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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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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 existence of an autocrine loop for self-stimulation of growth in malignant cells has been proposed for transforming growth factor-alpha (TGF alpha) and its receptor, the epidermal growth factor (EGF) receptor, in a variety of malignant cell types. Expression of both has been described in colon carcinoma. In order to investigate whether there is a correlation between TGF alpha and EGF receptor mRNA expression and differentiation, we studied the effects of differentiating agents on seven human colon carcinoma cell lines. All of the lines responded to the differentiating agents. In four of the seven lines there was increased EGF receptor mRNA two to five days after treatment with 2 mM sodium butyrate. In three of these lines TGF alpha mRNA and protein were also increased. In the one cell line treated with the differentiating agents DMF and DMSO, EGF receptor mRNA was also increased. [125I]-EGF binding to the cells was measured before and after treatment with butyrate. In two of three cell lines, increased EGF receptor mRNA was accompanied by a 2.4-fold increase in the number of binding sites per cell. In SW620 cells, no EGF receptor binding was detected before or after butyrate treatment. In the two cell lines in which butyrate increased EGF receptor binding, simultaneous treatment with EGF did not enhance growth. These data demonstrate increased expression of the TGF alpha/EGF receptor system after differentiation of colon carcinoma cell lines and suggest that their expression may be characteristic of a differentiated phenotype.
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PMID:Modulation of EGF receptor expression by differentiating agents in human colon carcinoma cell lines. 220 77

The erbB2 oncogene encodes a 185-kilodalton transmembrane protein whose sequence is similar to the epidermal growth factor receptor (EGFR). A 30-kilodalton factor (gp30) secreted from MDA-MB-231 human breast cancer cells was shown to be a ligand for p185erbB2. An antibody to EGFR abolished the tyrosine phosphorylation induced by EGF and transforming growth factor-alpha (TGF-alpha) but only partially blocked that produced by gp30 in SK-BR-3 breast cancer cells. In two cell lines that overexpress erbB2 but do not expresss EGFR (MDA-MB-453 breast cancer cells and a Chinese hamster ovary cell line that had been transfected with erbB2), phosphorylation of p185erbB2 was induced only by gp30. The gp30 specifically inhibited the growth of cells that overexpressed p185erbB2. An antibody to EGFR had no effect on the inhibition of SK-BR-3 cell colony formation obtained with gp30. Thus, it appeared that gp30 interacted directly with the EGFR and erbB2. Direct binding of gp30 to p185erbB2 was confirmed by binding competition experiments, where gp30 was found to displace the p185erbB2 binding of a specific antibody to p185erbB2. The evidence described here suggests that gp30 is a ligand for p185erbB2.
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PMID:Direct interaction of a ligand for the erbB2 oncogene product with the EGF receptor and p185erbB2. 221 96

To better understand the possible roles and interactions of transforming growth factor-alpha (TGF alpha) and its receptor, the epidermal growth factor (EGF) receptor in human breast epithelium, we have studied the expression of TGF alpha and the EGF receptor in a series of normal human mammary epithelial cells derived from reduction mammoplasty before in vitro propagation, during short term proliferation in vitro, and after immortalization. Increased TGF alpha mRNA expression coincided with conversion of the cells to a proliferative state in vitro. After establishment, propagation, and proliferation in vitro, the cells expressed high levels of both TGF alpha and EGF receptor mRNAs. Addition of diverse growth inhibitory agents, including 12-O-tetradecanoylphorbol-13-acetate (TPA), TGF beta, and sodium butyrate, to one of these rapidly proliferating cell populations (no. 184) failed to reduce the expression of either TGF alpha or the EGF receptor. Likewise, cessation of growth associated with both senescence and confluence of the 184 cells did not result in reduced expression. However, regulation of TGF alpha mRNA could be demonstrated by withdrawal of EGF from the medium or by antibody-mediated blockade of the EGF receptor in 184 cells. Antibody-mediated EGF receptor blockade also results in inhibition of growth and [3H]thymidine labeling. An autoregulatory autocrine loop appears operant in proliferating breast epithelial cells. Both growth and levels of TGF alpha mRNA expression are controlled by binding of ligand to the EGF receptor. These studies suggest a role for the TGF alpha/EGF receptor pathway in normal breast cell physiology.
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PMID:Expression of the transforming growth factor-alpha/epidermal growth factor receptor pathway in normal human breast epithelial cells. 229 6

Estrogen-stimulated growth of the human mammary adenocarcinoma cell line MCF-7 is significantly inhibited by monoclonal antibodies to the epidermal growth factor (EGF) receptor that act as antagonists of EGF's mitogenic events by competing for high-affinity EGF receptor binding sites. These antibodies likewise inhibit the EGF or transforming growth factor-alpha (TGF-alpha)-stimulated growth of these MCF-7 cells. An analogous pattern of specific EGF or TGF-alpha growth inhibitory activity was obtained using a synthetic peptide analog encompassing the third disulfide loop region of TGF-alpha, but containing additional modifications designed for increased membrane affinity [( Ac-D-hArg(Et)2(31),Gly32,33]HuTGF-alpha(31-43)NH2). The growth factor antagonism by this synthetic peptide was specific in that it inhibited EGF, TGF-alpha, or estrogen-stimulated growth of MCF-7 cells but did not inhibit insulin-like growth factor-1 (IGF-1)-stimulated cell growth. Altogether, these results suggest that a significant portion of the estrogen-stimulated growth of these MCF-7 cells is mediated in an autocrine/paracrine manner by release of EGF or TGF-alpha-like growth factors. The TGF-alpha peptide likewise inhibited EGF- but not fibroblast growth factor (FGF)- or platelet-derived growth factor (PDGF)-stimulated growth of NIH-3T3 cells in completely defined media; but had no effect on growth or DNA synthesis of G0-arrested cells, nor did it effect growth of NR-6 cells, which are nonresponsive to EGF. Although this synthetic peptide did not directly compete with EGF for cell surface receptor binding, it exhibited binding to a cell surface component (followed by internalization), which likewise was not competed by EGF. The peptide did not directly inhibit EGF-stimulated phosphorylation of the EGF receptor, nor did it inhibit phosphorylation of an exogenous substrate, angiotensin II, by activated EGF receptor. The TGF-alpha peptide did, however, affect the structure of laminin as manifested by laminin self-aggregation; this affect on laminin may, in turn, have a modulatory effect on EGF-mediated cell growth.
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PMID:Inhibition of epidermal growth factor/transforming growth factor-alpha-stimulated cell growth by a synthetic peptide. 253 Feb 43

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

Because of the influence of transforming growth factor-alpha (TGF alpha) on the cell growth in other cancer cell systems, we investigated the growth-regulatory role of TGF alpha in human prostate cancer cells. TGF alpha (5 ng/ml) stimulated LNCaP cell growth in monolayer to 60% of the level seen with dihydrotestosterone (DHT). Both DHT and TGF alpha increased cloning in soft agar twofold above that in controls. Metabolism of thymidine and uridine was also increased as evidenced by increased uptake of these macromolecule precursors. In addition, intracellular signalling as indicated by phosphatidyl inositol turnover was also increased by TGF alpha and DHT. Conditioned media contained TGF alpha by radioimmunoassay (RIA), transforming activity by rat kidney fibroblast (NRK) colony formation, and epidermal growth factor (EGF) receptor competable activity by radioreceptor assay. EGF receptors were present by binding assay and immunoprecipitation. These data demonstrate the presence of an autostimulatory growth loop in hormone-responsive human prostate cancer cells.
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PMID:Role of transforming growth factor-alpha in human prostate cancer cell growth. 279 27

Limited information is available concerning the involvement of growth factor receptors and their ligands in the pathogenesis of human pancreatic cancer. We analyzed 12 human pancreatic cancer cell lines by Northern blot analysis for the expression of 9 receptor tyrosine kinase (RTKs) and 6 growth factors. The effect of a monoclonal antibody (MAb) against transforming growth factor-alpha (TGF-alpha) on in vitro pancreatic cancer cell growth was also assessed, mRNA for EGF-R, c-erbB-2 and c-erbB-3 was expressed in 12 (100%), 12 (100%), and 7 (58%), respectively, of the cell lines examined. In addition, 8 (67%) cell lines expressed the c-met/receptor for hepatocyte growth factor. As for ligands, TGF-alpha mRNA was detected in 10 (83%) cell lines; MAb against TGF-alpha inhibited growth of the 2 cell lines examined. Furthermore, mRNA for amphiregulin (AR) was expressed in 10 (83%) cell lines. Coexpression of TGF-alpha, AR, and EGF-R was observed in 9 (75%) cell lines. These results support the concept that several specified types of RTKs and their ligands are closely involved in regulation of the growth of human pancreatic cancer cells.
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PMID:Frequent expression of genes for receptor tyrosine kinases and their ligands in human pancreatic cancer cells. 759 66

We examined the expression of epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), epidermal growth factor receptor (EGFR) and p185c-erbB-2 immunohistochemically and correlated the expression with growth in 66 cases of human gastric carcinoma. To evaluate growth, we used the bromodeoxyuridine (BrdU) labeling index in 51 cases and the radiographic growth rate in 15 cases. Expression of EGF was detected in 41 cases (62.1%), TGF-alpha in 42 cases (63.6%), EGFR in 34 cases (51.5%), and p185c-erbB-2 in 37 cases (56.1%). The BrdU labeling index ranged from 1.5 to 32.0%. The BrdU labeling index was higher in tumors that coexpressed EGF and EGFR or TGF-alpha and EGFR than in tumors without expression or in tumors that expressed growth factors or the receptors (p < 0.01). The BrdU labeling index was also significantly higher in tumors with the expression of EGFR and/or p185c-erbB-2. Tumors with simultaneous expression of EGF, TGF-alpha, EGFR and p185c-erbB-2 had an association with a high BrdU labeling index. Moreover, all of these growth factors and receptors were expressed simultaneously in gastric carcinomas with rapid growth. These results suggest that the expressions of EGF, TGF-alpha, EGFR and p185c-erbB-2 are closely related and then play an important role in the growth of human gastric carcinomas.
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PMID:Growth of human gastric carcinomas and expression of epidermal growth factor, transforming growth factor-alpha, epidermal growth factor receptor and p185c-erbB-2. 763 56

The stimulation of both phospholipase A2 (PLA2) enzymic activity and the production of prostaglandin E2 (PGE2) by transforming growth factor-alpha (TGF-alpha) and Ca2+ ionophore A23187 in TEA3A1 rat thymic epithelial cells were studied. TGF-alpha by itself at various concentrations (5-200 ng/ml) had no effect on the stimulation of PGE2 production. A23187 (1 microgram/ml) by itself stimulated PGE2 production on average by 18-fold over the control. When TGF-alpha (50 ng/ml) was added to the cells in the presence of A23187, a synergistic stimulation (on average 45-fold) of PGE2 production was observed. Synergistic stimulation was also observed at the level of arachidonic acid released from phospholipid pools, suggesting the activation of PLA2 enzymic activity. We have found that this synergistic activation of PLA2 enzymic activity and subsequent stimulation of PGE2 production required the activation of epidermal growth factor (EGF) receptor tyrosine kinase and Ca2+ influx. This was shown by the fact that genistein, an inhibitor of tyrosine kinase, blocks the synergistic stimulation by TGF-alpha and A23187 and by the fact that the stimulation of PGE2 production by TGF-alpha and A23187 is dependent on the culture-medium Ca2+ concentrations. The requirement for Ca2+ influx instead of intracellular mobilization of Ca2+ was shown by the fact that PGE2 production was not stimulated when cells were treated with TGF-alpha and thapsigargin. Moreover, the synergistic stimulation of PGE2 production by TGF-alpha and A23187 was not affected in protein kinase C down-modulated cells. In addition, the synergistic stimulation was not observed in cells treated with either phorbol 12-myristate 13-acetate (PMA) and TGF-alpha or PMA and A23187, and in cells treated with TGF-alpha and thapsigargin. The requirement for the activation of receptor tyrosine kinase seems to be specific to the EGF receptor, since a synergistic stimulation of PGE2 production was not observed when cells are treated with either insulin-like growth factor-I or fibroblast growth factor-I in the presence of A23187.
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PMID:Activation of phospholipase A2 and stimulation of prostaglandin E2 production by transforming growth factor-alpha in rat thymic epithelial cells requires influx of calcium. 768 26


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