In benign tumours, no such differences were found. In multivariate analysis, collagen IV immunoreactivity was related to the age of the patients (p = 0.007) and to tumour diameter > 4.0 cm (p = 0.005). Intense tenascin immunoreactivity was found in 45% (46/103) of the carcinomas and in 43% (50/116) of the benign tumours, 55% (57/103) and 57% (66/116) of the cases being entirely tenascin-negative, respectively. Tenascin immunoreactivity was not related to the clinical behaviour of malignant salivary gland tumours. In benign tumours, an intense staining for tenascin was a determinant of recurrent disease (p = 0.05). In multivariate analysis, tenascin immunoreactivity was intimately associated with erbB-2 positivity (p = 0.03) and weak staining of collagen IV (p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Collagen IV and tenascin immunoreactivity as prognostic determinant in benign and malignant salivary gland tumours. 757 38

Phosphorylation of two newly identified epidermal growth factor (EGF) receptor substrates, eps8 and eps15, which do not possess Src homology (SH2) domains, was investigated using EGF receptor mutants of the autophosphorylation sites and deletion mutants of the carboxyl-terminal region. Two mutants, F5, in which all five tyrosine autophosphorylation sites substituted by phenylalanine, and Dc 123F, in which four tyrosines were removed by deletion and the fifth (Tyr-992) was mutated into phenylalanine, phosphorylated eps8 and eps15 as efficiently as the wild-type receptor. In contrast, SH2-containing substrates, phospholipase C gamma, the GTPase-activating protein of Ras, the p85 subunit of phosphatidylinositol 3 kinase, and the Src and collagen homology protein, are not phosphorylated by the F5 and Dc 123F mutants. A longer EGF receptor deletion mutant, Dc 214, lacking all five autophosphorylation sites, was unable to phosphorylate eps15 but phosphorylated eps8 13-fold more than the wild-type receptor. To determine the EGF receptor region important for phosphorylation of eps8 and eps15, progressive deletion mutants lacking the final 123, 165, 196, and 214 COOH-terminal residues were used. eps8 phosphorylation was progressively increased in Dc 165, Dc 196, and Dc 214 EGF receptor mutants, indicating that removal of the final 214 COOH-terminal residues increases the phosphorylation of this substrate by the EGF receptor. In contrast, eps15 was phosphorylated by Dc 123 and Dc 165 EGF receptor mutants but not by Dc 196 and Dc 214 mutants. This indicates that a region of 30 residues located between Dc 165 and Dc 196 is essential for eps15 phosphorylation. This is the first demonstration of structural requirements in the EGF receptor COOH terminus for efficient phosphorylation of non-SH2-containing substrates. In addition, enhanced eps8 phosphorylation correlates well with the increased transforming potential of EGF receptor deletion mutants Dc 196 and Dc 214, suggesting that this substrate may be involved in mitogenic signaling.
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PMID:Structural requirements of the epidermal growth factor receptor for tyrosine phosphorylation of eps8 and eps15, substrates lacking Src SH2 homology domains. 760 94

Laryngeal papillomas are benign epithelial tumors caused by human papillomaviruses. These tumors are characterized by hyperplasia of the spinous layer and abnormal differentiation. Many tumor cell lines over-express the epidermal growth factor (EGF) receptor on their surface, and EGF regulates normal cell growth. We have asked about the relationship of the EGF receptor and EGF response in laryngeal papilloma cells. Papilloma cells showed markedly greater immunohistochemical staining for the EGF receptor, compared to uninfected cells. Both cell types showed a 2-3-fold increase in nuclei incorporating bromodeoxyuridine when EGF was present. Removal of EGF from papilloma cells cultured on collagen rafts permitted normal stratification and differentiation, as determined by synthesis of keratin 13. Inclusion of EGF induced abnormal differentiation with minimal expression of keratin 13. Uninfected laryngeal cells cultured on rafts in the presence of EGF synthesize keratin 13 in all suprabasal cells. EGF reduced both human papillomavirus RNA levels in the papilloma cells and expression of a reporter gene linked to the human papillomavirus 11 enhancers and E6 promoter in uninfected cells. These results suggest that the phenotype of papillomas is induced, in part, by EGF binding to the abundant EGF receptors.
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PMID:Laryngeal papilloma cells have high levels of epidermal growth factor receptor and respond to epidermal growth factor by a decrease in epithelial differentiation. 767 53

The HER4/erbB-4 gene has been isolated as the fourth member of the human EGFR subfamily of tyrosine kinases and has been reported to encode a receptor for NDF/heregulin. In the present study we determined the chromosomal location of the HER4/erbB-4 gene within the human genome. Using human cDNA probes in fluorescence in situ hybridization (FISH), we mapped the HER4/erbB-4 gene to human chromosome 2q33.3-34. This finding established that also the HER4/erbB-4 gene is located in close vicinity of homeobox and collagen gene loci, as is the case for the related EGFR, erbB-2/neu and erbB-3. Aberrations of this chromosomal region associated with T cell leukemias and lymphomas as well as alveolar rhabdomyosarcomas raise the possibility that HER4/erbB-4 might be activated in these tumour types.
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PMID:Localization of the human HER4/erbB-4 gene to chromosome 2. 770 Jun 49


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