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)

Synthesis and metabolism of the epidermal growth factor (EGF) receptor are extensively regulated to modulate cellular responses to ligand. To study regulation of EGF receptor gene expression, the 5' region of the gene was isolated from a human placental genomic library. A 5' proximal 1.1-kilobase fragment (-1100 to -19 relative to the ATG translation start site) and subfragments of this were subcloned in both forward and reverse orientations into the luciferase expression vector pSVOAL delta 5' and transfected into human cell lines. Luciferase activity was stimulated by treatment of transfected HeLa cells with EGF, 12-O-tetradecanoylphorbol 13-acetate (TPA), (Bu)2 cAMP, retinoic acid, and dexamethasone. Deletion analysis indicated full retention of activity after removal of the -1100 to -485 region (-485 to -19 fragment), but a 5-fold reduction in activity on removal of the -485 to -153 region (-153 to -19 fragment). Despite a reduction in basal activity, the proximal 134-basepair fragment retained responses to all inducers. Additivity was observed in response to maximal concentrations of TPA plus retinoic acid and of TPA plus (Bu)2 cAMP; the response to a combination of four inducers exceeded that to the RSV-LTR strong promoter. Differences in stimulated responses were observed in various recipients, with hepatoma HepG2 cells lacking responses to (Bu)2 cAMP and glioblastoma T98G cells lacking responses to EGF and TPA. These results indicate that a 134-basepair DNA fragment closely adjacent to the translation start site contains elements responsible for directing basal and stimulated expression of the EGF receptor gene.
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PMID:Regulation of epidermal growth factor receptor gene expression. 254 Apr 31

We here show that tetradecanoyl phorbol acetate (TPA) and 1-oleoyl 2-acetyl glycerol (OAG) cause the translocation of diacylglycerol (DG) kinase from the cytosol to the membrane fractions in chick embryo fibroblast (CEF) cells. However, this translocation is not marked in erbB-transformed chick embryo fibroblast (GEV) cells. The activities of phosphatidylinositol (PI) and phosphatidylinositol 4-phosphate (PIP) kinases in membrane fractions are not altered by TPA treatment in either CEF or GEV cells. Such reduced translocation of DG kinase by TPA is also observed in src-transformed cells, but not in myc-transformed cells. These results suggest that the defect in DG kinase translocation may result in failure to suppress the overactivation of protein kinase C in erbB-2 and src-transformed cells, which may lead to cell growth and transformation.
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PMID:Defect in phorbol acetate-induced translocation of diacylglycerol kinase in erbB-transformed fibroblast cells. 256 21

Previous studies have shown that palytoxin, a non-(12-O-tetradecanoylphorbol-13-acetate)-type tumor promoter, is able to down-modulate the epidermal growth factor (EGF) receptor through a sodium-dependent pathway in Swiss 3T3 cells. A role for sodium is supported by the observation that the sodium proton exchanger monensin and the sodium-conducting ionophore gramicidin mimic palytoxin action by causing a decrease in both high and low affinity EGF binding. However, in addition to causing sodium influx, these agents can induce other cellular effects including changes in membrane polarization, intracellular pH, and macromolecular synthesis. To determine whether any of these factors might be responsible for palytoxin action in our system, we examined the role of each of them in palytoxin-induced inhibition of EGF binding. Although palytoxin depolarizes the membrane, the observation that potassium-induced depolarization of the membrane does not cause a decrease in EGF binding, in conjunction with the fact that monensin hyperpolarizes the membrane, indicates that depolarization of the membrane is not responsible for palytoxin-induced changes in the EGF receptor. An investigation of intra-cellular pH suggests that the palytoxin effects are not mediated by proton flux. In addition, nigericin-mediated changes in intracellular pH do not cause an inhibition of EGF binding. Finally, studies conducted in the presence of cycloheximide indicate that protein synthesis is not required for palytoxin action and that inhibition of EGF receptor biosynthesis does not account for palytoxin-induced loss of EGF-binding sites. These results suggest that sodium may act as a second messenger in the signal transduction mechanism by which palytoxin modulates the EGF receptor.
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PMID:Sodium as a mediator of non-phorbol tumor promoter action. Down-modulation of the epidermal growth factor receptor by palytoxin. 257 66

We have previously reported the immunohistochemical localization of transforming growth factor-alpha (TGF alpha) in the intact bovine anterior pituitary gland. Furthermore, we have purified TGF alpha from the conditioned medium of cell cultures derived from the bovine anterior pituitary. We report her the identification of the TGF alpha mRNA from both the intact bovine anterior pituitary gland and the anterior pituitary derived cell cultures. The level of TGF-alpha mRNA in the cell cultures is greater than that present in the intact gland. The TGF-alpha mRNA level increased when the cell cultures were allowed to incubate in their conditioned medium for 3 days, suggesting that a secretory product from the cultured cells is capable of stimulating the accumulation of the TGF-alpha mRNA. 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulation of these cells resulted in a 6-fold increase in the level of TGF-alpha secreted into the conditioned medium. TPA appears to stimulate TGF-alpha secretion at the level of gene transcription as TPA treatment also resulted in an increased accumulation of the TGF-alpha mRNA. The epidermal growth factor (EGF) receptor mRNA was examined in these cell cultures and it increased with TPA treatment in an analogous manner to the TGF-alpha mRNA. EGF treatment of the pituitary cells resulted in an increased level of TGF-alpha mRNA which followed the same time course as TPA, maximal stimulation occurred after 8 h of treatment. The magnitude of EGF stimulated TGF-alpha mRNA was not as great as that seen by TPA stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transforming growth factor-alpha expression in the anterior pituitary gland: regulation by epidermal growth factor and phorbol ester in dispersed cells. 278 91

Primary cultures of hepatocytes derived from adult Fischer 344 rats were used to test for effects of the liver tumor promoter phenobarbital on several components of the epidermal growth factor (EGF) receptor signal transduction pathway. Phenobarbital had no effect on the binding of 125I-labeled EGF by its hepatocyte receptor at 4 degrees C or on EGF-induced receptor down-regulation. However, pretreatment of hepatocytes with phenobarbital (3 mM) at 37 degrees C caused inhibition of subsequent 125I-labeled EGF binding. This response temporally resembled that of hepatocytes to 12-O-tetradecanoylphorbol-13-acetate (TPA) in that maximal inhibition occurred after 1 h of pretreatment but was reversed after longer pretreatment times. The inhibitory effects of phenobarbital and TPA on EGF binding were additive, suggesting that distinct mechanisms mediated the responses to these two tumor promoters. In addition, treatment with TPA, but not phenobarbital, caused a redistribution of the activity of Ca2+/phospholipid-dependent protein kinase C. In untreated and phenobarbital-treated hepatocytes, 20% of protein kinase C activity was isolated with a membranous fraction, while 75% of the activity was membrane associated in TPA-treated hepatocytes. These results demonstrate that phenobarbital, like TPA and other tumor promoters, can modulate the EGF receptor system but suggest that it does so without directly competing with EGF for binding to its receptor or by activating protein kinase C.
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PMID:Independent mechanisms for tumor promoters phenobarbital and 12-O-tetradecanoylphorbol-13-acetate in reduction of epidermal growth factor binding by rat hepatocytes. 279 Aug 4

Previous results have established that 12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters can alter the properties of the epidermal growth factor (EGF) receptor through activation of protein kinase C. In order to determine whether other, non-TPA-type tumor promoters might similarly influence growth-mediating receptors, we investigated the effect of palytoxin on EGF binding in Swiss 3T3 fibroblasts and human epidermal carcinoma (A431) cells. In both cell types, pretreatment with a low dose of palytoxin (1-11 pM) at 37 degrees C causes a decrease in EGF binding. In Swiss 3T3 cells the inhibitory effect is temperature dependent and does not occur at 4 degrees C, indicating that palytoxin is not directly competing with EGF for binding. As assessed by effects on DNA synthesis, palytoxin is not toxic at these concentrations and does not appear to be mitogenic for these cells. Although palytoxin, like phorbol esters, alters EGF binding, its action in Swiss 3T3 cells differs from that of TPA-type tumor promoters in at least 4 respects: (a) the kinetics and dose dependence differ significantly from that of phorbol dibutyrate; (b) the effect is not readily reversible; (c) there is loss of low-affinity as well as high-affinity binding sites; (d) the effect is independent of cellular protein kinase C levels. These results indicate that palytoxin is capable of heterologous regulation of the EGF receptor through a novel mechanism and suggest that certain non-TPA-type tumor promoters as well as TPA-type tumor promoters may act in part through modulation of growth regulatory pathways.
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PMID:Heterologous regulation of the epidermal growth factor receptor by palytoxin, a non-12-O-tetradecanoylphorbol-13-acetate-type tumor promoter. 288 82

Treatment of human adenocarcinoma MKN-7 cells with epidermal growth factor (EGF) or phorbol tetradecanoate acetate (TPA) stimulated phosphorylation of the c-erbB-2 gene product. EGF induced a rapid increase in phosphotyrosine followed by relatively gradual increases in phosphoserine and phosphothreonine. On the other hand, the TPA-induced increase in phosphorylations occurred exclusively on serine and threonine residues. Tryptic phosphopeptide mapping analysis suggested that treatments with EGF and TPA induced phosphorylation of many common sites in the c-erbB-2 gene product. However, in contrast to TPA, EGF increased the phosphorylation of the c-erbB-2 protein in cells whose protein kinase C had been down-regulated by long-term pretreatment with TPA, suggesting that EGF and TPA induce phosphorylation by different mechanisms. Since the c-erbB-2 gene product did not show detectable EGF-binding activity, phosphorylation of tyrosine of the c-erbB-2 gene product might be catalyzed directly by the EGF receptor kinase that was activated by EGF.
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PMID:Tumor promoter and epidermal growth factor stimulate phosphorylation of the c-erbB-2 gene product in MKN-7 human adenocarcinoma cells. 289 79

The structural requirements for diacylglycerols to mimic the action of tumor-promoting phorbol diesters on the epidermal growth factor (EGF) receptor of A431 human epidermoid carcinoma cells were investigated. Five biological effects were considered: inhibition of high affinity 125I-EGF binding, change in the phosphorylation state of the EGF receptor, inhibition of the EGF-dependent tyrosine phosphorylation of the EGF receptor, inhibition of [3H]phorbol 12 beta, 13 alpha-dibutyrate binding, and stimulation of calcium- and phospholipid-dependent protein kinase (C-kinase) in vitro. A marked effect of the acyl chain length, 3-10 carbons, of symmetric sn-1,2-diacylglycerols was observed on their ability to mimic the effect of 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA). sn-1,2-Dipropanoylglycerol did not mimic the effects of PMA, but sn-1,2-didecanoylglycerol potently mimicked PMA action. A correlation was found between the ability of these diacylglycerols to stimulate the activity of C-kinase in vitro and to mimic the effects of PMA on the EGF receptor in intact cells. Analogues of sn-1,2-dioctanoylglycerol in which the 3' hydroxyl group was substituted with hydrogen, thio or chloro moieties were inactive when assayed for their ability to stimulate C-kinase in vitro and mimic PMA action in intact cells. We conclude that the hydroxyl group of a diacylglycerol is vital for the interaction with the phorbol diester receptor. The stringent correlation between the potency of the 11 diacylglycerol analogues tested to modulate C-kinase in vitro and to mimic PMA action in vivo provides strong evidence for the hypothesis that C-kinase plays a central role in the regulation of A431 cell EGF receptors by tumor-promoting phorbol diesters.
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PMID:Structural requirements for diacylglycerols to mimic tumor-promoting phobol diester action on the epidermal growth factor receptor. 298 88

The epidermal growth factor (EGF) receptor gene is the cellular homolog of the avian erythroblastosis virus erbB oncogene. Control of EGF receptor expression determines cellular responsiveness to EGF and might play an important role in neoplastic development. Using RNA blot hybridization, we have found that exposure of human KB carcinoma cells to EGF results in elevated levels of EGF receptor mRNA. The phorbol ester 4 beta-phorbol 12-myristate 13-acetate also stimulates EGF receptor RNA accumulation. Immunoprecipitation of metabolically labeled (30 min) EGF receptor protein revealed that synthesis of new EGF receptor follows the increase in receptor RNA. Addition of cycloheximide together with EGF further enhances EGF receptor RNA accumulation. Results of nuclear runoff-transcription experiments suggest that the stimulatory effects of EGF and cycloheximide are most likely due to a posttranscriptional control mechanism.
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PMID:Epidermal growth factor regulates the expression of its own receptor. 300

The effects of the tumor promoter phorbol 12-tetradecanoate 13-acetate (TPA) on the epidermal growth factor (EGF) receptor levels were investigated in hormone-dependent (MCF-7, T-47-D, and ZR-75-1) and hormone-independent (MDA-MB-231, HBL-100, and BT-20) human mammary carcinoma cell lines. In the absence of TPA, hormone-independent cell lines contained high concentrations of low-affinity EGF receptors (apparent Kd = 8 X 10(-10) M), whereas hormone-dependent cell lines exhibited low concentrations of high-affinity receptors (apparent Kd = 1 X 10(-10) M). TPA causes a change of the receptor from a high- to the low-affinity state in hormone-dependent cell lines (MCF-7, T-47-D, and ZR-75-1), as well as in the hormone-independent HBL-100, whereas the affinity remained unchanged in MDA-MB-231 and BT-20 cells. In addition, progesterone receptor levels are decreased after TPA treatment in the hormone-dependent cell lines MCF-7, T-47-D, and ZR-75-1, whereas the estrogen receptor levels remained unchanged. Tumor promoters such as TPA or teleocidin inhibited the proliferation of these cell lines at concentrations above 10 microM with the exception of the T-47-D cells. The most sensitive cell line towards growth inhibition by tumor promoter was the hormone-dependent MCF-7 cell line. Evaluation of different TPA analogs indicated a positive correlation between the growth-inhibitory effects and their ability to stimulate the subcellular redistribution of protein kinase C activity in MCF-7 cells. These data suggest a protein kinase C-mediated down-regulation of the progesterone receptor concentration and of the EGF receptor affinity, which is supposed to mediate the mitogenic response. Furthermore, these results support the hypothesis that the tumor-derived growth factors induced by estradiol act via the EGF receptor in hormone-dependent mammary carcinoma cells.
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PMID:Correlation between hormone dependency and the regulation of epidermal growth factor receptor by tumor promoters in human mammary carcinoma cells. 300 36


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