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

The human erbB-2 oncogene encodes a tyrosine kinase receptor. A ligand for the erbB-2 receptor (gp30), with an apparent molecular weight of 30,000, was reported to modulate the growth of cells overexpressing erbB-2. Whereas low concentrations of gp30 induced proliferation of these cells, higher concentrations inhibited their growth. To elucidate the cellular mechanisms underlying cell growth inhibition by gp30, we tested the effect of this ligand on cell growth and differentiation of the human breast cancer cells AU-565 and MDA-MB-453 (which overexpress erbB-2) and MCF-7 cells (which express low levels of this protooncogene). Ligand concentrations that inhibited growth in cells overexpressing erbB-2 induced apparent differentiation of cells with a more mature phenotype, i.e., with characteristics such as inhibited cell growth, altered cytoplasmic and nuclear morphology, and increased synthesis of milk components (casein and lipids). No significant effect of the ligand was observed in the human breast cancer cell line MCF-7. Concomitant with the induction of differentiation in AU-565 and MDA-MB-453 cells, the erbB-2 protein was translocated from membrane to the cytoplasm and perinuclear sites. These findings indicate that ligand-induced growth inhibition in cells overexpressing erbB-2 is associated with an apparent induction of differentiation.
 ...
PMID:A ligand for the erbB-2 oncogene product (gp30) induces differentiation of human breast cancer cells. 135 80

The HER-2/neu protooncogene (also called erbB-2) encodes a tyrosine kinase receptor for a polypeptide growth-regulatory molecule. Amplification and overexpression of the gene have been frequently observed in human adenocarcinomas and correlated with poor prognosis. To explore the potential of antibody therapy directed at the HER-2/Neu receptor, we have raised a panel of murine monoclonal antibodies to the human protein, and tested their effect on the tumorigenic growth of HER-2/neu-transfected fibroblasts in athymic mice. We previously reported that the i.p. injected antibodies either inhibited or accelerated the tumorigenic growth of HER-2/neu transfectants in athymic mice. Here we report that these opposing effects were induced also by i.v. injected antibodies, they lasted over 7 weeks, and were probably mediated by distinct epitopes on the receptor molecule. To understand the cellular mechanisms underlying antibody-induced tumor inhibition, we tested the effect of the monoclonal antibodies on various cultured human breast cancer cells. Our analysis revealed that the tumor-inhibitory antibodies specifically induced phenotypic cellular differentiation that included growth arrest at late S or early G2 phase of the cell cycle, markedly altered cytoplasm and nuclear morphology, synthesis and secretion of milk components (casein and lipids), and translocation of the HER-2/Neu protein to cytoplasmic and perinuclear sites. The extent of cellular differentiation by various antibodies could be correlated with their tumor-inhibitory potential, whereas a tumor-stimulatory monoclonal antibody or control immunoglobulin were completely inactive with respect to cellular differentiation. Taken together, our in vivo and in vitro studies correlate the tumor inhibitory potential of monoclonal antibodies to HER-2/Neu with their capacity to induce cellular differentiation in vitro. This observation may hold promise for immunotherapy of cancers that express the HER-2/neu oncogene.
 ...
PMID:Tumor-inhibitory monoclonal antibodies to the HER-2/Neu receptor induce differentiation of human breast cancer cells. 137 72

The neu oncogene product, p185neu, is a tyrosine kinase receptor with structural similarity to the epidermal growth factor (EGF) receptor. We have recently described that coexpression of EGF receptors and high levels of normal p185c-neu lead to transformation of rodent fibroblasts. Anti-EGF receptor and anti-p185neu monoclonal antibodies inhibited tumorigenic growth of these transformants implanted into nude mice. These monoclonal antibodies also suppressed focus formation of the cells transformed by the synergistic action of these receptor proteins in vitro. However, EGF enhanced focus formation and stimulated cell growth when added to cells transfected just with the EGF receptor encoding cDNA. These data suggest that receptor specific effectors may have potentially useful applications in cancer therapy for neoplasms which demonstrate increased receptor densities. In addition the data suggest novel differences in the actions of tyrosine kinases when acting alone or in concert with other receptors.
 ...
PMID:Anti-receptor antibodies reverse the phenotype of cells transformed by two interacting proto-oncogene encoded receptor proteins. 197 Jan 51

p185neu, the protein product of the neu gene, is a tyrosine kinase receptor with structural similarity to the epidermal growth factor (EGF) receptor. The cognate ligand for the p185neu receptor remains unknown. We have defined: 1) stage and tissue-specific expression patterns of the neu gene product in developing tissues; 2) p185neu phosphorylation and the regulation of p185neu tyrosine kinase activity by EGF. 3) Synergistic interactions of cellular rat p185neu and EGF receptor leading to cell transformation; 4) structural and functional differences of normal and oncogenic p185neu. These observations explain some features of how p185neu is involved in normal development and neoplastic transformation.
 ...
PMID:The role of the neu oncogene product in cell transformation and normal development. 290 55

The amplification and overexpression of the HER-2/neu proto-oncogene, which encodes the tyrosine kinase receptor p185neu, have been observed frequently in tumors from human breast cancer patients and are correlated with poor prognosis. To explore the potential of chemotherapy directed at the tyrosine kinase of p185neu, we have found that emodin (3-methyl-1,6,8-trihydroxyanthraquinone), a tyrosine kinase inhibitor, suppresses autophosphorylation and transphosphorylation activities of HER-2/neu tyrosine kinase, resulting in tyrosine hypophosphorylation of p185neu in HER-2/neu-overexpressing breast cancer cells. Emodin, at a 40-microM concentration, which repressed tyrosine kinase of p185neu, efficiently inhibited both anchorage-dependent and anchorage-independent growth of HER-2/neu-overexpressing breast cancer cells. However, the inhibition was much less effective for those cells expressing basal levels of p185neu under the same conditions. Emodin also induced differentiation of HER-2/neu-overexpressing breast cancer cells by exhibiting a morphological maturation property of large lacy nuclei surrounded by sizable flat cytoplasm and by showing a measurable production of large lipid droplets, which is a marker of mature breast cells. Therefore, our results indicate that emodin inhibits HER-2/neu tyrosine kinase activity and preferentially suppresses growth and induces differentiation of HER-2/neu-overexpressing cancer cells. These results may have chemotherapeutic implications for using emodin to target HER-2/neu-overexpressing cancer cells.
 ...
PMID:Suppressed transformation and induced differentiation of HER-2/neu-overexpressing breast cancer cells by emodin. 754 19

The c-erbB-2 gene encodes a M(r) 185,000 tyrosine kinase receptor (p185) with extensive homology to the epidermal growth factor receptor. We have conducted mechanistic studies with several anti-p185 monoclonal antibodies (TAb 250, -255, -257, -260, and -263) directed against the extracellular domain of p185 utilizing the SKBR-3, BT-474, and SKOV-3 cancer cell lines. Several of these antibodies exhibited ligand-mimicking properties: they induced tyrosine phosphorylation of p185; increased the catalytic activity of the receptor substrate phospholipase C-gamma 1; exhibited time- and pH-dependent internalization; induced receptor down-regulation; and increased the turnover of the p185 protein delta 3-fold. However, there was not a universal correlation between the antibody-mediated ligand-like effects and growth inhibition. TAb 250 inhibited BT-474 cells but did not alter p185 phosphotyrosine content or increase receptor turnover in these cells. TAb 260 increased p185 protein turnover but did not affect proliferation of the SKOV-3 cell line. Furthermore, blockade of TAb 250-induced receptor phosphorylation with the tyrosine kinase inhibitor tyrphostin 50864-2 did not abrogate TAb 250-mediated growth inhibition of SKBR-3 cells. These data suggest that ligand-like effects mediated by p185 antibodies are not critical for the growth inhibition of c-erbB-2-overexpressing carcinoma cells.
 ...
PMID:Ligand-like effects induced by anti-c-erbB-2 antibodies do not correlate with and are not required for growth inhibition of human carcinoma cells. 790 1

SH2 domain proteins are important components of the signal transduction pathways activated by growth factor receptor tyrosine kinases. We have been cloning SH2 domain proteins by bacterial expression cloning using the tyrosine phosphorylated C-terminus of the epidermal growth factor receptor as a probe. One of these newly cloned SH2 domain proteins, GRB-7, was mapped on mouse chromosome 11 to a region which also contains the tyrosine kinase receptor, HER2/erbB-2. The analogous chromosomal locus in man is often amplified in human breast cancer leading to overexpression of HER2. We find that GRB-7 is amplified in concert with HER2 in several breast cancer cell lines and that GRB-7 is overexpressed in both cell lines and breast tumors. GRB-7, through its SH2 domain, binds tightly to HER2 such that a large fraction of the tyrosine phosphorylated HER2 in SKBR-3 cells is bound to GRB-7. GRB-7 can also bind tyrosine phosphorylated SHC, albeit at a lower affinity than GRB2 binds SHC. We also find that GRB-7 has a strong similarity over > 300 amino acids to a newly identified gene in Caenorhabditis elegans. This region of similarity, which lies outside the SH2 domain, also contains a pleckstrin homology domain. The presence of evolutionarily conserved domains indicates that GRB-7 is likely to perform a basic signaling function. The fact that GRB-7 and HER2 are both overexpressed and bound tightly together suggests that this basic signaling pathway is greatly amplified in certain breast cancers.
 ...
PMID:The SH2 domain protein GRB-7 is co-amplified, overexpressed and in a tight complex with HER2 in breast cancer. 790 78

Human parotid tumors were evaluated for the activation of the phosphotyrosine signaling pathway by Western blot, enzyme activity assay, and reverse transcriptase-polymerase chain reaction. Warthin's tumor and mucoepidermoid carcinomas had the greatest level of tyrosine phosphorylated proteins identified in plasma membrane fractions. These tumors, along with pleomorphic adenocarcinoma, showed high levels of membrane expression of the tyrosine kinase receptor, c-erbB-2, and phosphatidylinositol-3-kinase. Expression of the epidermal growth factor receptor was confined to normal tissue. The level of mRNA for c-erb was elevated only in mucoepidermoid carcinomas. Messenger RNA levels for ras were unchanged from control levels in all tumors, while the level of src mRNA was higher in the tumor samples than the normal parotid tissue. The activities of several signal transduction kinases, including protein kinase A and C were elevated in tumor tissue (7.7- to 18.9- and 0.4- to 3.7-fold higher, respectively), relative to surrounding normal tissue. While the level of glandular amylase was reduced (22%-0% of normal levels) in the tumor tissue, epidermal growth factor (EGF) and transforming growth factor-alpha (TGFalpha) content was dramatically higher in the neoplastic tissue (10- to 170-fold and 4.6- to 6.0-fold, respectively). These results suggest that with the presence of elevated levels of EGF, TGFalpha, and the oncoprotein receptor c-erbB-2 in the membrane of parotid tumors, cell proliferation and activation of the phosphotyrosine signal transduction pathway may involve autocrine stimulation through the expression of high levels of growth factor and receptor in the same tissue.
 ...
PMID:Alterations in the level of phosphotyrosine signal transduction constituents in human parotid tumors. 863 6

Overexpression of the HER-2/neu proto-oncogene which encodes tyrosine kinase receptor p185neu, has been observed frequently in many human cancers, including non-small cell lung cancer (NSCLC), and is correlated with poor patient survival in these cancers. In addition, HER-2/neu overexpression in NSCLC is known to induce chemoresistance. Recently, we demonstrated that emodin, a tyrosine kinase inhibitor, suppresses HER-2/neu tyrosine kinase activity in HER-2/neu-overexpressing breast cancer cells and preferentially represses proliferation of these cells. The work described here was carried out to examine (1) whether the tyrosine kinase activity of p185neu is required for resistance to chemotherapeutic drugs of HER-2/neu-overexpressing NSCLC cells and (2) whether the tyrosine kinase inhibitor emodin can sensitize these cells to chemotherapeutic drugs. We found that emodin decreased tyrosine phosphorylation of HER-2/neu and preferentially suppressed proliferation of HER-2/neu-overexpressing NSCLC cells. Furthermore, the combination of emodin with cisplatin, doxorubicin or etoposide (VP16) synergistically inhibited the proliferation of HER-2/neu-overexpressing lung cancer cells, whereas low doses of emodin, cisplatin, doxorubicin, or VP16 alone had only minimal antiproliferative effects on these cells. These results indicate that tyrosine kinase activity is required for the chemoresistant phenotype of HER-2/neu-overexpressing NSCLC cells and that tyrosine kinase inhibitors such as emodin can sensitize these cells to chemotherapeutic drugs. The results may have important implications in chemotherapy for HER-2/neu-overexpressing cancers.
 ...
PMID:Sensitization of HER-2/neu-overexpressing non-small cell lung cancer cells to chemotherapeutic drugs by tyrosine kinase inhibitor emodin. 863 14

In this report, we have discussed a series of results obtained in our laboratory that, together with data by other authors, demonstrate that the expression of the erbB-2 tyrosine kinase receptor oncogene in breast cancer cells is regulated by multiple factors and hormones, which modulate their growth and differentiation. In particular, we have shown that estrogens specifically inhibit erbB-2 expression by transcriptional repression, which is exerted through a sequence within the erbB-2 gene promoter. Estrogens control mammary cell growth directly, by inducing early gene expression, and indirectly, by increasing autocrine growth factor production or decreasing growth inhibitors. The data presented here suggest that mammary cells respond to estrogen also by modifying the receptor array on their surface, thus setting their own sensitivity to the different autocrine and paracrine factors. As a first consequence, the modulation of erbB-2 expression level by antiestrogen may represent a point to consider when selecting breast cancer patients for hormonal therapy, in those (few) cases where estrogen receptor positivity accompanies erbB-2 amplification. On the other hand, antiestrogen-induced upregulation of erbB-2 may improve tumor targeting of drugs designed to interact or interfere with erbB-2, such as humanized antibodies, immunotoxins, or engineered ligands. These possibilities should be tested in appropriate model systems in the future.
 ...
PMID:Hormonal control of growth factor receptor expression. 865 82


1 2 3 4 5 6 Next >>