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 protein product of the neu protooncogene, p185, is a tyrosine kinase with a high degree of sequence homology to the epidermal growth factor (EGF) receptor. Although p185 does not bind EGF, EGF stimulates tyrosine phosphorylation of p185. To determine the mechanism of this interaction we have used a vaccinia virus/bacteriophage T7-based transient gene expression system to induce production of normal and kinase-deficient forms of p185 in the absence and presence of EGF receptors. Tyrosine phosphorylation of kinase-deficient p185 was observed, but only in the presence of the EGF receptor. These findings strongly support the hypothesis that p185 is a substrate for the EGF receptor tyrosine kinase in a tyrosine kinase cascade.
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PMID:The epidermal growth factor receptor and the product of the neu protooncogene are members of a receptor tyrosine phosphorylation cascade. 197 18

We previously demonstrated that occupancy of the epidermal growth factor (EGF) receptor reduced the ability of vaccinia virus to infect L cells [Eppstein et al: Nature 318:663, 1985]. This result suggested that vaccinia virus was utilizing the EGF receptor as one pathway to infect cells. We have studied this system further, and now find that antibodies to the EGF receptor also reduce the ability of vaccinia virus to infect cells productively. Inclusion of both EGF and antibodies to the EGF receptor did not cause inhibition over that obtained by EGF alone, providing another line of evidence that the antiviral effects on vaccinia virus were at the level of the EGF receptor. The antiviral effects of EGF or synthetic peptides corresponding to the third disulfide loop of TGF-alpha or the vaccinia virus growth factor were specific to vaccinia virus and did not inhibit replication of herpes simplex virus type 2 or vesicular stomatitis virus. The inhibitory effects on replication of vaccinia virus were obtained when EGF (but not insulin or growth hormone) was present prior to, but not after, productive viral adsorption. These results provided further evidence that the antivaccinia viral effects of EGF were at the level of initial receptor occupancy. As interferon (IFN) treatment has been shown to interfere with the action of some growth factors, including EGF, we examined the effects of IFN treatment of cells on the antivaccinia viral activity of EGF. Our results show that the antivaccinia effect of IFN-beta either interfered with or partially coalesced with the inhibitory effects of EGF.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vaccinia virus and the EGF receptor: a portal for infectivity? 349 35

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 oncogene HER-2/neu is genetically amplified and overexpressed in a large number of human adenocarcinomas and has been implicated in the tumorigenic phenotype. Although it is a nonmutated self-protein, it is barely detectable in adult tissues, and immune responses toward it have been described in a number of patients. It is, thus, an attractive candidate antigen for the immunotherapy of cancer patients. HLA-A2+ patients with metastatic breast, ovarian, or colorectal adenocarcinomas that overexpressed HER-2/neu were immunized with the HLA-A2-binding epitope p369-377 (p369). Patients were treated by repeated immunization with 1 mg of p369 in Freund's incomplete adjuvant every 3 weeks. Peripheral blood mononuclear cells were collected prior to immunization and following two and four immunizations and were stimulated in vitro with peptide and assayed for peptide and tumor recognition. In three of four patients, peptide-specific CTLs were detected in post- but not preimmunization blood. These CTLs recognized peptide-pulsed target cells at peptide concentrations of > or =1 ng/ml yet failed to react with a panel of HLA-A2+ HER-2/neu+ tumor lines. In addition, infecting HLA-A2+ cells with recombinant vaccinia virus encoding HER-2/neu or up-regulating HLA-A2 with IFN-gamma in HER-2/neu+ cells also failed to confer reactivity by p369-reactive T-cells. A T-cell response to the HLA-A2 binding epitope p369 can be easily generated by immunizing patients with peptide in Freund's incomplete adjuvant. However, the CTLs failed to react with HER-2/neu+ tumor cells. Further studies are needed to determine whether and how HER-2 might serve as an antigen for tumor immunotherapy.
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PMID:Immunization with a peptide epitope (p369-377) from HER-2/neu leads to peptide-specific cytotoxic T lymphocytes that fail to recognize HER-2/neu+ tumors. 980 97

HER-2/neu (neu-N) transgenic mice, which express the nontransforming rat proto-oncogene, develop spontaneous focal mammary adenocarcinomas beginning at 5-6 months of age. The development and histology of these tumors bears a striking resemblance to what is seen in patients with breast cancer. We have characterized the immunological responses to HER-2/neu (neu) in this animal model. neu-positive tumor lines, which were derived from spontaneous tumors that formed in neu-N animals, are highly immunogenic in parental, FVB/N mice. In contrast, a 100-fold lower tumor challenge is sufficient for growth in 100% of transgenic animals. Despite significant tolerance to the transgene, neu-specific immune responses similar to those observed in breast cancer patients can be demonstrated in neu-N mice prior to vaccination. Both cellular and humoral neu-specific responses in transgenic mice can be boosted with neu-specific vaccination, although to a significantly lesser degree than what is observed in FVB/N mice, indicating that the T cells involved are less responsive than in the nontoleragenic parental strain. Using irradiated whole-cell and recombinant vaccinia virus vaccinations we are able to protect neu-N mice from a neu-expressing tumor challenge. T-cell depletion experiments demonstrated that the observed protection is T cell dependent. The vaccine-dependent neu-specific immune response is also sufficient to delay the onset of spontaneous tumor formation in these mice. These data suggest that, despite tolerance to neu in this transgenic model, it is possible to immunize neu-specific T cells to achieve neu-specific tumor rejection in vivo. These transgenic mice provide a spontaneous tumor model for identifying vaccine approaches potent enough to overcome mechanisms of immune tolerance that are likely to exist in patients with cancer.
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PMID:HER-2/neu is a tumor rejection target in tolerized HER-2/neu transgenic mice. 1091 70

HER-2/neu is a tumor-associated antigen overexpressed in a large variety of human tumors. Eight HER-2/neu peptides displaying HLA-A*0201 anchoring motifs were selected and tested for their binding affinity to HLA-A*0201 and their capacity to elicit cytotoxic T lymphocyte (CTL) responses in both HLA-A*0201 transgenic mice and in HLA-A*0201(+) healthy donors. Two high-affinity (p5 and p48) and one intermediate-affinity (p1023) peptides triggered CTL responses in both transgenic mice and humans, comparable to those observed for the well-known HER2/neu dominant peptide p369. CTL induced in transgenic mice lysed HLA-A*0201(+) RMA cells infected with recombinant HER-2/neu but not cells infected with wild-type vaccinia virus. Human CTL lysed HLA-A*0201(+) HER-2/neu(+) tumor cells of different origins (breast, colon, lung and renal cancer) irrespective of the expression levels of HER-2/neu. Importantly, primed CTL specific for these epitopes were detected in freshly isolated tumor-infiltrating lymphocytes from three renal cell carcinoma patients. Therefore, the HER-2/neu peptides p5, p48 and p1023 may be good candidates for immunotherapy of a broad spectrum of tumors, including renal cell carcinoma.
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PMID:Identification of HER-2/neu immunogenic epitopes presented by renal cell carcinoma and other human epithelial tumors. 1174 43