Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Normal tissues, primary tumors, and metastases of mammary and salivary glands and oral/laryngeal mucosa have been analyzed with Northern-blots employing 32P-labeled RNA probes for the expression of the neu oncogene. Neu oncogene expression of a mRNA species of 4.6 kilobases was found in all normal salivary (five) and mammary glands (four) as well as in two normal or inflamed samples of tongue mucosa. This expression was regarded as baseline activity of the neu gene for the respective tissues and was used as standard for the evaluation of benign and malignant tumors. None of 14 squamous cell carcinomas of the oral and laryngeal mucosa showed enhanced neu transcription level. Five fibroadenomas, one benign variant of phylloid tumor, one carcinosarcoma, and one of two proliferative fibrocystic diseases of the breast showed lacking or normal baseline expression of the neu oncogene, as did one monomorphous cystadenolymphoma of the parotid gland. In contrast, four parotid pleomorphic adenomas and one salivary gland adenocarcinoma showed enhanced neu expression. For mammary adenocarcinomas, increased neu oncogene expression concerned ten of 34 cases--all being variants of ductal carcinomas--and all metastases analyzed (six) deriving from three primaries. One adenoid cystic carcinoma also showed enhanced neu expression. Neu overexpression may reflect accidents of genomic reconstitutional events occurring regularly within the differentiation pathway of epithelial/myoepithelial cells. This assumption was supported by further immunohistochemical analysis which showed stainings of myoepithelial and myoepithelia-like cell populations in tumors, especially pleomorphic adenomas and adjacent normal-looking tissues.
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PMID:Comparative investigation of c-erbB2/neu expression in head and neck tumors and mammary cancer. 167 62

Four human ovarian and breast tumor lines expressing the HER2/neu oncogene were resistant to the cytotoxic and DNA-degradative activity of TNF. The resistance was not associated with altered TNF receptor function because Scatchard analysis of 125I-rTNF binding to HER2/neu-expressing target cells revealed receptors with normal binding parameters. Furthermore, the TNF receptors on the resistant lines were capable of signal transduction as evidence by the induction of ADP-ribose polymerase activity and MHC expression. TNF resistance was not reversed by coincubation with drugs that interrupted the glutathione redox cycle. In addition, although coincubation of HER2/neu-expressing targets with cycloheximide resulted in significant TNF-induced lysis, when compared to HER2/neu-nonexpressing targets similarly treated with cycloheximide, a significant relative resistance was still present. To investigate the role of ADP-ribosylation in the resistance of these targets, we used nontoxic concentrations of two inhibitors of ADP-ribose polymerase, 3-aminobenzamide, and nicotinamide. Both inhibitors completely reversed the resistance of HER2/neu-expressing targets to TNF-mediated cytotoxicity and DNA injury in a concentration-dependent fashion. These inhibitors of ADP-ribose polymerase did not act by down-regulating expression of HER2/neu oncogenes. In contrast, aminobenzamide and nicotinamide significantly diminished TNF-induced cytotoxicity of L929 targets. These data suggest that the activity of ADP-ribose polymerase may play a pivotal role in determining the fate of the target cell during exposure to TNF.
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PMID:Inhibitors of ADP-ribose polymerase decrease the resistance of HER2/neu-expressing cancer cells to the cytotoxic effects of tumor necrosis factor. 167 41

In order to obtain further information on the biological role of the HER2/neu oncoprotein monoclonal antibodies (MAbs) were produced against the p185 extracellular domain. To immunize the mice and screen the hybridoma supernatants we selected a lung adenocarcinoma cell line (Calu-3), which demonstrated an over-expression of p185HER2 measured as the reactivity with polyclonal rabbit serum to the 14-amino-acid carboxy-terminal-HER2/neu. Two MAbs, designated MGR2 (IgG1) and MGR3 (IgG2), selected for reactivity on Calu-3 and negativity on A43I live cells, the reference target cell for EGF receptor expression, were found to immunoprecipitate a 185-kDa molecule. Immunodepletion experiments with the polyclonal antiserum and cross-competition experiments indicated that the 2 reagents recognized 2 different epitopes located on the p185HER2 molecule. One of the 2 MAbs, MGR3, was found to internalize, induce p185HER2 phosphorylation and inhibit tumor cell growth in vitro. These results indicate that MGR3 is directed against a determinant located in the p185HER2 ligand binding site and may compete with the p185HER2 ligand, but is incapable of inducing a complete mitotic signal.
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PMID:Selection of monoclonal antibodies which induce internalization and phosphorylation of p185HER2 and growth inhibition of cells with HER2/NEU gene amplification. 167 68

The neu protooncogene (also called HER2 and c-erbB2) encodes a cell-surface tyrosine kinase structurally related to the receptor for the epidermal growth factor (EGF). We have previously reported that a candidate ligand for the neu receptor is secreted by ras-transformed fibroblasts. Biochemical analyses of the neu stimulatory activity indicate that the ligand is a 35-kDa glycoprotein that is heat stable but sensitive to reduction. The factor is precipitable by either high salt concentrations or acidic alcohol. Partial purification of the molecule by selective precipitation, heparin-agarose chromatography, and gel filtration in dilute acid resulted in an active ligand, which is capable of stimulating the protooncogenic receptor but is ineffective on the oncogenic neu protein, which is constitutively active. The purified fraction, however, retained the ability to stimulate also the related receptor for EGF, suggesting that these two receptors are functionally coupled through a bidirectional mechanism. Alternatively, the presumed ligand interacts simultaneously with both receptors. The presented biochemical characteristics of the factor are expected to enable a completely purified factor with which to explore these possibilities.
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PMID:Biochemical analysis of the ligand for the neu oncogenic receptor. 167 25

Ten astrocytomas were tested for gene amplification or rearrangement utilizing distinct probes to nine different oncogenes by Southern hybridization. The probes spanned the four major protein-coding classes of oncogenes; growth factor proteins (csis); growth factor receptor/tyrosine kinase-related proteins [erbB1 (epidermal growth factor receptor, EGF-R), neu (HER2/neu, erbB2), mos, yes]; nuclear binding proteins (c-myc, c-fos); and guanosine 5'-triphosphate binding proteins (N-ras, H-ras). Three astrocytomas, all glioblastomas, showed amplification of EGF-R-related sequences, and two of these amplifications were rearranged. Both rearrangements appeared similar by two different restriction endonucleases. Our findings suggest that it is primarily the EGF-R protooncogene (erbB1) that is amplified or rearranged in astrocytic neoplasms. No other oncogenes were amplified or rearranged, although EGF-R and neu cross-hybridization produced a "pseudo-rearranged" pattern for neu in EGF-R-amplified cases. The similar EGF-R restriction endonuclease abnormalities seen in two patients warrant further study.
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PMID:Oncogene abnormalities in astrocytomas: EGF-R gene alone appears to be more frequently amplified and rearranged compared with other protooncogenes. 167 68

We have previously described a novel series of low molecular weight protein tyrosine kinase inhibitors which we named tyrphostins. The characteristic active pharmacophore of these compounds was the hydroxy-cis-benzylidenemalononitrile moiety. In this article we describe three novel groups of tyrphostins: (i) one group has the phenolic moiety of the cis-benzylidenemalononitrile replaced either with other substituted benzenes or with heteroaromatic rings, (ii) another is a series of conformationally constrained derivatives of hydroxy-cis-benzylidenemalononitriles in which the malononitrile moiety is fixed relative to the aromatic ring, and (iii) two groups of compounds in which the position trans to the benzenemalononitrile has been substituted by ketones and amides. Among the novel tyrphostins examined we found inhibitors which discriminate between the highly homologous EGF receptor kinase (HER1) and ErbB2/neu kinase (HER2). These findings may lead to selective tyrosine kinase blockers for the treatment of diseases in which ErbB2/neu is involved.
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PMID:Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases. 167 28

The neu/HER2 proto-oncogene encodes a transmembrane tyrosine kinase homologous to receptors for polypeptide growth factors. The oncogenic potential for the presumed receptor is released through multiple genetic mechanisms including a specific point mutation, truncation at the extracellular domain and overexpression of the protooncogene. Here we show that all these modes of oncogenic activation result in a constitutively phosphorylated neu protein and an increase in tyrosine phosphorylation of a phosphatidylinositol-specific phospholipase (PLC gamma). The examined transforming neu/HER2 proteins, unlike the normal gene product, also co-immunoprecipitated with PLC gamma molecules. A kinase-defective mutant of a transforming neu failed to mediate both tyrosine phosphorylation and association with PLC gamma, suggesting direct interaction of the neu kinase with PLC gamma. This possibility was examined by employing a chimeric protein composed of the extracellular ligand-binding domain of the epidermal growth factor receptor and the neu cytoplasmic portion. The chimeric receptor mediated rapid ligand-dependent modification of PLC gamma on tyrosine residues. It also physically associated, in a ligand-dependent manner, with the phosphoinositidase. Based on the presented results we suggest that the mechanism of cellular transformation by the neu/HER2 receptor involves tyrosine phosphorylation and activation of PLC gamma.
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PMID:Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase C gamma. 167 73

A partially agonistic monoclonal antibody, 4D5, known to bind to the extracellular domain of p185HER2 and shown to inhibit long term growth of p185HER2-overexpressing breast cancer cells, was used to study signal transduction and phosphotyrosyl protein substrates associated with this receptor. Normal breast epithelial cells and breast carcinoma cells expressing low levels of p185HER2 were not affected by 4D5. HER2/neu-overexpressing breast cancer cells (BT-474 and SK-Br-3) exposed to 4D5 exhibited rapid phosphorylation of both p185HER2 and an associated 56-kDa phosphotyrosyl protein (ptyr56). Paralleling the 4D5- stimulated phosphorylation of p185HER2 and ptyr56 was a 5-10-fold induction of c-fos mRNA and phosphatidylinositol 4-kinase activity and a 2-fold induction of inositol 1,4,5-trisphosphate 3'-kinase activity. The increased phosphatidylinositol 4-kinase activity immunoprecipitated with p185HER2 and also co-eluted with ptyr56 from an antiphosphotyrosine immunoaffinity column. These results indicate that short term (less than 6 h) 4D5 activation of p185HER2 in overexpressing breast cancer cells produces agonistic-like signaling typical of homologous tyrosine kinase growth factor receptors such as epidermal growth factor receptor. The data also suggest that ptyr56 represents a novel phosphorylated substrate associated with 4D5-stimulated p185HER2.
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PMID:p185HER2 signal transduction in breast cancer cells. 167 43

Using a panel of somatic cell hybrids that segregate rat chromosomes, the localization of five cancer-related rat genes was determined: (i) two thyroid receptor genes, THRA1/ERBA1 and THRB/ERBA2 on chromosomes 10 and 15 respectively, (ii) two ERBB genes, namely the epidermal growth factor gene (EGFR, also called ERBB1) and the ERBB2 gene (also designated neu) on chromosomes 14 and 10 respectively, and (iii) the retinoblastoma gene, RB1, on chromosome 15. The THRA1/ERBA1 and ERBB2/neu genes are thus included in a synteny group, conserved on rat chromosomes 10 and human chromosome arm 17q.
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PMID:Chromosomal assignment of five cancer-associated rat genes: two thyroid hormone receptor (ERBA) genes, two ERBB genes and the retinoblastoma gene. 167 28

Epidermal growth factor (EGF) and EGF-related growth factors are present in the urine, and EGF has been identified as a urinary component that enhances urinary bladder tumor formation in rats. Neu oncogene encodes a cell surface receptor similar to the EGF receptor and is known to be activated by a point mutation of DNA that encodes the transmembrane domain of the neu protein (p185). In this study, we examined the possible mutational activation of neu oncogene in 50 urinary bladder transitional cell carcinomas (TCC) induced in F344 rats by the following carcinogenesis models: (i) 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) (4 weeks)----3% uracil (20 weeks); (ii) 0.2% N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) (6 weeks)----5% sodium saccharin (72 weeks); and (iii) N-methyl-N-nitrosourea (MNU) 20 mg/kg body wt, i.p. twice per week for 4 weeks----3% uracil (20 weeks). The DNA sequence around the transmembrane domain of neu gene was amplified by PCR and sequenced. The results showed no mutation within the examined DNA sequences, indicating that neu oncogene is not activated by a point mutation in the transmembrane domain in urinary bladder carcinomas induced by BBN, FANFT or MNU.
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PMID:Direct DNA sequencing of the rat neu oncogene transmembrane domain reveals no mutation in urinary bladder carcinomas induced by N-butyl-N-(4-hydroxybutyl)nitrosamine, N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide or N-methyl-N-nitrosourea. 168 63


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