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)

Receptor status and gene amplification were studied in advanced human ovarian adenocarcinoma tissues, borderline and benign ovarian tumours and normal ovarian tissues. Sixty-five percent (53/82) of ovarian adenocarcinomas, 57% (8/14) of benign/borderline tumours and only 31% (5/16) of normal ovarian tissues studied showed specific 125I-EGF (epidermal growth factor) binding (median: 17; 10; and 0 fmol EGF-R/mg protein, respectively) and a significant increase in progesterone receptor (PgR) levels was observed in these groups (median: 5; 33; and 152 fmol/mg protein, respectively). No correlations were observed between the levels of EGF-R and the levels of either oestrogen receptors (ER) or PgR. All membrane samples of 25 adenocarcinomas studied by Scatchard analysis were positive for insulin-like growth-factor-I receptors (IGF-I-R) and contained higher IGF-I-R levels than membranes of 10 normal ovarian tissues, of which 9 were positive (median: 64 and 26 fmol IGF-I-R/mg membrane protein, respectively). Also, as measured by autoradiography, 37 adenocarcinoma tissues showed a higher expression of IGF-I-R (1.5+ to 4+) than sections derived from 10 normal ovarian tissues (1+). 125I-IGF-I binding was predominantly associated with epithelial tumour cells, the surrounding connective tissue was negative and in several samples high expression of IGF-I-R was found in areas of tumour necrosis. Southern blot analysis of DNAs isolated from 25 ovarian adenocarcinomas revealed no amplification of the IGF-I-R or the EGF-R gene. The HER2/neu gene was amplified only in 2 out of 3 histologically confirmed endometrioid adenocarcinomas studied but not in 22 other tumours. An amplification of the c-myc gene was observed in 28% (7/25) of the tumours. All c-myc-amplified tumours were PgR-negative. No rearrangement was observed for any of the genes studied. In conclusion, ovarian adenocarcinoma tissues show a decrease in PgR levels and an increased expression of IGF-I-R and EGF-R, in the absence of gene amplification, when compared to benign/borderline ovarian tumours and normal ovarian tissues. In addition, amplification of the c-myc and HER2/neu genes, without rearrangement of these genes, occurs in a minority of these tumours.
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PMID:Receptors for hormones and growth factors and (onco)-gene amplification in human ovarian cancer. 132 50

The levels of cell membrane epidermal growth factor receptor EGFR and cytosol (c) and nuclear (n), oestrogen (E) and progesterone (P) receptors (R) were determined in 132 specimens of primary breast cancers. In the tumours of postmenopausal women an inverse significant correlation was demonstrated between the concentrations of EGFR vs. ERc, ERn, and PRc while no such correlation was noted in the tumours of premenopausal women. Premenopausal and postmenopausal EGFR positive tumours (> or = 10 fmol/mg membrane protein) could be regarded as homogenous with respect to the concentration of ER and PR whose mean values were low and without being significantly different. EGFR negative tumours were heterogeneous with respect to the ER and PR concentrations. Postmenopausal EGFR negative (< 10 fmol/mg membrane protein) tumours had evidently higher mean values of ER and PR than premenopausal EGFR negative tumours, but these differences were statistically significant for oestrogen receptors only. The levels of ER and PR of premenopausal EGFR negative tumours were approximated to the corresponding levels of EGFR positive tumours.
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PMID:Relations between epidermal growth factor receptor and oestrogen and progesterone receptors in breast cancers of premenopausal and postmenopausal patients in Kuwait. 144 50

Since mortality from breast cancer remains unacceptably high, hopes for future treatment depend, in large part, on the development of pharmacologic interventions based on an increased understanding of the biology of cancer. A fruitful area of exploration may be that of antisense RNAs which may inhibit the expression of a given growth factor or a given cellular product. It is also possible that an antisense RNA can be developed that will inhibit the production of proteins responsible for drug resistance. Another potential approach is the use of the Her-2-Neu oncogene cell membrane protein target for monoclonal antibody radioimmunoconjugates for therapy. Finally, since low-fat, reduced-calorie diets are considered an important part of preventive programs, the use of artificial fats may also make a significant difference in changing life-style habits.
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PMID:Recent advances in the management of lung and breast cancer. Future directions. 238 47

The prognostic significance of EGFR (epidermal growth factor receptor) was studied in a cohort of 68 node-positive patients with breast cancer, who entered a controlled protocol of adjuvant therapy between February 1980 and June 1984. EGFR radioligand binding assay was carried out on frozen stored samples. Twenty five (37%) of 68 primary sites and 9 (41%) of 19 lymph node metastases assayed were EGFR-positive with a cut off value of 5 fmol/mg membrane protein; there is no statistical difference between the two distributions. EGFR was significantly correlated to ER and histological grade. EGFR-positive tumors and high levels of EGFR were mainly found in the ER-negative group of tumors (p = 0.008) and in histological grade III (p = 0.007). Fifty five patients could be followed for 40 to 92 months. EGFR was an independent prognostic factor for survival after 40 months (p = 0.05). EGFR+/ER- patients had the lowest survival probability, but statistical significance was not reached (p = 0.06). The EGFR phenotype appeared as a patients with different early outcome, with potential therapeutic implication especially in the group of ER-negative patients. These results emphasize the need for a standardized assay methodology and for further clinical studies, particularly in protocols where adjuvant hormonal therapy is prescribed on the basis of steroid hormone receptor status, in order to assess the respective prognostic worth of EGFR and ER (or PR).
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PMID:Prognostic value of epidermal growth factor receptor in node-positive breast cancer. 269 Sep 71

Type II integral membrane proteins are anchored by a signal-peptide/membrane-anchor domain (SA domain) located near their N-terminus, whereas type I membrane proteins are anchored by stop-transfer sequences usually located near the C-terminus. In this study we have attempted to transform neutral endopeptidase-24.11 (EC 3.4.24.11; NEP), a type II membrane protein, into a type I membrane protein. Three type I mutant proteins were constructed by fusion of topogenic sequences to the C-terminus of SecNEP, a soluble form of NEP. The first two type I mutants, SecNEP-TMC and SecNEP-TMIC, were constructed by fusing in frame the cytosolic and SA domains of NEP to the C-terminus of SecNEP. These two fusion proteins differ only in the orientation of the cytosolic tail. The third type I mutant, SecNEP-ACE, was constructed by fusing in frame the stop-transfer and cytosolic domains of angiotensin I-converting enzyme (EC 3.4.15.1; ACE) to the C-terminus of SecNEP. Our results suggest that: (1) the NEP ectodomain can be anchored with a type I topology in the endoplasmic reticulum (ER) membrane by both NEP and ACE topogenic sequences; (2) SecNEP-TMC and SecNEP-TMIC were transport-incompetent and needed proteolytic cleavage in the C-terminal region to leave the ER, whereas SecNEP-ACE was transported out of the ER as a type I membrane protein. Therefore we concluded that the nature of topogenic sequences determines the transport-competence of topological mutants of neutral endopeptidase-24.11.
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PMID:The nature of topogenic sequences determines the transport competence of topological mutants of neutral endopeptidase-24.11. 749 41

EGFR was determined, before treatment; in tumors biopsies obtained from 109 consecutive patients with head and neck cancer (100 men and nine women), using iodine labelled recombinant EGF. The median age of the study population was 60 years. EGFR levels varied from 2 to 2302 fmol/mg membrane protein (median 71). There was a significant difference of distribution for EGFR levels between stages I and II tumors and stages III and IV tumors (P = 0.03). The EGFR cut-off value for overall survival was 120 fmol/mg protein and the median follow-up was 18 months (3-35) EGFR overexpression was associated with shorter relapse-free (P = 0.0125) and overall survival (P = 0.028). By multivariate analysis the only significant variables were EGFR for relapse-free survival and tumor staging and EGFR for overall survival. Analyzed in 60 patients treated by first-line chemotherapy CDDP-5FU, the longest survival was achieved for patients who had a complete response to chemotherapy and the lowest EGFR levels (P = 0.018). EGFR expression in the primary tumor allows survival among first line chemotherapy responder categories to be discriminated.
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PMID:[EGF receptor, a prognostic factor in epidermoid cancers of the upper aerodigestive tracts]. 774 4

In the present work we have investigated activation of phosphorylation of plasma membrane insulin-like growth factor-I receptors (IGF-IR) by diethylstilbestrol (DES). Insulin-like growth factor-I (IGF-I) stimulated the activity of membrane protein tyrosine kinase(s) (PTK) in both normal and DES-treated hamster kidneys. The level of IGF-I-stimulated PTK(s) almost doubled after 15 days of DES treatment. Autophosphorylation experiments revealed that phosphorylation of a 95 kDa band (presumably the beta subunit of IGF-IR) was 2-fold higher in the membranes of kidney from DES-treated animals compared with controls. To understand the mechanism of activation of IGF-I-dependent PTK by DES, we investigated the relationship between the binding capacity of IGF-I to membrane proteins and the level of IGF-IR. The binding of [125I]IGF-I to membranes from the DES-treated group was 30% higher than that of age-matched normal kidney (P < 0.001). Scatchard analysis of the binding data for both normal and DES-treated hamster kidney revealed a single class binding site for IGF-I with a dissociation constant (Kd) of 4.1 and 4.6 nM and a maximum binding capacity (Bmax) of 1786 and 2086 fmol/200 micrograms protein respectively. Therefore, the difference observed in [125I]IGF-I binding between DES-treated and normal kidney membranes may be partially due to an increase in the number of IGF-I binding sites, with no change in the affinity of the receptors for IGF-I. An enhanced level of IGF-IRs in membranes from DES-treated animals was visualized by autoradiography following affinity labeling of membrane proteins subjected to SDS-PAGE. Under reducing conditions a molecular band of 132 kDa was evident. The 132 kDa band represents the alpha-subunit of IGF-IRs. Northern blot analyses revealed that DES treatment increased the level of IGF-IR mRNA 2-fold compared with that of controls. These findings suggest that an enhanced level of IGF-IR coupled with qualitative changes may be responsible for the activation of IGF-I-dependent PTK on DES exposure. Whether the stimulation of IGF-IR phosphorylation by exposure to a carcinogenic dose of DES may be a factor in the induction of renal cancer in Syrian hamsters is not clear.
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PMID:Activation of phosphorylation of plasma membrane insulin-like growth factor-I receptors in the kidney of Syrian hamsters by diethylstilbestrol. 778 52

We showed previously that the TCR and CD2 fail to couple efficiently with their signal transduction machinery in J45.01, a CD45-deficient variant of the Jurkat T-cell line. Transfection into J45.01 of a cDNA encoding a chimeric membrane protein containing the cytoplasmic sequence of CD45 and extracellular and transmembrane sequences derived from the A2 allele of MHC class I rescues proximal signaling events after TCR stimulation. In this report, we describe rescue of CD2-mediated signaling and evaluate further the characteristics of TCR signaling in J45.01 after expression of the chimeric protein. Cells expressing the chimeric molecule demonstrate TCR- and CD2-mediated increases in PTK activity and PI turnover. Stimulation of the TCR and CD2 on the transfected cells also results in the expression of CD69 on the cell surface, a more distal signaling event. Although these measures of signal transduction via the TCR and CD2 are restored in the transfected cells, the magnitude of the responses are less than those seen in the wild-type Jurkat cells. These findings demonstrate that the cytoplasmic domain of CD45, expressed as a chimeric membrane protein, is sufficient for mediating signal transduction through CD2 as well as through the TCR complex. In addition, these results suggest that the extracellular and/or transmembrane domains of CD45 may contribute to the efficiency of signal transduction.
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PMID:Restoration of CD2-mediated signaling by a chimeric membrane protein including the cytoplasmic sequence of CD45. 792 41

Receptor-specific or homologous desensitization of beta 2-adrenergic receptors is thought to be effected via phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK), followed by binding of beta-arrestin. We have generated stably transfected Chinese hamster ovary cell lines overexpressing either of the two regulatory proteins and also expressing low or high levels of beta 2-adrenergic receptors (approximately 80 and approximately 600 fmol/mg of membrane protein). In these cells, we studied the process of desensitization induced by the beta-adrenergic receptor agonist isoproterenol. In cells expressing high levels of beta 2-adrenergic receptors, desensitization to high concentrations of isoproterenol (previously shown to be mediated by both beta ARK and protein kinase A) amounted to approximately 50% in control cells, approximately 80% in beta ARK-overexpressing cells, and approximately 90% in beta-arrestin-overexpressing cells. In cells expressing low levels of beta 2-adrenergic receptors, these values were approximately 50, approximately 60, and approximately 60%, respectively. Desensitization to low concentrations of isoproterenol (previously shown to be essentially protein kinase A-mediated and not receptor-specific, i.e. heterologous) was not affected by overexpression of either beta ARK or beta-arrestin. These data suggest that in cells expressing high levels of beta 2-adrenergic receptors, beta-arrestin and beta ARK become limiting for homologous receptor desensitization. They provide further support for the involvement of these two proteins in the regulation of beta 2-adrenergic receptor function.
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PMID:Overexpression of beta-arrestin and beta-adrenergic receptor kinase augment desensitization of beta 2-adrenergic receptors. 838 21

We have previously demonstrated that membrane receptor protein tyrosine kinase(s) activities are higher in estrogen-induced kidney tumors in comparison with such activities in the normal kidney. In the present work we have investigated the growth factor binding sites in estrogen-induced kidney tumor and in normal kidney membranes in an attempt to understand the mechanism of activation of membrane protein tyrosine kinase(s) and their possible relationship to the induction of estrogen-induced tumors. The characteristics of the normal hamster kidney membrane insulin-like growth factor 1 (IGF-1) receptor are similar to those reported for kidney and extrarenal tissues of other rodents. The binding of 125I-IGF-1 to the normal kidney or tumor membranes was saturable and dependent on time, protein, pH, and temperature. The binding of 125I-IGF-1 to the tumor membranes was significantly higher when compared to the binding activity of the membranes obtained from age-matched normal kidney. The Scatchard analysis of the binding data of both tumor and normal kidney revealed a single class binding site for IGF-1 with Kd of 1.7 and 1.8 nM and maximum binding capacities of 4150 and 2050 fmol/mg protein, respectively. Therefore, the difference observed in 125I-IGF-1 binding between tumor and normal kidney membranes was due to an increase in the number of IGF-1 binding sites with no change in the affinity of receptors for IGF-1. An enhanced level of IGF-1 receptors in tumor membranes also was visualized by autoradiography following affinity labeling of membrane proteins subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Under reducing conditions of electrophoresis, two molecular bands of M(r) 240,000 and M(r) 130,000 were evident. The M(r) 130,000 band represents the alpha subunit of IGF-1 receptors, and the M(r) 240,000 band may represent the aggregates of the receptor subunits which were not reduced completely. IGF-1 stimulated normal kidney or tumor membrane protein tyrosine kinase(s) (wheat germ lectin agarose-purified membrane proteins) in a dose-dependent fashion. Therefore, the alteration of IGF-1 binding activity of the tumor membrane receptors and stimulation of IGF-1-mediated membrane protein tyrosine kinase activity in tumor tissues suggest that events coupled to this membrane receptor may play a role in estrogen stimulation of renal carcinoma.
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PMID:Insulin-like growth factor 1 receptors are increased in estrogen-induced kidney tumors. 848 11


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