Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although in Fischer-344 rats aging is found to be associated with increased gastric mucosal proliferative activity, little is known about the intracellular events that regulate this process. The present investigation examines the age-related changes in gastric mucosal tyrosine kinase activity and expression of epidermal growth factor receptor(EGFR) and its structural and functional analog p185c-erbB-2, the protein product of c-erbB-2/c-neu protooncogene. We observed a significantly higher intrinsic tyrosine kinase activity and tyrosine phosphorylation of EGFR and p185c-erbB-2 in the gastric mucosa of 24-mo-old (aged) rats than in that of their 4- or 12-mo-old counterparts. This was associated with increased levels of EGFR protein and steady-state mRNA levels of EGFR and p185c-erbB-2. In addition, we also observed threefold higher steady-state mRNA levels of transforming growth factor-alpha (TGF-alpha; one of the primary ligands of EGFR) in the gastric mucosa of aged rats than in that of 4-mo-old (young) animals. This was accompanied by a fivefold increase in the relative concentration of the 18-kDa precursor form of TGF-alpha in gastric mucosal membranes but not in the cytosol. In conclusion, our data demonstrate that aging is associated with increased tyrosine kinase activity of EGFR and p185c-erbB-2 in the gastric mucosa. Moreover, the observation that aging results in increased accumulation of TGF-alpha in gastric mucosal membranes raises the possibility that the membrane-bound TGF-alpha could partly be responsible for the constitutively active EGFR-induced signaling pathway in the gastric mucosa of aged rats and, in turn, for stimulation of mucosal proliferative activity.
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PMID:Increased expression of EGFR in gastric mucosa of aged rats. 927 18

We generated DNA expression vectors encoding the full-length neu cDNA (designated pNeuN), the neu extracellular domain (pNeuE), or the neu extracellular and transmembrane domains (pNeuTM). The 293 cells transfected with pNeuN or pNeuTM expressed the neu extracellular domain on the surface membrane, whereas 293 cells transfected with pNeuE secreted the extracellular domain of neu into the culture supernatant. We examined whether i.m. injection of either of these plasmids could induce protective immunity in FVB/N mice against the adoptive transfer of Tgl-1 cells, a neu-expressing tumor cell line generated from a mouse mammary tumor that spontaneously arose in a FVB/N neu-transgenic mouse. The i.m. injection of pNeuTM or pNeuE, and to a lesser extent pNeuN, induced protective immunity against a subsequent challenge with Tgl-1 cells in FVB/N mice. In addition, the coinjection of a plasmid encoding interleukin-2 (designated pIL-2) augmented the efficacy of each of the pNeu plasmids for inducing protective immunity. The plasmid pNeuTM seemed to be the most effective for inducing anti-neu antibodies. However, the generation of detectable anti-neu antibodies in response to any one of these pNeu plasmids was not enhanced by coinjection of pIL-2 and was not required for protective immunity against Tgl-1 cells. These studies demonstrate that DNA expression vectors encoding soluble or membrane-bound forms of neu lacking the cytoplasmic kinase domain can be effective in inducing protective antitumor immunity.
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PMID:DNA vaccines encoding full-length or truncated Neu induce protective immunity against Neu-expressing mammary tumors. 1048

HER2/neu, a Mr 185,000 tyrosine kinase receptor that is overexpressed in breast cancer, undergoes proteolytic cleavage of its extracellular domain (ECD). In contrast with other membrane-bound proteins, including growth factor receptors, that are cleaved by a common machinery system, we show that HER2 cleavage is a slow process and is not activated by protein kinase C. Pervanadate, a general inhibitor of protein-tyrosine phosphatases, induces a rapid and potent shedding of HER2 ECD. The shedding of HER2 ECD is inhibited by the broad-spectrum metalloprotease inhibitors EDTA, TAPI-2, and batimastat. The tissue inhibitor of metalloproteases-1; an inhibitor of matrix metalloproteases that does not inhibit cleavage by the general protein kinase C-dependent shedding machinery, also inhibited HER2 ECD shedding, whereas tissue inhibitor of metalloproteases-2 did not. These data suggest that HER2 cleavage is a process regulated by an as-yet-unidentified distinct protease.
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PMID:Cleavage of the HER2 ectodomain is a pervanadate-activable process that is inhibited by the tissue inhibitor of metalloproteases-1 in breast cancer cells. 1009 47

The pathogenesis and interrelationships of neuroendocrine lung carcinomas are not well understood. Tissue macro-arrays prepared from surgical resection specimens from 35 patients with typical carcinoid (TC), six with atypical carcinoid (AC), 13 with large cell neuroendocrine carcinoma (LCNEC), and 15 with small cell lung carcinoma (SCLC) were investigated by fluorescence in situ hybridization (FISH) and immunohistochemistry. Hybridizations with locus-specific DNA probes demonstrated a high incidence of deletion for the tumour suppressor genes p53 and retinoblastoma (Rb), and for the oncogene cyclin D1, comparable in all carcinoma types. Similarly, an increase of DNA copy number for the Her-2/neu and c-myc oncogenes was noted in all neoplasms. A more detailed quantitative analysis of the results, however, demonstrated increasing numbers of cells harbouring these genomic alterations, from low-grade TC to highly malignant SCLC, with the exception of cyclin D1 deletion. Mutations of the p53 and Rb genes, as assayed by immunohistochemical studies, were observed at high incidence in high-grade carcinomas, compared with a low incidence in the low-grade carcinomas. Conversely, in all carcinoma types, neither membrane-bound Her-2/neu nor nuclear cyclin D1 was detected. It is concluded that structural genomic alterations are frequent in neuroendocrine lung carcinomas and that their occurrence may be underestimated by immunohistochemical studies alone. The quantitative expansion of the Rb, p53, c-myc, and Her-2/neu alterations towards high-grade carcinomas suggests common pathogenetic mechanisms in the spectrum of these neoplasms.
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PMID:Quantitative expansion of structural genomic alterations in the spectrum of neuroendocrine lung carcinomas. 1192 Jul 36

Existing prognostic algorithms for localized prostate cancer (PC) are hampered by poor validation for endpoints other than biochemical relapse such as clinical disease progression or survival. Therefore, the prognostic relevance of Her-2 (Her-2/neu, c-erbB2) protein expression in patients undergoing curative radiotherapy (RT) was compared to widely accepted prognostic factors such as pretreatment prostate-specific antigen (PSA) levels, biopsy Gleason score and T category of the primary tumor. Biopsies from 112 homogeneously treated patients with T1-4pN0M0 PC were examined by immunohistochemistry and 37% of cases showed membrane-bound Her-2 expression in more than 10% of cancer cells. No definite membrane staining was seen in normal prostate epithelium. With 25 patients dead of PC and a median follow-up of surviving patients of 71 months (range 48-144), the prognostic relevance of Her-2 expression was univariately associated with adverse outcome in terms of biochemical or clinical progression-free survival (B/C-PFS; p = 0.04), clinical progression-free survival (C-PFS; p = 0.02) and disease-specific survival (DSS; p = 0.02). In multivariate analysis, Her-2 expression, T category and Gleason score were independently associated with C-PFS, whereas only Her-2 expression and Gleason score were associated with DSS. Her-2 expression and Gleason score together discriminated 2 groups of patients with 5-year DSS of 95% and 79%, respectively (p < 0.001). Pretreatment PSA levels were associated only with B/C-PFS but not with C-PFS or DSS. Together the data show for the first time that expression of Her-2 is of prognostic relevance in localized PC undergoing RT and suggest that analysis for Her-2 may improve prognostic algorithms for clinically relevant endpoints other than biochemical relapse.
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PMID:Independent prognostic significance of HER-2 oncoprotein expression in pN0 prostate cancer undergoing curative radiotherapy. 1194 99

The EGF family of receptors belongs to the tyrosine kinase receptor (TKR) family and plays an important role during embryonic and postnatal development and also in the progression of tumors. Her-2/neu/c-erbB-2, a member of the epidermal growth factor receptor family, can be cleaved into a soluble extra cellular domain (ECD) and a membrane-bound stub fragment. Her-2 ECD from a breast cancer cell line SKBR3 was immunopurified and analyzed with matrix-assisted laser desorption ionization (MALDI) and carboxyl terminal amino acid sequencing. A sequence within the juxtamembrane region (only 11 amino acid residues) PAEQR ASP was identified most likely as a primary site of cleavage, PA EQRASP as a minor site, that generate the ECD. The sites of cleavage are within the signature motif P/GX(5-7)P/G highly conserved in the EGF receptor family.
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PMID:Purification of Her-2 extracellular domain and identification of its cleavage site. 1276 12

The MUC4 mucin is a high molecular weight membrane-bound glycoprotein. It is aberrantly expressed in pancreatic tumors and tumor cell lines with no detectable expression in the normal pancreas. A progressive increase of MUC4 expression has also been observed in pancreatic intraepithelial neoplasia, suggesting its association with disease development. Here, we investigated the consequences of silencing MUC4 expression in an aggressive and highly metastatic pancreatic tumor cell line CD18/HPAF that expresses high levels of MUC4. The expression of MUC4 was down-regulated by the stable integration of a plasmid-construct expressing antisense-MUC4 RNA. A decrease in MUC4 expression, confirmed by Western blot and immunofluorescence analyses, resulted in diminished growth and clonogenic ability of antisense-MUC4-transfected (EIAS19) cells compared with parental, empty vector (ZEO) and sense transfected (ES6) control cells. In addition, EIAS19 cells displayed a significant decrease in tumor growth and metastatic properties when transplanted orthotopically into the immunodeficient mice. In vitro biological assays for motility, adhesion, and aggregation demonstrated a 3-fold decrease in motility of EIAS19 cells compared with control cells, whereas these cells adhered more and showed an increase in cellular aggregation. Interestingly, MUC4 down-regulation also correlated with the reduced expression of its putative interacting partner, HER2/neu, in antisense-MUC4-transfected cells. In conclusion, the present work demonstrates, for the first time, a direct association of the MUC4 mucin with the metastatic pancreatic cancer phenotype and provides experimental evidence for a functional role of MUC4 in altered growth and behavioral properties of the tumor cell.
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PMID:Inhibition of MUC4 expression suppresses pancreatic tumor cell growth and metastasis. 1474 77

A causative role of the membrane-bound tyrosine kinase ErbB-2 in breast tumorigenesis has been well established. MMTV/neu transgenic mice which overexpress ErbB-2 consistently develop mammary carcinomas with a high incidence. In human breast cancer, ErbB-2 is overexpressed in 25-30 of all cases and is representing a clinical marker of a poor prognosis. Besides to gene amplification, ErbB-2 overexpression has been attributed to transcription factors of the AP-2 family which were shown to control the ErbB-2 gene promoter in cell culture studies. Particularly AP-2alpha and gamma are often coexpressed in ErbB-2-positive breast carcinomas. However, LTRgamma transgenic mice which overexpress AP-2gamma in their mammary epithelium display only a very weak upregulation of the erbB-2 gene and do not develop mammary carcinoma. These findings therefore raise the possibility of functional cooperativity between both genes in breast cancer. To experimentally address the impact of AP-2gammaon ErbB-2-induced breast carcinogenesis we crossed MMTV/neu transgenic mice with LTRgamma transgenic mice and monitored tumor development in bitransgenic female progeny. AP-2gamma overexpression negatively influenced tumor incidence, as reflected by a reduced tumor number and a prolonged tumor latency. Histological analysis revealed three major types of tumors corresponding to different stages of tumor progression. Interestingly, an increased proportion of advanced stage carcinomas was observed in bitransgenic mice. Moreover, the AP-2gamma transgene differentially affected proliferation rates between the different progression stages: proliferation was enhanced at early stages but reduced in advanced stages in comparison to control tumors. Therefore, AP-2gamma while reducing the incidence of mammary tumors is promoting tumor progression.
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PMID:Dual role of AP-2gamma in ErbB-2-induced mammary tumorigenesis. 1583 Jan 41

Lung cancer is the leading cause of mortality worldwide. The median survival of advanced disease is in the range of 8 to 10 months. Intrinsic or acquired drug resistance pose major challenges to the success of chemotherapy. The HER2 gene, also known as c-erbB-2 or neu, is a proto-oncogene that encodes a membrane-bound receptor tyrosine kinase of the epithelial growth factor receptor (EGFR) family. It has a possible role in tumor cell proliferation, tumor invasion, tumor metastasis and drug resistance. We retrospectively investigated 88 samples of non-small cell lung cancer (NSCLC) and assessed the correlation between HER2 expression and tumor histology. The expression of HER2 protein was analyzed by immunohistochemical staining (IHC) and HER2 DNA amplification was detected by using fluorescence in situ hybridization (FISH). HER2 overexpression (2+, 3+) was detected in 5 (5.7%) out of 88 specimens. All of the HER2-overexpressing tumors histologically proved to be squamous cell carcinoma (SCC). Cases with 2+ HER2 immunoreactivity showed either no amplification (3.875 and 2.525), or borderline amplification (4.75). Cases with 3+ HER2 immunoreactivity showed moderate amplification (7.35) and strong amplification (15-20 - cluster), respectively. The HER2 expression in NSCLC was relatively low in the selected Hungarian population; consequently, there is no indication for introduction of trastuzumab for the treatment of lung cancer.
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PMID:Investigation of HER2 overexpression in non-small cell lung cancer. 1608 May 66

A "bottom-up" proteomics approach and a two-dimensional (strong cation exchange followed by reversed-phase) LC-MS/MS strategy on a linear ion trap (LTQ) were utilized to identify and compare expressions of extracellular and membrane-bound proteins in the conditioned media of three breast cell lines (MCF-10A, BT474, and MDA-MB-468). Proteomics analysis of the media identified in excess of 600, 500, and 700 proteins in MCF-10A, BT474, and MDA-MB-468, respectively. We successfully identified the internal control proteins, kallikreins 5, 6, and 10 (ranging in concentration from 2 to 50 microg/liter) in MDA-MB-468 conditioned medium as validated by ELISA and confidently identified Her-2/neu in BT474 cells. Subcellular localization was determined based on Genome Ontology terms for all the 1,139 proteins of which 34% were classified as extracellular and membrane-bound. Proteomics analysis of MDA-MB-468 cell lysate demonstrated that only 5% of all identified proteins were extracellular. This confirmed our hypothesis that examining the CM of cell lines, as opposed to the cell lysates, leads to a significant enrichment in secreted proteins. Tissue specificity, functional classifications, and spectral counting were performed. Elafin, a protease inhibitor, identified in the conditioned media of BT474 and MDA-MB-468 and the three kallikreins (KLK5, KLK6, and KLK10) were validated using an immunoassay on various serum and biological samples. Some of the secreted proteins identified have established roles in breast cancer development (cell growth, differentiation, and metastasis) and/or are linked to early onset breast cancer. Our approach to mining for low abundance molecules could identify proteins in various stages of breast cancer development. Many of the identified proteins are potentially useful to investigate as circulating serum breast cancer biomarkers.
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PMID:Proteomics analysis of conditioned media from three breast cancer cell lines: a mine for biomarkers and therapeutic targets. 1765 55


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