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 occurrence of ERBB-2 (HER-2/NEU) oncogene amplification was studied in 203 DNA samples obtained from 175 cancer patients. Amplification of ERBB-2 oncogene was established in 14 out of 63 (22%) patients with breast cancer, 1 out of 23 cases of ovarian tumor, 1 out of 19 cases of large bowel cancer and 1 out of 27 patients with cancer of the thyroid. Patients with lung cancer (34), soft tissue sarcoma (6) and malignant melanoma (3) failed to reveal any changes in the above oncogene. A tendency was established for ERBB-2 oncogene amplification to be associated with lymph node involvement in female patients with breast cancer: amplification was observed in 9 out of 28 patients presenting with lymph node metastases and only in 5 out of 29 metastases-free cases. To summarize, ERBB-2 oncogene is fairly often activated in human tumors but a high occurrence of the gene amplification was observed in female patients with breast cancer only.
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PMID:[The search for amplification of the ERBB-2 oncogene in human tumors]. 130 Jul 65

Transforming growth factor-alpha-Pseudomonas exotoxin-40 (TP40) is a recombinant fusion protein. TP40 consists of the entire human transforming growth factor-alpha (TGF alpha) protein fused to a 40,000 Da. segment of the Pseudomonas exotoxin A protein. TP40 is a bifunctional molecule that possesses the epidermal growth factor (EGF) receptor binding properties of TGF alpha and the cell killing properties of Pseudomonas exotoxin A. These properties make TP40 a selective cytotoxic agent that kills EGF receptor bearing cells. TP40 has been shown to effectively kill human tumor cell lines that possess EGF receptors in vitro and in nude mice. In the present study, TP40 was tested against tumors taken directly from patients and grown in a soft agar human tumor cloning system. A total of 107 patients' tumors (taken from patients with tumors refractory to chemotherapy) were tested with a continuous exposure to 0.5-50 nM concentrations of the agent. TP40 exhibited a clear dose response effect against a wide variety of human solid tumor colony-forming units with greater than or equal to 84% of evaluable tumors responding at a drug concentration greater than or equal to 24 nM. When used as a continuous exposure, concentrations of TP40 as low as 5 nM demonstrated substantial in vitro activity. This activity included cytotoxicity against breast, colorectal, endometrial, head and neck, non small-cell lung, gastric, sarcoma, and pancreatic cancer tumor colony-forming units. Additional in vivo testing of this compound is warranted.
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PMID:Activity of a recombinant transforming growth factor-alpha-Pseudomonas exotoxin hybrid protein against primary human tumor colony-forming units. 160 49

Streptomyces and other microorganisms produce antibiotics, and enzyme inhibitors as secondary metabolites. Thus, they could be said as a treasury of organic compounds which have various structures and biological functions. Since oncogene theory has been extensively developed, we have screened oncogene function inhibitors from microorganisms as a new group of microbial secondary metabolites. Erbstatin is an inhibitor of epidermal growth factor (EGF) receptor and p60v-src-associated tyrosine kinase. Its inhibitory pattern vs. peptide is competitive. In cell culture it inhibited both EGF receptor autophosphorylation and internalization. Recently, we have isolated lavendustin A, an extremely potent inhibitor of tyrosine kinase, from Streptomyces. Lavendustin A is a novel compound and about 50 times stronger than erbstatin in inhibiting tyrosine kinase. Oxanosine is an inhibitor of ras oncogene product activity. It induces normal phenotypes in temperature-sensitive Kirsten sarcoma virus-infected rat kidney cells, lowering the intracellular levels of guanine nucleotides. Many oncogenes including src, ras, sis, fms and erbB are known to activate cellular phosphatidylinositol (PI) turnover. Therefore we have screened inhibitors of PI turnover and isolated psi-tectorigenine and pendolmycin from Nocardiopsis and inostamycin from Streptomyces. PI kinase is an enzyme involved in PI turnover pathways. We have isolated 2, 3-dihydroxybenzoic acid from Streptomyces as an inhibitor of PI kinase. These oncogene function inhibitors from microorganisms will be useful for the mechanistic study of oncogene product activities.
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PMID:[Inhibitors of oncogene product functions]. 215 83

A subpopulation of cells was derived from the Hs431 connective tissue sarcoma cell line which possessed high affinity (estimated Kd = 0.38-0.55 nM) binding sites for human recombinant [125I]-IL-1 alpha. Binding at 4 degrees C was slow approaching equilibrium by 4 hrs. Dissociation of [125I]-IL-1 alpha was also slow and unaffected by high concentrations of cold ligand. The binding site also underwent ligand-induced internalization at 37 degrees C. An Mr = 83,000 protein was identified in affinity crosslinking studies. Despite these similarities to previously reported IL-1 receptors, Hs431 cells did not exhibit biological responses to IL-1 which have been observed in other cell lines. IL-1 did not induce PGE2 or collagenase synthesis. IL-1 also failed to induce ornithine decarboxylase activity (ODC) or stimulate [3H]-thymidine incorporation. In contrast, the Hs431 cells did contain a functional epidermal growth factor (EGF) receptor as determined from binding studies, protein kinase activity, induction of ODC, and stimulation of [3H]-thymidine incorporation. Thus, the refractoriness of Hs431 cells to IL-1 was fairly specific and did not result from a generalized defect associated with cell transformation.
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PMID:Characterization of a high affinity interleukin-1 (IL-1) specific binding site in a human synovial sarcoma (Hs431) cell line. 216 29

We previously isolated a Fisher rat fibroblast mutant, B812, that has the unique property of temperature-dependent transformation by various oncogenic retroviruses. At the permissive temperature (35 degrees C), this mutant was sensitive to oncogenic transformation and formed foci on a dish at the same frequency as did the parental fibroblast cell line. When Kirsten murine sarcoma virus (Ki-MSV) was applied to the cells, the frequency of focus formation decreased more than 25-fold at the nonpermissive temperature (39 degrees C), whereas the cells expressed nearly the same level of the ras transcript as well as the ras protein. The temperature-restricted focus formation was fully reversible and was completely suppressed upon fusion with the wild-type parent cell. In addition to ras, the mos, fos, src, and erbB-2 oncogenes transformed this mutant with the same temperature dependence as described above; polyomavirus middle T antigen, adenovirus type 12, and human papillomavirus 16-E67 also transformed, but without temperature dependence. These results suggest that ras, fos, mos, src, and erbB-2 use a common cellular pathway for transforming cells.
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PMID:A cell mutant that exhibits temperature-dependent sensitivity to transformation by various oncogenes. 247 32

We first describe the characterization of proto-oncogene of v-ros in chicken and human genomes. v-ros sequence of UR2 avian sarcoma virus carries a hydrophobic short stretch upstream of the kinase domain, suggesting that its proto-oncogene encodes for a receptor molecule. Using v-ros DNA as a probe we isolated chicken and human c-ros proto-oncogenes. These c-ros DNAs contained a tyrosine kinase domain, transmembrane domain and a part of an extracellular domain carrying an N glycosylation site which was not acquired by UR2 sarcoma virus. These results strongly suggest that proto-oncogene c-ros encodes for a receptor of cell growth or differentiation factor(s) and that the v-ros sequence is a truncated form of this receptor molecule. Structural alteration and overexpression under the control of viral promoter may be crucial for transforming activity of v-ros gene. We then report another example where a receptor-type oncogene is qualitatively and quantitatively activated. By screening with various onc probes we detected two human glioblastomas which have amplification of structurally altered c-erbB1 (epidermal growth factor (EGF) receptor) gene. c-erbB1 gene in these tumors bears a small deletion within the extracellular domain, and the gene product 140 kd protein shorter than the normal 170 kd EGF receptor was heavily phosphorylated on tyrosine residue even without ligand in in vitro phosphorylation reaction. Thus, these mutated EGF receptors seem to be fixed as a "switch-on" form in signal transduction for cell growth and might be involved in the transformation of glial cells.
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PMID:Analysis of structure and activation of some receptor-type tyrosine kinase oncogenes. 345 14

Cells transformed by murine sarcoma viruses (MSV) produce and release into their tissue culture media several polypeptide growth stimulating factors. One of these has been partially purified using Bio-Gel P-60 column chromatography followed by DEAE-cellulose chromatography. This growth factor was assigned the name sarcoma growth factor (SGF), and is here shown to require the epidermal growth factor (EGF) receptor in order to function as a growth factor. DEAE-cellulose chromatography yielded a product that was several-fold purer than the material present in the Bio-Gel P-60 column pool II. The biologically active material from the DEAE-cellulose column, when labeled with 125I, showed specific binding to EGF membrane receptors. The specific binding could be prevented with the addition of either unlabeled EGF or SGF. Both radiolabeled SGF and EGF will bind to live or fixed cells. We were able to bind 125I-SGF as well as 125I-EGF to fixed cells and elute the bound material from fixed receptors. The eluted SGF showed a greater than 25-fold increase in specific binding. The biological activities of EGF and SGF could be bound to and eluted from fixed receptors. The eluted SGF showed a greater than 25-fold increase in specific binding. The biological activities of EGF and SGF could be bound to and eluted from fixed cells. A 3T3 clone lacking EGF receptors was unable to respond to either EGF or SGF, whereas it responded well to serum and several other purified growth factors. The SGF isolated using DEAE-cellulose chromatography was unable to compete in a radioimmune assay using 125I-EGF and antibody to purified mouse submaxillary gland EGF; it also was not precipitated by anti-EGF antibody. From these studies it appears that the SGF produced and released by these MSV-transformed cells combines with and requires the EGF receptor in order to exert its biological effects. The peptide, however, is antigenically distinct from mouse submaxillary gland EGF.
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PMID:Sarcoma growth factor (SGF): specific binding to epidermal growth factor (EGF) membrane receptors. 624 30

The role of the epidermal growth factor (EGF) receptor system in mediating the biological activities of sarcoma growth factor (SGF) has been assessed by using specific anti-EGF receptor antibodies. There are two classes of anti-EGF receptor antibodies, those that block binding of 125I-labeled EGF (125I-EGF) and those that do not block binding but do interact with a portion of the EGF receptor on the surface of intact cells. Antisera of both types have been assayed for their capacity to affect the biological activities of SGF. The antisera that block 125I-EGF binding to its receptor block the induction of DNA synthesis in human fibroblasts by either EGF or SGF but not by other polypeptide mitogens. Titration of the anti-EGF receptor antiserum indicates the presence of one population of antibody that blocks the site of both EGF and SGF action. Antisera to the EGF receptor that block 125I-EGF binding also inhibited the SGF-dependent anchorage-independent growth of normal cells in soft agar. The antisera to the EGF receptor that does not block 125I-EGF binding or EGF activity did not inhibit any of the biological activities of SGF. The results suggest that occupation of the EGF receptor is required for both the mitogenic and colony-forming activity of SGF.
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PMID:Antibodies to the epidermal growth factor receptor block the biological activities of sarcoma growth factor. 631 May 84

The relation between the concentration of epidermal growth factor (EGF) receptor/kinase and effects of EGF on cell proliferation has been studied using variant A431 cells and antagonist anti-EGF receptor monoclonal antibodies. Clonal A431 cell variants selected for escape from the EGF-mediated growth inhibition of parental A431 cells all have reduced concentrations of EGF receptor/kinase; Harvey sarcoma virus-transformed A431 cells, which have escaped from EGF-mediated growth inhibition, also have reduced EGF receptors. Three clonal variants which have reacquired EGF-mediated growth inhibition have 2- to 4-fold more EGF receptor than their respective parent variant. A biphasic response with stimulation at low and inhibition at high concentrations of EGF was especially evident in revertants of clone 29. Three separate antagonist monoclonal anti-EGF receptor antibodies block the growth inhibitory effects of EGF and uncover EGF-mediated growth stimulation. These studies indicate that in A431 cell variants a continuum of ligand-activated EGF receptors determines proliferative responses from low concentrations of active receptors under basal conditions to intermediate concentrations causing growth stimulation to high concentrations, causing inhibition of cell proliferation.
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PMID:Relation of epidermal growth factor receptor concentration to growth of human epidermoid carcinoma A431 cells. 633 80

The c-erbB-2 gene and its products (also designated HER-2 and c-neu) encode for a 185-kd transmembrane glycoprotein with intracellular tyrosine kinase activity. c-erbB-2 belongs to the epidermal growth factor receptor family, of which there are four known members, and has molecular homology to the epidermal growth factor receptor. It seems that this family is critical in control of growth, differentiation, and mobility of many normal and transformed epithelial cell types. We have looked for overexpression of c-erbB-2 gene product in paraffin-embedded material from 230 cases of soft tissue sarcoma, in order to establish a possible new prognostic marker and a potentially new treatment option. In all the cases, irrespective of the sarcoma histological type, the immunostaining for erbB-2 was negative. Applications of erbB-2 for prognostication as well as the option of receptor targeting by trastuzumab monoclonal antibodies were aborted.
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PMID:Lack of ErbB-2 oncogene product overexpression in soft tissue sarcomas. 1223 29


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