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)

Using ELISAs, we determined the concentrations of transforming growth factor alpha (TGF-alpha), the extracellular domain of the erbB-2 receptor (erbB-2 ECD), and mutant p53 protein in stored serum samples of asbestosis patients with and without cancer and control subjects (without asbestosis or cancer). The percentage of individuals in these three groups with increased serum concentrations of TGF-alpha, erbB-2 ECD, and mutant p53, respectively, were: asbestosis patients with cancer, 36%, 16%, 19%; asbestosis patients without cancer, 38%, 19%, 6%; control subjects, 0%, 5%, 10%. Although differences in serum positivity for these oncoproteins were apparent among these groups, the differences did not achieve statistical significance (P > 0.05). In several of the cancer cases, increased concentrations of TGF-alpha, erbB-2 ECD, and mutant p53 were also detected in the stored serum samples collected years before the clinical diagnosis of disease.
Clin Chem 1995 Dec
PMID:Serum oncoproteins in asbestosis patients. 749 43

Overproduction of v-Crk, but not of c-Crk, in chicken embryo fibroblasts results in cell transformation. The transforming activity of v-Crk mutants correlates with their ability to cause increased tyrosine phosphorylation of specific cellular proteins, a property that depends on the binding of v-Crk to phosphotyrosine residues via its SH2 domain. In this study, proteins translated in rabbit reticulocyte lysates were used to analyze interactions between Crk derivatives and tyrosine-phosphorylated proteins, particularly the epidermal growth factor (EGF) receptor. The results demonstrate that the binding affinity of c-Crk is much lower than that of v-Crk, despite the fact that both proteins contain identical SH2 domains. Moreover, a 31-amino-acid N-terminal extension of c-Crk, resulting from upstream translational initiation at a CUG codon, significantly increases the ability of the resulting protein to bind to phosphotyrosine-containing proteins. Of those 31 amino acids, 24 can be found in the 27-amino-acid region between Gag and Crk sequences in v-Crk, and removal of this region results in a protein with lower affinity toward the EGF receptor. In addition, fusion of Gag to the amino terminus of c-Crk yields a protein with a binding activity that is lower than that of v-Crk but significantly higher than that of c-Crk without the fusion. These data suggest that sequences N terminal to the Crk SH2 regulate binding activity to tyrosine-phosphorylated proteins and that the amino acids encoded immediately 5' to the c-Crk initiator AUG specifically increase binding affinity. In contrast, deletion of one or two SH3 domains of c-Crk proteins did not change their affinity for the EGF receptor. These results were confirmed in vivo by using A431-derived cell lines overproducing either the chicken c-Crk protein or c-Crk with the 31-amino-acid N-terminal extension. Furthermore, the in vivo experiments suggest that binding of Crk proteins to the stimulated EGF receptor results in Crk phosphorylation and subsequent loss of binding affinity.
Mol Cell Biol 1993 Dec
PMID:A 31-amino-acid N-terminal extension regulates c-Crk binding to tyrosine-phosphorylated proteins. 750 72

Mitogen-induced mammary cell growth is often accompanied by decreased levels of expression of the p185erbB-2 protein. We have previously reported that oestrogen inhibits erbB-2 mRNA and protein expression in breast cancer cells, while epidermal growth factor (EGF) treatment has been shown to decrease p185erbB-2 levels in normal mouse mammary epithelial cells. In the present work, we studied the effect of oestrogen and EGF on erbB-2 expression in oestrogen-responsive breast cancer cells. We observed that both oestrogen and EGF comparably down-regulated p185erbB-2 levels, while stimulating growth of T47D and ZR75.1 cells. Oestrogens, but not EGF, concomitantly down-regulated erbB-2 mRNA. Run-on analysis showed a reduced erbB-2 transcription rate in the presence of oestrogens. Furthermore, the transcriptional activity of a 219 bp proximal fragment of the human erbB-2 promoter was repressed by oestrogens, whereas it was enhanced by EGF. EGF stimulated both tyrosine phosphorylation and autokinase activity of p185erbB-2 down-regulates p185erbB-2 at a post-translational level. Thus, two factors converging in terms of effects on cell growth, display divergent mechanisms of regulation of erbB-2 expression.
Br J Cancer 1994 Dec
PMID:Oestrogen and epidermal growth factor down-regulate erbB-2 oncogene protein expression in breast cancer cells by different mechanisms. 752 84

Grb2, composed entirely of SH2 and SH3 domains, serves as an adaptor protein in signaling from growth factor-activated tyrosine kinase receptors. It interacts via its SH2 domain with the autophosphorylated carboxyl-terminal tail of activated epidermal growth factor (EGF) receptor and via its SH3 domains with proline-rich sequences in the Ras guanine nucleotide releasing factor, Son of sevenless (Sos). Recruitment of the Grb2-Sos complex to the receptor upon its stimulation leads to Ras activation. A major question remains as to whether SH2-mediated binding of Grb2 to the activated receptor results in conformational changes that influence its SH3-mediated association with Sos, thereby affecting Sos activity. This question is addressed through studies of the binding to intact Grb2 of an EGF receptor-derived phosphotyrosine-containing peptide and a Sos-derived proline-rich peptide using isothermal titration calorimetry and surface plasmon resonance measurements. The phosphopeptide binds to Grb2 in a 1:1 complex, with a KD of 0.4 microns. The Sos proline-rich peptide binds to Grb2 in a 2:1 complex, with a KD of 22 microns. Saturation of the SH2 domain of Grb2 with the EGFR phosphopeptide was found not to affect its subsequent binding to the Sos peptide. Thus we detected no influence of SH2 binding upon SH3-mediated interactions, suggesting that the domains do not communicate, and that recruitment itself of Sos to the cell surface is sufficient for Ras signaling.
J Biol Chem 1994 Dec 16
PMID:Independent binding of peptide ligands to the SH2 and SH3 domains of Grb2. 752 91

A differential PCR-based assay is presented that increases the accuracy of quantification of C-erbB-2 gene-copy number in DNA extracted from archival tumors. The C-erbB-2 gene is amplified in a high percentage of human adenocarcinomas arising at numerous sites, including breast, lung, and stomach. A number of studies have correlated C-erbB-2 with poor prognosis. Gene copy number may be relevant in identifying patients with different clinical outcomes. In this study a target gene and a single copy reference gene were coamplified in the same reaction tube. The level of target gene amplification was reflected by the ratio of the two resulting PCR products. Cell lines exhibiting variable copies ranging from 1 to > 8 of the C-erbB-2 gene were used as quality controls. This technique can reliably show a single copy difference between cell lines and can be used to semiquantitatively estimate gene copy number in DNA extracted from archival paraffin-embedded samples.
PCR Methods Appl 1994 Dec
PMID:An improved method for semiquantification of gene amplification from archival material. 758 Sep 3

We reported previously that the adenovirus E1a gene reversed the transformed phenotype of one human melanoma and one fibrosarcoma cell line (S. Frisch, Proc. Natl. Acad. Sci. USA, 88: 9077-9081, 1991). To determine the generality of the tumor suppression effects of E1a, a diversity of tumor cell lines, including A204 rhabdomyosarcoma, RD rhabdomyosarcoma, Saos-2 osteosarcoma, NCI-H23 non-small cell lung carcinoma, MDA-MB435S breast carcinoma, and ras-transformed MDCK kidney epithelial cells, were infected with a retrovirus bearing the 12S E1a coding sequence. We demonstrate here that the expression of E1a severely reduced the anchorage-independent and tumorigenic growth of these cell lines without affecting their growth under normal culture conditions. The parental tumor cells used in this study did not overexpress c-erbB-2/neu, and E1a did not affect its expression in these cells. Thus, tumor suppression by E1a can operate in a wide variety of human tumor cells by c-erbB-2/neu-independent mechanisms. E1a also sensitized these cell lines to the cytotoxic effects of the anticancer drugs etoposide and cisplatin. The results suggest that E1a could prove useful for the gene therapy of a wide variety of human cancers.
Cancer Res 1995 Dec 01
PMID:Adenovirus E1a-mediated tumor suppression by a c-erbB-2/neu-independent mechanism. 758 33

Few molecular genetic alterations have been identified in endometrial cancers that are associated with poor clinical outcome. Overexpression of HER-2/neu, transforming growth factor alpha, and p53 proteins have all been associated with poor prognosis in women with endometrial cancer. In this study, the level of HER-2/neu gene amplification and expression was characterized in 92 endometrial cancers. Fluorescence in situ hybridization (FISH) was used to characterize HER-2/neu gene copy number, and immunohistochemistry was used to characterize expression. Forty-seven of the 90 (52%) endometrial cancers were characterized as showing moderate or high immunostaining. HER-2/neu gene amplification was detected in 17 of 81 (21%) cases. Immunohistochemical staining and FISH results were both available for 80 cases. Fourteen of these cases showed both moderate or high immunostaining and gene amplification. Clinical follow-up information was available for 76 women in this study. Women whose endometrial cancer exhibited HER-2/neu gene amplification by FISH had a shorter overall survival than women whose endometrial cancer lacked amplification (P = 0.018). Likewise, tumors with moderate or high HER-2/neu immunostaining were associated with a lower cumulative overall survival than tumors with low immunostaining by log rank analysis (P < 0.0001). Multivariate analysis of survival rates revealed HER-2/neu overexpression to be an independent predictor of overall survival (P = 0.0163). Among those patients with HER-2/neu overexpression, adjuvant chemotherapy or radiation therapy was associated with an improved overall survival (P = 0.039). However, among those women whose tumor lacked overexpression, overall survival was not improved by adjuvant treatment.
Cancer Res 1995 Dec 01
PMID:Amplification and overexpression of HER-2/neu (c-erbB2) in endometrial cancers: correlation with overall survival. 758 56

Overexpression of the c-erbB-2 protein (gp185c-erbB-2) is correlated with a tumorigenic phenotype and may contribute to disease progression. We have reported previously on an anti-gp185c-erbB-2 antibody, TAb 250, that inhibits in vitro and in vivo growth of breast and ovarian cell lines that overexpress the protein and enhances the inhibitory activity of cisplatin (CDDP). To assess whether CDDP resistance is related to gp185c-erbB-2 expression levels, alterations in tumor cell growth characteristics, or efficacy of antibody plus drug combination treatments, an SKOV-3 ovarian tumor cell line was made resistant to escalating doses of CDDP. Parental cells were 12-fold more sensitive to CDDP with 7 times more gp185c-erbB-2 sites than the most resistant variant (SKOV-3/C12). Additionally, the resistant cells demonstrated a longer lag phase for in vivo growth than the parental cells. While TAb 250 enhanced the in vivo inhibitory effect of CDDP against parental SKOV-3 cells, the antibody did not significantly alter the CDDP responsiveness of the resistant population. Growth inhibition by TAb 250 alone of both the parental and the SKOV-3-resistant variants was similar; however, TAb 250 was able to prolong the lag-phase of tumor growth of the resistant variant by up to 25 days. These results indicate that the development of CDDP resistance is associated with lowered levels of gp185c-erbB-2 expression, slower tumor cell growth, and enhanced efficacy of antibody treatment of the resistant cells.
Cell Growth Differ 1994 Dec
PMID:Development of resistance to cisplatin is associated with decreased expression of the gp185c-erbB-2 protein and alterations in growth properties and responses to therapy in an ovarian tumor cell line. 769 85

In order to determine the prognostic value of c-erbB-2 protein and Epidermal Growth Factor Receptor (EGF-R), we used an immunohistochemical procedure with specific antibodies on paraffin-embedded material from a series of 73 operable breast cancer carcinomas. c-erbB-2 protein (c-erbB-2 score > 1) was overexpressed in 10/73 cases (14%) and EGF-R (EGF-R ratio > 1) in 42/73 cases (58%). c-erbB-2 overexpression was correlated with tumour size (P < 0.02) and lymph-node involvement (P = 0.05) whereas EGF-R overexpression did not correlate with any of the variables tested. The relative risk of relapse was respectively 1 vs 4.5 (P = 0.001) for patients with a negative (0-1) or positive (> 1) c-erbB-2 score and 1 vs 3 for patients with an EGF-R ratio < or = 1 and > 1 (P = 0.03). Moreover, c-erbB-2 protein overexpression is more specifically an early factor of poor prognosis whereas EGF-R overexpression is a long-term factor of poor prognosis. Patients with an early good prognosis (c-erbB-2 score = 0-1) are found to relapse with time when EGF-R is overexpressed. In a multivariate analysis including axillary lymph-node status, histological grade, tumour size, ER status, c-erbB-2 score, EGF-ratio and hormonal treatment, c-erbB-2 overexpression was the most powerful parameter (P = 0.001) followed by EGF-R overexpression (P = 0.02). We concluded that, in our series, the combined determination of c-erbB-2 protein and EGF-R appeared to be a prognostic indicator whereby both early and long term prognosis could be determined in breast cancer patients.
Bull Cancer 1994 Dec
PMID:Combined overexpression of c-erbB-2 protein and epidermal growth factor receptor (EGF-R) could be predictive of early and long-term outcome in human breast cancer: a pilot study. 774 95

Shc is a ubiquitously expressed Src homology 2 (SH2) domain protein that can transform fibroblasts and differentiate PC12 cells in a Ras-dependent fashion. Shc binds a variety of tyrosine-phosphorylated growth factor receptors presumably via its carboxyl-terminal SH2 domain. We cloned a fragment of Shc when screening a bacterial expression library with tyrosine-phosphorylated epidermal growth factor (EGF) receptor. Surprisingly, this fragment encodes the amino terminus of Shc, a region that has no significant similarity to an SH2 domain. When expressed as a glutathione S-transferase fusion protein, this amino-terminal domain binds to autophosphorylated EGF receptor, as well as HER2/neu and TrkA receptors. This fragment acts like an SH2 domain in that it does not bind non-phosphorylated EGF receptor or EGF receptor with all tyrosine phosphorylation sites mutated or deleted. Our data define a novel domain in Shc that has the potential to interact with growth factor receptors and other tyrosine-phosphorylated proteins.
J Biol Chem 1994 Dec 23
PMID:A region in Shc distinct from the SH2 domain can bind tyrosine-phosphorylated growth factor receptors. 779 94


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