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)

Growth of epithelial ovarian cancer is influenced by several factors including transforming growth factor-alpha and transforming growth factor-beta, macrophage colony stimulating factor, tumor necrosis factor-alpha, interleukin-1 and interleukin-6, c-erb B-2 (HER-2/neu), and mutant p53. Continued expression of the epidermal growth factor receptor, new expression of c-fms, and overexpression of HER-2/neu are associated with a poor prognosis. A number of cytokines have been used to treat patients with ovarian cancer, including interferon-alpha, interferon-gamma, tumor necrosis factor-alpha, and interleukin-2. Judging from preclinical models, interferon-gamma may be more active than interferon-alpha against human ovarian cancer. Although tumor necrosis factor-alpha can stimulate proliferation of some ovarian cancers, the cytotoxic activity of tumor necrosis factor-alpha has been amplified ex vivo by inhibitors of protein synthesis. Similar heterogeneity exists with regard to interleukin-1 where stimulation or inhibition of cell proliferation has been observed. Tumor-infiltrating lymphocytes from ascites fluid contain cells capable of major histocompatibility complex-restricted and major histocompatibility complex-nonrestricted cytotoxicity. Tumor-infiltrating lymphocytes and interleukin-2 have been combined with cytotoxic chemotherapy to treat advanced or recurrent disease. Bispecific monoclonal antibodies that react both with T cells and ovarian tumor cells have produced tumor inhibition in human tumor xenografts. Immunotoxins that contain OVB3 and pseudomonas exotoxin have been evaluated in a phase I clinical trial. Dose-limiting central neurotoxicity has been observed without tumor regression. A monoclonal antibody designated OVX1 has been developed against a high-molecular-weight mucinlike molecule associated with ovarian cancers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biology and therapy with biologic agents in gynecologic cancer. 145 11

The discovery of cancer-causing genes has provided us with the exciting opportunity to begin to understand the molecular pathology of ovarian cancer. Activation of several of these genes including HER-2/neu, myc, ras, and p53 has been described in some ovarian cancers (Table 2). In addition, some proto-oncogenes such as the EGF receptor (erbB) and the M-CSF receptor (fms) are expressed along with their respective ligands in some ovarian cancers. Finally, for every oncogene that has been studied in ovarian cancer, there are at least a half-dozen that remain unexplored. In the future, when we have a better understanding of the molecular pathology involved in the development of ovarian cancer, this may allow us to better diagnose and treat, and eventually prevent, ovarian cancer.
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PMID:Oncogenes in ovarian cancer. 150 Mar 87

A role for proto-oncogenes in the regulation and modulation of cell proliferation has been suggested by the findings that the B-chain of platelet-derived growth factor (PDGF) is encoded by the proto-oncogene sis and that the erb-B oncogene product is a truncated form of the epidermal growth factor (EGF) receptor. Furthermore, the product of the proto-oncogene fms (c-fms) may be related or identical to the receptor for macrophage colony-stimulating factor (CSF-1). v-fms is the transforming gene of the McDonough strain of feline sarcoma virus (SM-FeSV) and belongs to the family of src-related oncogenes which have tyrosine-specific kinase activity. Furthermore, nucleotide sequence analysis of the v-fms gene product revealed topological properties of a cell-surface receptor protein. To elucidate the features involved in the conversion of a normal cell-surface receptor gene into an oncogenic one, we have now determined the complete nucleotide sequence of a human c-fms complementary DNA. The 972-amino-acid c-fms protein has an extracellular domain, a membrane-spanning region, and a cytoplasmic tyrosine protein kinase domain. Comparison of the feline v-fms and human c-fms sequences reveals that the proteins share extensive homology but have different carboxyl termini.
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PMID:Structural alteration of viral homologue of receptor proto-oncogene fms at carboxyl terminus. 242 Nov 65

The c-cbl protooncogene product (c-Cbl) is a 120-kDa protein that has been shown to bind to the Src homology 3 domains of various proteins, suggesting its involvement in signal transduction pathways. We identified one of the most prominent tyrosine-phosphorylated proteins in Fc gamma receptor (Fc gamma R)-stimulated macrophages to be c-Cbl. Tyrosine phosphorylation of c-Cbl occurred within 20 s after stimulation and reached maximum levels within 3-5 min. c-Cbl was also tyrosine-phosphorylated in epidermal growth factor (EGF) receptor-overexpressing cells upon EGF stimulation, in macrophages in response to CSF-1 treatment, and in v-src transformed cells. Furthermore, we found that c-Cbl associated with these kinases in vivo. In vitro, c-Cbl bound to the Src homology 3 domains of Src, Fyn, and Lyn in both unstimulated and Fc gamma R-stimulated macrophages. Examination of cells by immunofluorescence revealed that c-Cbl is diffusely distributed in the cytoplasm in both unstimulated macrophages and EGF receptor-overexpressing cells and translocated to a more specific compartment of the cell, consistent with the trans-Golgi region, following Fc gamma R clustering and EGF stimulation, respectively. These results suggest that c-Cbl is involved in the signaling pathways utilized by different types of tyrosine kinases.
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PMID:Tyrosine phosphorylation and translocation of the c-cbl protein after activation of tyrosine kinase signaling pathways. 778 94

More fundamental understanding of cell growth regulation will provide novel approaches for detecting, preventing, and treating different cancers. Activation of protooncogenes or loss of tumor-suppressor genes can have both prognostic and therapeutic importance. In epithelial ovarian cancer, poor prognosis is associated with continued expression or overexpression of tyrosine kinase growth factor receptors p170EGFR, p165fms, and p185erbB-2. Over-expression of erbB-2 (HER-2/neu) by breast and ovarian cancers already permits effective targeting of antibodies and immunotoxins. Ultimately, molecular analysis of individual cancers will guide the application of specific therapies to inhibit activated oncogenes or restore the function of tumor-suppressor genes. Circulating growth factors, oncogene products, and tumor-associated antigens may provide markers for earlier detection of some cancers. In epithelial ovarian cancer, concentrations of CA 125 can be increased 1-5 years before clinical diagnosis, and approximately 50% of patients with stage I disease have had an abnormal CA 125 concentration. Combining CA 125 with two novel markers--OVX1 and M-CSF--has retrospectively detected > 98% of stage I ovarian cancers. Although the specificity of the three markers is insufficient for cost-effective screening, serum tests for them could prompt the performance of transvaginal sonography, substantially decreasing the number of sonograms required. Genetic markers in the germ line of patients at increased risk for certain cancers will almost certainly influence strategies for prevention or detection. In familial breast, and ovarian cancer, a locus on chromosome 17q tracks risk of cancer in a fraction of kindreds. How often germline abnormalities will be detected in patients with apparently sporadic cancer remains to be determined.
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PMID:Perspectives on the future of cancer markers. 822 57

The feline sarcoma virus oncogene v-fms has significantly contributed to the dissection of peptide growth factor action since it encodes the transmembrane tyrosine kinase gp140v-fms, a transforming version of colony-stimulating factor 1 receptor, a member of the growth factor receptor tyrosine kinase family. In this study, the functional significance of structural differences between distinct tyrosine kinase types, in particular between cellular receptors and viral transforming proteins of distinct structural types, has been further investigated, and their functional compatibility has been addressed. For this purpose, major functional domains of three structurally distinct tyrosine kinases were combined into two chimeric receptors. The cytoplasmic gp140v-fms kinase domain and the kinase domain of Rous sarcoma virus pp60v-src were each fused to the extracellular ligand-binding domain of the epidermal growth factor (EGF) receptor to create chimeras EFR and ESR, respectively, which were studied upon stable expression in NIH 3T3 fibroblasts. Both chimeras were faithfully synthesized and routed to the cell surface, where they displayed EGF-specific, low-affinity ligand-binding domains in contrast to the high- and low-affinity EGF-binding sites of normal EGF receptors. While the EFR kinase was EGF controlled for autophosphorylation and substrate phosphorylation in vitro, in vivo, and in digitonin-treated cells, the ESR kinase was not responsive to EGF. While ESR appeared to recycle to the cell surface upon endocytosis, EGF induced efficient EFR internalization and degradation, and phorbol esters stimulated protein kinase C-mediated downmodulation of EFR. Despite its ligand-inducible kinase activity, EFR was partly EGF independent in mediating mitogenesis and cell transformation, while ESR appeared biologically inactive.
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PMID:Epidermal growth factor (EGF) modulation of feline sarcoma virus fms tyrosine kinase activity, internalization, degradation, and transforming potential in an EGF receptor/v-fms chimera. 825 51

The discovery of peptide growth factors and cancer-causing genes (oncogenes and tumor-suppressor genes) has provided us with the exciting opportunity to begin to understand the molecular pathology of human ovarian cancer. Activation of several genes, including HER-2/neu, myc, ras, and p53 have been described in some ovarian cancers. In addition, some protooncogenes such as the epidermal growth factor receptor (erbB) and the M-CSF receptor (fms) are expressed along with the respective ligands (peptide growth factors) in some ovarian cancers. Although the studies reviewed in this paper represent a promising beginning, we remain far from a comprehensive understanding of growth regulation and transformation of human ovarian epithelium.
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PMID:Growth regulation and transformation of ovarian epithelium. 842 Jun 75

In an increasing number of hematopoietic cytokine receptor systems (T-cell receptor, B-cell receptor, and macrophage colony-stimulating factor, stem cell factor, interleukin-3, and erythropoietin [EPO] receptors), inhibitory roles for the protein tyrosine phosphatase hematopoietic cell phosphatase (HCP; SHPTP1, PTP1C, and SHP1) have been defined in proliferative signaling. However, evidence exists to suggest that HCP also may exert important effects on blood cell differentiation. To investigate possible roles for HCP during late erythroid differentiation, effects of manipulating HCP expression or recruitment on EPO-induced hemoglobinization in erythroleukemic SKT6 cells have been investigated. No effects of EPO on levels of HCP, Syp, Stat5, the EPO receptor, or GATA-1 expression were observed during induced differentiation. However, the tyrosine phosphorylation of JAK2, the EPO receptor, and Stat5 was efficiently activated, and HCP was observed to associate constitutively with the EPO receptor in this differentiation-specific system. In studies of HCP function, inhibition of HCP expression by antisense oligonucleotides enhanced hemoglobinization, whereas the enforced ectopic expression of wild-type (wt) HCP markedly inhibited EPO-induced globin expression and Stat5 activation. Based on these findings, epidermal growth factor (EGF) receptor/EPO receptor chimeras containing either the wt EPO receptor cytoplasmic domain (EECA) or a derived HCP binding site mutant (EECA-Y429,431F) were expressed in SKT6 cells, and their abilities to mediate differentiation were assayed. Each chimera supported EGF-induced hemoglobinization, but efficiencies for EECA-Y429,431F were enhanced 400% to 500%. Thus, these studies show a novel role for HCP as a negative regulator of EPO-induced erythroid differentiation. In normal erythroid progenitor cells, HCP may act to prevent premature commitment to terminal differentiation. In erythroleukemic SKT6 cells, this action also may enforce mitogenesis.
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PMID:Hematopoietic cell phosphatase negatively regulates erythropoietin-induced hemoglobinization in erythroleukemic SKT6 cells. 931 Apr 68

Dendritic cells (DCs) are bone marrow-derived leukocytes that function as potent antigen presenting cells capable of initiating T cell-dependent responses from quiescent lymphocytes. DC pulsed with tumor-associated antigen (TAA) peptide or protein have recently been demonstrated to elicit antigen-specific protective antitumor immunity in a number of murine models. Transduction of DCs with TAA genes may allow stable, prolonged antigen expression as well as the potential for presentation of multiple, or unidentified, epitopes in association with major histocompatibility complex class I and/or class II molecules. To evaluate the potential efficacy of retrovirally transduced DCs, bone marrow cells harvested from BALB/c mice were transduced with either a model antigen gene encoding beta-galactosidase (beta-gal) or a control gene encoding rat HER-2/neu (Neu) by coculture with irradiated ecotropic retroviral producer lines. Bone marrow cells were differentiated into DC in vitro using granulocyte/macrophage colony-stimulating factor and interleukin-4. After 7 d in culture, cells were 45-78% double positive for DC phenotypic cell surface markers by FACS(R) analysis, and DC transduced with beta-gal were 41-72% positive for beta-gal expression by X-gal staining. In addition, coculture of beta-gal transduced DC with a beta-gal-specific T cell line (CTLx) resulted in the production of large amounts of interferon-gamma, demonstrating that transduced DCs could process and present endogenously expressed beta-gal. DC transduced with beta-gal and control rat HER-2/neu were then used to treat 3-d lung metastases in mice bearing an experimental murine tumor CT26.CL25, expressing the model antigen, beta-gal. Treatment with beta-gal-transduced DC significantly reduced the number of pulmonary metastatic nodules compared with treatment with Hank's balanced salt solution or DCs transduced with rat HER-2/neu. In addition, immunization with beta-gal-transduced DCs resulted in the generation of antigen-specific cytotoxic T lymphocytes (CTLs), which were significantly more reactive against relevant tumor targets than CTLs generated from mice immunized with DCs pulsed with the Ld-restricted beta-gal peptide. The results observed in this rapidly lethal tumor model suggest that DCs transduced with TAA may be a useful treatment modality in tumor immunotherapy.
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PMID:Dendritic cells retrovirally transduced with a model antigen gene are therapeutically effective against established pulmonary metastases. 933 60

HER-2/neu is a "self" tumor antigen that is overexpressed in 15-30% of human adenocarcinomas. Vaccine strategies directed against HER-2/neu and other self tumor antigens require development of methods to overcome immune tolerance to self-proteins. In rats, rat neu peptide vaccines have been shown to be an effective way of circumventing tolerance to rat neu protein and generating rat neu-specific immunity. The present report validates that a similar peptide-based vaccine formulation is effective for inducing T-cell immunity to HER-2/neu protein in humans with breast and ovarian cancer. The vaccine formulation included groups of peptides derived from the HER-2/neu extracellular domain (ECD) or intracellular domain (ICD) mixed with granulocyte macrophage colony stimulating factor as an adjuvant. These peptides were 15-18 amino acids in length and designed to elicit a CD4 T helper-specific immune response. Patients underwent intradermal immunization once a month for a total of two to six immunizations. To date, all of the patients immunized with HER-2/neu peptides developed HER-2/neu peptide-specific T-cell responses. The majority of patients (six of eight) also developed HER-2/neu protein-specific responses. Responses to HER-2/neu protein occurred with epitope spreading. Immune T cells elicited by vaccination were shown to migrate outside the peripheral circulation by virtue of generating delayed type hypersensitivity responses distant from the vaccine site, which indicated the potential ability to traffic to the site of tumor. The use of peptide-based vaccines may be a simple, yet effective, vaccine strategy for immunizing humans to oncogenic self-proteins.
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PMID:Generation of immunity to the HER-2/neu oncogenic protein in patients with breast and ovarian cancer using a peptide-based vaccine. 1038 11


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