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 epidermal growth factor (EGF) receptor is activated by both EGF and transforming growth factor-alpha (TGF-alpha). Using immunohistochemical and immunoblotting techniques we now report that the EGF receptor, EGF, and TGF-alpha are found in both pancreatic acini and ducts in the normal human pancreas, and that all three proteins are expressed at higher levels in human pancreatic cancer tissues. Using in situ hybridization techniques, we also report that the mRNA encoding the EGF receptor, EGF, and TGF-alpha colocalize with their respective proteins. Northern blot analysis of total RNA indicates that, by comparison with the normal pancreas, the pancreatic tumors exhibit a 3-, 15-, and 10-fold increase in the mRNA levels encoding the EGF receptor, EGF, and TGF-alpha, respectively. Furthermore, by in situ hybridization, there is a marked increase in these mRNA moieties within the tumor mass. These findings suggest that EGF and TGF-alpha may participate in the regulation of normal pancreatic exocrine function, and that overexpression of the EGF receptor and its two principal ligands may contribute to the pathophysiological processes that occur in human pancreatic cancer.
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PMID:Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. 140 Oct 70

The hyperplastic capacity of adipose tissue resides in a group of fibroblast-like adipocyte precursor cells. There is evidence to suggest that their proliferation and differentiation is regulated by insulin-like growth factor-I (IGF-I) and transforming growth factor-beta (TGF-beta) but there is less information about other growth factors which may also participate in adipocyte precursor cell hyperplasia. Transforming growth factor-alpha (TGF-alpha) is a 50 amino acid polypeptide which has been shown to stimulate proliferation in both neoplastic and normal cell types acting through the epidermal growth factor (EGF) receptor. We have studied the regulation of DNA synthesis and the activity of lipoprotein lipase by TGF-alpha in chicken adipocyte precursor cells in vitro. Both TGF-alpha and EGF stimulated incorporation of [3H]thymidine into DNA in a dose-dependent manner. TGF-alpha was approximately 180-fold more potent than EGF. Addition of TGF-alpha in combination with IGF-I, TGF-beta 1 or platelet-derived growth factor produced a synergistic increase in DNA synthesis. Short-term incubation with TGF-alpha reduced lipoprotein lipase activity by 23%. These results show that TGF-alpha is a potent mitogen in these adipocyte precursor cells and can inhibit their differentiation in vitro and may participate in the regulation of adipose tissue development in vivo.
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PMID:Effects of transforming growth factor-alpha on chicken adipocyte precursor cells in vitro. 140 26

This study investigated the effect of two major ingredients in cigarette smoke, benzo[a]pyrene (BP) and nicotine, on epidermal growth factor (EGF) receptor binding and EGF-mediated cellular functions in rat buccal mucosa. Rat buccal tissue was incubated in DMEM in the absence (control) and presence of 10 microM BP or nicotine for 2.5 h at 25 degrees C. There were no significant differences in [125I]EGF binding to the buccal mucosal membranes between the control and treatment groups. Protein tyrosine kinase assay showed that EGF stimulated phosphorylation of a 170-kDa protein band in the controls, but not in the BP- and nicotine-treated samples. The basal [3H]thymidine incorporations were not significantly different between the groups. Nevertheless, addition of 5 nM EGF increased [3H]thymidine incorporation by 22% in the control, but not in the BP- or nicotine-treated group. The results demonstrate that BP and nicotine change the buccal mucosal functions associated with alteration of EGF receptor.
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PMID:Benzo[a]pyrene and nicotine impair epidermal growth factor mediated cellular functions of buccal mucosa. 141 11

Growth factors and growth factor receptors are considered to be key elements in the pathogenesis of arteriosclerosis and restenosis formation. To study the local expression of epidermal growth factor (EGF) receptor, plaque tissue specimens from advanced lesions (10 coronary, two femoral, seven carotid) of 19 patients were taken for in situ hybridization studies using an EGF-specific cDNA probe. In serial vascular sections of three lesions with increased focal cellularity, autoradiographic silver grains were clearly localized to intimal cells adjacent to the internal elastic lamina. EGF mRNA transcripts were not observed in the fibrous cap, the plaque shoulders, necrotic intimal areas, or in the media. In smooth muscle cells (SMCs) cultured from human plaque tissue, EGF increased SMC proliferative activity in a dose-dependent manner (ED50: 3-6 ng of EGF/ml). Proliferative responsiveness to EGF (10 ng/ml) was found to be significantly (p < 0.01) enhanced in coronary SMCs derived from restenotic lesions as compared to those from primary stenoses. The expression of EGF receptor mRNA in human atheromatous lesions could be of prognostic value to predict an increased SMC proliferative response to stimulatory growth factors.
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PMID:[In situ detection of EGF receptor mRNA in arteriosclerotic lesions in man: implications for the proliferative activity of smooth muscle cells]. 144 90

The pathogenesis of cutaneous paraneoplastic syndromes is still under discussion. Since many of these syndromes, including acanthosis nigricans, are proliferative skin disorders it is believed that products secreted by the tumour stimulate the keratinocytes to proliferate. Growth factors like transforming growth factor alpha (TGF-alpha) are known to be highly mitogenic for keratinocytes in vitro. Here we report on a patient with a poorly differentiated gastric cancer and a full clinical picture of acanthosis nigricans characterized by diffuse hyperkeratosis and multiple papillomatous lesions of the skin with involvement of the conjunctivae. In Southern blot analysis of the tumour tissue from this patient amplification of the epidermal growth factor (EGF) receptor, the common ligand for TGF-alpha and EGF, was shown. Immunohistochemically, prominent staining was found throughout the tumour using anti-TGF-alpha antibodies. In a series of 25 investigated gastric tumour biopsies, four tumours showed amplification of the EGF receptor and one additional biopsy was positive for TGF-alpha. Since there is no other report describing the link between TGF-alpha and acanthosis nigricans, except that of Ellis et al. 1987, we present a new case suggesting a possible link between growth factors and acanthosis nigricans maligna.
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PMID:Further evidence that acanthosis nigricans maligna is linked to enhanced secretion by the tumour of transforming growth factor alpha. 144 75

Promotion of 'initiated' JB6 epidermal cells to the tumor phenotype can be effected by 12-O-tetradecanoylphorbol-13-acetate treatment, by stimulation of epidermal growth factor (EGF) receptor activity with EGF or transforming growth factor alpha and by exposure to the isoquinoline derivative H7. When these cells were incubated with pertussis toxin (PTX), induction of anchorage-independent growth by all four promoting substances was suppressed. The inhibition is specific since cell proliferation is not affected, suggesting that activation of a Gi protein is essential for promotion of the epidermal cells. This interpretation is strongly supported by the observation that the wasp poison mastoparan, which is known to mimic receptor-mediated activation of certain Gi proteins, also promoted anchorage independence. Immunological data and partial amino acid sequence analysis of ADP-ribosyl alpha i isolated from PTX-treated JB6 cells indicate that a Gi-2 protein is a mediator to tumor promotion in this system. The inhibitory action of 4-bromophenacyl bromide may point to a coupling of the Gi protein to phospholipase A2. From our data we infer that promoters induce the tumor phenotype in 'initiated' JB6 epidermal cells by activating epigenetically the same Gi protein that in a number of adrenal and ovarian tumors appears to be persistently activated by mutational events.
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PMID:Epigenetic activation of Gi-2 protein, the product of a putative protooncogene, mediates tumor promotion in vitro. 147 50

Transforming growth factor beta (TGF-beta) increased the phosphorylation of the epidermal growth factor (EGF) receptor and inhibited the growth of A431 cells. Incubation with TGF-beta induced maximal EGF receptor phosphorylation to levels 1.5-fold higher than controls. Phosphorylation increased more prominently (4-5-fold) on tyrosine residues as determined by phosphoamino acid analysis and antiphosphotyrosine antibody immunoblotting. The kinase activity of EGF receptor was also elevated 2.5-fold when cells were cultured in the presence of TGF-beta. The antiproliferative effect of TGF-beta on A431 cells was accompanied by prolongation of G0-G1 phase and by morphological changes. TGF-beta augmented the growth inhibition of A431 cells which could be induced by EGF. In parallel, the specific EGF-induced increase in total phosphorylation of the EGF receptor was also augmented in the presence of TGF-beta. In cells cultured with TGF-beta, the phosphorylation of EGF receptor tyrosines induced by 20-min exposure to EGF was further increased 2-3-fold, suggesting additive effects upon receptor phosphorylation. EGF receptor activation by TGF-beta is characterized by kinetics quite distinct from that induced by EGF and therefore appears to take place through an independent mechanism. The TGF-beta-induced elevation in the phosphorylation of the EGF receptor may have a role in the augmented growth inhibition of A431 cells observed in the presence of EGF and TGF-beta.
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PMID:Transforming growth factor beta modulates phosphorylation of the epidermal growth factor receptor and proliferation of A431 cells. 150 15

We have isolated two recessive, mutually complementary NRK cell mutants that are refractory to transformation by epidermal growth factor (EGF) and transforming growth factor-beta. Both mutants are defective in a signal transduction cascade shared by EGF and platelet-derived growth factor (PDGF). Analysis of the mutants suggests that transformation of NRK cells by the v-fms, v-erbB, activated erbB-2, v-ras, v-fos, v-mos, v-fes, v-src, SV40 large T, polyomavirus middle T, and human papillomavirus type 16 E6,E7 oncogenes is mediated by the EGF/PDGF signal cascade. The data also suggest that the EGF/PDGF cascade branches into mitogenic and oncogenic signals, the latter of which is required for soft agar growth and focus formation.
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PMID:Signal transduction cascade shared by epidermal growth factor and platelet-derived growth factor is a major pathway for oncogenic transformation in NRK cells. 151 13

A 94 year old man with an invasive ductal carcinoma of the breast (T4N2M1, stage IV), underwent a modified radical mastectomy to improve his quality of life. The estrogen receptor status of both the breast tumor and the metastatic axillar lymph nodes was high. Immunohistochemical staining for epidermal growth factor, epidermal growth factor receptor, or c-erbB-2 protein was negative. The patient received only tamoxifen continuously for 3 months, and later apparently showed a complete remission. Therefore, in advanced male breast cancer with a high estrogen receptor status, operation in conjunction with hormone therapy may lead to a favorable result in some cases.
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PMID:A 94 year old male stage IV breast cancer patient showing complete remission under tamoxifen treatment after operation. 151 97

Several cytoplasmic tyrosine kinases contain a conserved, non-catalytic stretch of approximately 100 amino acids called the src homology 2 (SH2) domain, and a region of approximately 50 amino acids called the SH3 domain. SH2/SH3 domains are also found in several other proteins, including phospholipase C-gamma (PLC gamma). Recent studies indicate that SH2 domains promote association between autophosphorylated growth factor receptors such as the epidermal growth factor (EGF) receptor and signal transducing molecules such as PLC gamma. Because SH2 domains bind specifically to protein sequences containing phosphotyrosine, we examined their capacity to prevent tyrosine dephosphorylation of the EGF and other receptors with tyrosine kinase activity. For this purpose, various SH2/SH3 constructs of PLC gamma were expressed in Escherichia coli as glutathione-S-transferase fusion proteins. Our results show that purified SH2 domains of PLC gamma are able to prevent tyrosine dephosphorylation of the EGF receptor and other receptors with tyrosine activity. The inhibition of tyrosine dephosphorylation paralleled the capacity of various SH2-containing constructs to bind to the EGF receptor, suggesting that the tyrosine phosphatase and the SH2 domain compete for the same tyrosine phosphorylation sites in the carboxy-terminal tail of the EGF receptor. Analysis of the phosphorylation sites protected from dephosphorylation by PLC gamma-SH2 revealed substantial inhibition of dephosphorylation of Tyr992 at 1 microM SH2. This indicates that Tyr992 and its flanking sequence is the high-affinity binding site for SH2 domains of PLC gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:SH2 domains prevent tyrosine dephosphorylation of the EGF receptor: identification of Tyr992 as the high-affinity binding site for SH2 domains of phospholipase C gamma. 153 35


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