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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that an intracellular mechanism down regulates epidermal growth factor (EGF) receptor levels in rodent fibroblasts transformed by the src oncogene (W. J. Wasilenko, L. K. Shawver, and M. J. Weber, J. Cell. Physiol. 131:450-457, 1987). We now report that this down regulation is due to an inhibition of EGF receptor biosynthesis. With Rat-1 (R1) cells infected with a temperature-sensitive src mutant, we found that 125I-labeled EGF binding to cells began to decrease soon after the activation of pp60v-src by shift down to the permissive temperature for transformation. This effect of src on EGF receptors was reversible. Pulse-chase studies with [35S]methionine-labeled cells revealed that the tyrosine protein kinase activity of pp60v-src had little if any effect on EGF receptor degradation rate. By contrast, the expression of pp60v-src caused a large reduction in the apparent rate of EGF receptor biosynthesis. Northern (RNA) blot analysis demonstrated that pp60v-src also caused marked reductions in the steady-state level of EGF receptor mRNA. These data indicate that one way the expression of the src oncogene can affect the machinery of growth control is by affecting the expression of specific genes for growth factor receptors.
Mol Cell Biol 1990 Mar
PMID:Inhibition of epidermal growth factor receptor biosynthesis caused by the src oncogene product, pp60v-src. 210 69

Studies investigated the effects of benzo(a)pyrene (BP) treatment on epidermal growth factor (EGF) receptor binding and kinase activity in human placental cell cultures. Specific binding of 125I-EGF to cells from early gestation placentae was significantly decreased by 37 and 60% following exposure to 1 and 10 microM BP, respectively, for 24 hr. In contrast, cells cultured from term placentae showed no inhibitory effect of either concentration of BP. Specific binding of 125I-labeled insulin and insulin-like growth factors-I and -II to early gestation cells was decreased only 15-18% at 10 microM BP, which indicates that loss of membrane receptors appears to be selective for EGF. Scatchard analysis of early gestation cells revealed that BP was associated with a dose-dependent loss in the number of high affinity EGF binding sites. Evidence from cross-linking and autophosphorylation experiments confirmed that the Mr 170,000 binding protein was decreased in a dose-dependent manner following BP treatment. In comparison, term placental cells exhibit a 26% loss of EGF receptor autophosphorylation without alteration in binding following exposure to 10 microM BP. Thus, early gestation cells exhibit a BP-related down-regulation of EGF receptors, whereas term placental cells show receptor desensitization. No adverse effect of BP treatment was observed on the incorporation of [35S] methionine into proteins secreted by early gestation cells. Further experiments compared the effects of BP with the related poly-cyclic compounds beta-naphthoflavone, alpha-naphthoflavone, and 3-methylcholanthrene. In early gestation cells, EGF binding and receptor autophosphorylation were measurably decreased at 10 microM concentrations of these polycyclic compounds, but to a lesser extent than observed with BP. In term placental cells, however, EGF binding was unchanged or increased, whereas receptor autophosphorylation was decreased 10-26%. Thus, exposure of term placental cells to these polycyclic compounds leads to a dissociation between EGF binding and receptor protein kinase activity. Finally, aryl hydrocarbon hydroxylase activity was induced 20- to 200-fold in early placental cells exposed to BP, beta-naphthoflavone, and 3-methylcholanthrene. In summary, the direct effects of BP and related compounds observed on placental EGF receptors may indicate altered function of EGF in the regulation of cell growth and differentiation in the human placenta.
Mol Pharmacol 1990 Feb
PMID:Benzo(a)pyrene inhibits epidermal growth factor binding and receptor autophosphorylation in human placental cell cultures. 215 66

The erbB-2 gene product, gp185erbB-2, displays a potent transforming effect when overexpressed in NIH 3T3 cells. In addition, it possesses constitutively high levels of tyrosine kinase activity in the absence of exogenously added ligand. In this study, we demonstrate that its carboxy-terminal domain exerts an enhancing effect on erbB-2 kinase and transforming activities. A premature termination mutant of the erbB-2 protein, lacking the entire carboxy-terminal domain (erbB-2 delta 1050), showed a 40-fold reduction in transforming ability and a lowered in vivo kinase activity for intracellular substrates. When the carboxy-terminal domain of erbB-2 was substituted for its analogous region in the epidermal growth factor receptor (EGFR) (EGFR/erbB-2COOH chimera), it conferred erbB-2-like properties to the EGFR, including transforming ability in the absence of epidermal growth factor, elevated constitutive autokinase activity in vivo and in vitro, and constitutive ability to phosphorylate phospholipase C-gamma. Conversely, a chimeric erbB-2 molecule bearing an EGFR carboxy-terminal domain (erbB-2/EGFRCOOH chimera) showed reduced transforming and kinase activity with respect to the wild-type erbB-2 and was only slightly more efficient than the erbB-2 delta 1050 mutant. Thus, we conclude that the carboxy-terminal domains of erbB-2 and EGFR exert different regulatory effects on receptor kinase function and biological activity. The up regulation of gp185erbB-2 enzymatic activity exerted by its carboxy-terminal domain can explain, at least in part, its constitutive level of kinase activity.
Mol Cell Biol 1990 Jun
PMID:The carboxy-terminal domains of erbB-2 and epidermal growth factor receptor exert different regulatory effects on intrinsic receptor tyrosine kinase function and transforming activity. 218 97

The HC11 cell line was isolated from mammary gland cells of pregnant mice. The cells displayed a normal phenotype and retained some characteristics of mammary epithelial cell differentiation. After treatment with the lactogenic hormones prolactin and glucocorticoids, the HC11 cells expressed the milk protein beta-casein. Various oncogenes were transfected and expressed in HC11 cells. The oncogenes were tested for their transformation ability and for their effects upon the differentiation of the HC11 cells. All of the oncogenes tested, including activated human Ha-ras, human transforming growth factor-alpha, activated rat neuT, and human c-erbB-2 activated by a point mutation in the transmembrane domain, caused transformation of the HC11 cells, as shown by tumor formation in nude mice. HC11 cells expressing the neuT and activated c-erbB-2 genes synthesized beta-casein in response to lactogenic hormones, whereas those expressing the Ha-ras or transforming growth factor-alpha oncogenes were no longer able to respond to the lactogenic hormones. This inhibition of beta-casein production occurs at the transcriptional level and in the transforming growth factor-alpha-transformed cells is due to an autocrine mechanism involving the activation of the epidermal growth factor receptor. This suggests that, although the c-erbB-2 and epidermal growth factor receptors are structurally quite similar, their activation has different effects upon mammary epithelial cell differentiation.
Mol Cell Biol 1990 Aug
PMID:Epidermal growth factor receptor, but not c-erbB-2, activation prevents lactogenic hormone induction of the beta-casein gene in mouse mammary epithelial cells. 219 43

The neu gene in rat neuro/glioblastoma was found to be activated by a single point mutation in the DNA sequence encoding the transmembrane region of the neu-encoded p185 protein. The human homologue of the rat neu gene, termed c-erbB-2 or HER-2, can also be activated in vitro by a similar mutation in the corresponding region. Although the human neu gene was shown to be amplified/overexpressed in a large portion of human breast and ovarian cancer, no reports indicate that the human neu gene is activated by a point mutation in human tumor. To study the possible point mutation of neu gene in human tumors, we characterized the genomic structure in the transmembrane region of human neu gene, which in turn allowed us to determine DNA sequence in this region directly following DNA amplification by polymerase chain reaction. We analyzed 7 tumor cell lines (2 breast cancer, 1 neuroblastoma, 1 rhabdomyosarcoma, and 3 glioma) and 11 tumor tissue samples (8 breast and 3 ovarian cancers). No mutation was found in the transmembrane region of human neu gene. Our results suggest that unlike the rat neuro/glioblastoma, the single point mutation in the transmembrane region of the human neu gene is a rare event in human tumors. In this study, we developed a technique for direct DNA sequencing of the transmembrane region of the human neu gene. This technique makes it possible to screen a large number of tumor samples.
Mol Carcinog 1990
PMID:Direct sequencing analysis of transmembrane region of human Neu gene by polymerase chain reaction. 220 83

While steroid hormones act as endocrine effectors of growth and development of normal breast and of carcinogenesis and progression of malignant breast, recent evidence suggests that local hormonal effectors also exist. These are the growth regulatory growth factors. This article summarizes current status of our understanding of structure and function of growth factors secreted by the normal and malignant mammary epithelium. While growth inhibitory factors and their receptors generally suppress development of the transformed phenotype and promote differentiation, growth stimulatory factors and their receptors may be necessary for both normal proliferation and early stages of malignant progression of breast cancer. Overexpression of two receptors, c-erbB-2 and EGF receptor, have also been associated with poor prognosis in the clinical disease.
J Steroid Biochem Mol Biol 1990 Dec 20
PMID:Stimulatory and inhibitory growth factors and breast cancer. 228 93

Treatment of immature female Sprague-Dawley rats with 17 beta-estradiol (5 micrograms/animal) resulted in an increase in uterine epidermal growth factor (EGF) receptor binding activity. Moreover, in a separate study it was also shown that 17 beta-estradiol increased steady-state levels of rat uterine EGF receptor mRNA as determined by Northern analysis. In contrast, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) caused a dose-response decrease in constitutive rat uterine EGF receptor binding activity and this was paralleled by a decrease in steady-state levels of uterine EGF receptor mRNA. Cotreatment of the animals with both TCDD (16 nmol/kg) and 17 beta-estradiol (5 micrograms/rat) gave results which showed that TCDD significantly inhibited the estrogen-induced increases in rat uterine EGF receptor binding activity and EGF receptor mRNA levels. These results further extend the range of antiestrogenic properties of TCDD and suggest that the inhibition of growth factor expression may play a role in the growth-inhibiting properties of TCDD in estrogen-responsive tissues or cells.
Mol Cell Endocrinol 1990 Sep 10
PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibition of 17 beta-estradiol-induced increases in rat uterine epidermal growth factor receptor binding activity and gene expression. 228 33

Synthesis of the epidermal growth factor (EGF) receptor has been analyzed in a series of variant A431 human epidermoid carcinoma cell clones reported to contain different amounts of EGF binding sites. The amount of EGF receptor protein, quantitated by immunoaffinity chromatography, and EGF receptor mRNA, quantitated by cDNA hybridization, were closely correlated to the extent of EGF receptor gene amplification. This correlation existed in variants selected for reduced EGF receptors and in revertants from those variants with increased EGF receptors. There was also a correlation between the frequency of translocation of chromosome 7, containing the EGF receptor gene, and EGF receptor protein. These results support gene amplification as the mechanism enhancing A431 cell EGF receptor protein and determining growth responses.
Somat Cell Mol Genet 1985 Jul
PMID:Relationship between production of epidermal growth factor receptors, gene amplification, and chromosome 7 translocation in variant A431 cells. 241 Sep 84

The c-erbB-2 gene is a v-erbB-related proto-oncogene which is distinct from the gene encoding the epidermal growth factor receptor. By using two independent methods, hybridization of both sorted chromosomes and metaphase spreads with cloned c-erbB-2 DNA, we mapped the c-erbB-2 locus on human chromosome 17 at q21, a specific breakpoint observed in a translocation associated with acute promyelocytic leukemia. Furthermore, we observed amplification and elevated expression of the c-erbB-2 gene in the MKN-7 gastric cancer cell line. These data suggest possible involvement of the c-erbB-2 gene in human cancer.
Mol Cell Biol 1986 Mar
PMID:Localization of a novel v-erbB-related gene, c-erbB-2, on human chromosome 17 and its amplification in a gastric cancer cell line. 243 Jan 75

The human epidermoid carcinoma cell line A431, containing an amplification in the epidermal growth factor (EGF) receptor gene, was examined for its sensitivity to the growth inhibitory effects of synthetic double-stranded RNAs (dsRNAs). Poly(I).poly(C), poly(A).poly(U) and rln.r(C13,U)n at 5 to 100 micrograms/ml produced 20 to 60% growth inhibition, whereas poly(ICLC) produced 40 to 80% growth inhibition at 0.05 to 25 micrograms/ml.Poly(I).poly(C) did not cause the secretion of interferon (IFN) into the medium, and addition of polyclonal antibodies to IFN-alpha and IFN-beta did not block the growth inhibition produced by poly(I).poly(C). Clone 29, which proliferates in response to EGF, and clone 29R, which is sensitive to the growth inhibitory effects of EGF, showed sensitivities to the antiproliferative effects of poly(I).poly(C) similar to those of the parent cell line. Incubation of cell membrane extracts with poly(I).poly(C) or treatment of cells with the dsRNA did not affect EGF receptor tyrosine kinase activity. On the other hand, poly(I).poly(C) produced a dose-dependent induction of (2',5')oligo(A) synthetase activity and degradation of 45S preribosomal RNA and 28S and 18S rRNA. These results indicate that the growth inhibitory properties of poly(I).poly(C) in A431 cells are independent of the action of IFN but are associated with degradation of rRNA, an effect that may be related to the (2',5')oligo(A)-RNase L pathway.
Mol Pharmacol 1988 Oct
PMID:The epidermal growth factor- and interferon-independent effects of double-stranded RNA in A431 cells. 245 91


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