Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An antibiotic, azatyrosine [L-beta-(5-hydroxy-2-pyridyl) alanine], specifically converts ras-, raf- or c-erbB2 (neu)-transformed NIH3T3 cells to apparently normal phenotype. The reversion induced by azatyrosine is permanent, and the phenotype of the revertant cells does not change even after prolonged culture in the absence of azatyrosine [N. Shindo-Okada, O. Manabe, H. Nagahara & S. Nishimura (1989). Mol. Carcinogen., 2, 159-167]. In the present study, we found that neurite outgrowth of PC12 cells induced by expression of either the ras or raf oncogenes was inhibited by addition of azatyrosine to the medium. Azatyrosine also inhibited neurite outgrowth induced by microinjection of oncogenic Ras protein into PC12 cells. The dose dependency was much the same for the two systems, inhibition of neurite outgrowth of PC12 cells and reversion of the transformed NIH3T3 cells. Microinjection of azatyrosine into the cells was as effective as addition to the medium, indicating that the target of azatyrosine is intracellular. In contrast, neurite outgrowth induced by nerve growth factor, which has been shown to be mediated by normal Ras [N. Hagag, S. Halegouna & M. Viola (1986). Nature, 319, 680-682], was found to be resistant to azatyrosine. Azatyrosine also showed no effect on neurite outgrowth induced by a membrane-permeant cyclic AMP analog through another pathway. These findings suggest that azatyrosine sensitivity is the result of abnormal signal transduction by oncogenic Ras. It was shown that azatyrosine also inhibited differentiation-associated growth arrest of PC12 cells induced by oncogenic Ras. In Ras-induced neurite outgrowth, the azatyrosine-sensitive process was found to be completed in the first 6-9 h, and is probably essential for the commitment of PC12 cells to differentiation rather than to growth.
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PMID:Azatyrosine inhibits neurite outgrowth of PC12 cells induced by oncogenic Ras. 132 88

A small number of p185c-neu receptors have been found on PC12 cells. These receptors show some basal phosphorylation in quiescent cells. When the cells are treated with nerve growth factor (NGF) for a short time, some increase in phosphorylation is seen, mainly on serine and threonine residues, and this is accompanied by a slight shift in the apparent molecular weight. Epidermal growth factor (EGF) also increases the phosphorylation of p185c-neu, in this case on tyrosine residues. Neither heregulin-beta 1 nor gp30 stimulates the tyrosine phosphorylation of p185c-neu, and neither has a proliferative effect on the cells. Treatment of the cells with NGF for 5 days produces a 70-80% reduction in the number of p185c-neu receptors. This down-regulation does not occur when PC12nnr5 cells, which lack the high-affinity NGF receptor, p140trk, are treated with NGF. The level of p185c-neu mRNA is not altered by NGF treatment, suggesting that the down-regulation is due to either a translational or a posttranslational alteration.
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PMID:Down-regulation of c-neu receptors by nerve growth factor in PC12 cells. 779 Aug 89

Wild type PC12 pheochromocytoma cells that had been infected with a Wnt-1-carrying virus and thus express Wnt-1 (PC12/Wnt-1) are known to acquire the same flat cell phenotype as that of spontaneously occurring PC12 flat cell variants except that the latter do not presently express Wnt-1. Flat cell variants of PC12 cells exhibit markedly altered morphology and gene expression. In order to assess the possibility that the spontaneously occurring flat cell variants could have been induced in wild type PC12 cells by previous transient expression of the cell's endogenous Wnt-1, we have isolated PC12/Wnt-1 cells expressing little or no Wnt-1. In spite of absent Wnt-1 expression, they retained their flat cell morphology, glutamate/aspartate transporter activity, increased neu mRNA levels and lack of both norepinephrine transporter activity and nerve growth factor-induced differentiation. Thus, Wnt-1 expression is not required to maintain the flat cell phenotype. However, we identified one gene, ret, whose mRNA level in PC12 was not only increased by Wnt-1 expression, but whose increased mRNA level was also dependent on continual Wnt-1 expression. This finding suggests that the induction of ret by Wnt-1 can be used to elucidate the Wnt-induced signalling pathway in mammalian cells.
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PMID:The induction of ret by Wnt-1 in PC12 cells is atypically dependent on continual Wnt-1 expression. 863 12

It is not clear which growth factors are crucial for the survival, proliferation, and differentiation of pancreatic beta-cells. We used the relatively differentiated rat insulinoma cell line INS-1 to elucidate this issue. Responsiveness of the DNA synthesis of serum-starved cells was studied to a wide variety of growth factors. The most potent stimulators were PRL, GH, and betacellulin, a member of the epidermal growth factor (EGF) family that has not previously been shown to be mitogenic for beta-cells. In addition to these, only vascular endothelial growth factor, insulin-like growth factor-1 and -2, had significant mitogenic activity, whereas hepatocyte growth factor, nerve growth factor-beta, platelet-derived growth factors, basic fibroblast growth factor, EGF, transforming growth factor-alpha (TGF-alpha), neu differentiation factor, and TGF-beta were inactive. None of these factors affected the insulin content of INS-1 cells. In contrast, certain differentiation factors, including nicotinamide, sodium butyrate, activin A, and 1,25-dihydroxyvitamin D3 inhibited the DNA synthesis and increased the insulin content. Also all-trans-retinoic acid had an inhibitory effect on cell DNA synthesis but no effect on insulin content. From these findings betacellulin emerges as a novel growth factor for the beta-cell. Half-maximal stimulation of INS-1 DNA synthesis was obtained with 25 pM betacellulin. Interestingly, betacellulin had no effect on RINm5F cells, whereas both EGF and TGF-alpha were slightly mitogenic. These effects may possibly be explained by differential expression of the erbB receptor tyrosine kinases. In RINm5F cells a spectrum of erbB gene expression was detected (EGF receptor/erbB-1, erbB-2/neu, and erbB-3), whereas INS-1 cells showed only expression of EGF receptor. Expression of the erbB-4 gene was undetectable in these cell lines. In summary, our results suggest that the INS-1 cell line is a suitable model for the study of beta-cell growth and differentiation because the responses to previously identified beta-cell mitogens were essentially similar to those reported in primary cells. In addition, we have identified betacellulin as a possible modulator of beta-cell growth.
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PMID:Growth factor-mediated proliferation and differentiation of insulin-producing INS-1 and RINm5F cells: identification of betacellulin as a novel beta-cell mitogen. 952 26

Constitutive overexpression of c-erbB2 in the mammary epithelial cell line MTSV1-7 has been shown to result in epithelial-mesenchymal conversion, anchorage-independent growth and loss of organized morphogenesis in collagen. To elucidate the events leading to this drastic change, MTSV1-7 cells and its subclone HB2 (which shows a more strictly epithelial phenotype) were transfected with the hybrid trk-neu receptor consisting of the extracellular domain of the trkA nerve growth factor (NGF) receptor and the transmembrane and cytoplasmic domains of c-erbB2 (neu). In cells expressing this construct, c-erbB2 homodimerization can be mimicked by addition of NGF. In trk-neu transfectants of HB2 cells, modest expression led to increased cell proliferation upon NGF treatment. When clones with higher expression levels were grown in collagen, NGF instead induced cell scattering, diminished viability and dramatically increased apoptosis. Interestingly, both the dissociation of colonies and loss of cell viability could be completely reversed by treatment of the cells with antibodies that activate the adhesive capacity of the alpha2beta1 integrin. Long-term NGF treatment of high-expressing transfectants generated fibroblastic clones displaying a reduced expression of integrin alpha2 and E-cadherin, and extensive apoptosis in collagen. These results, which indicate that strong c-erbB2 signalling may lead to downregulation and/or inactivation of the alpha2beta1 integrin, promoting apoptosis in collagen, provide one possible explanation to the increased apoptosis frequently seen in early tumour development.
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PMID:Activation of the alpha2beta1 integrin prevents c-erbB2-induced scattering and apoptosis of human mammary epithelial cells in collagen. 1103 Jan 48

Overexpression of the growth factor receptor subunit c-erbB2, leading to its ligand-independent homodimerization and activation, has been implicated in the pathogenesis of mammary carcinoma. Here, we have examined the effects of c-erbB2 on the adhesive properties of a mammary epithelial cell line, HB2/tnz34, in which c-erbB2 homodimerization can be induced by means of a transfected hybrid "trk-neu" construct. trk-neu consists of the extracellular domain of the trkA nerve growth factor (NGF) receptor fused to the transmembrane and cytoplasmic domains of c-erbB2, allowing NGF-induced c-erbB2 homodimer signaling. Both spreading and adhesion on collagen surfaces were impaired on c-erbB2 activation in HB2/tnz34 cells. Antibody-mediated stimulation of alpha(2)beta(1) integrin function restored adhesion, suggesting a direct role for c-erbB2 in integrin inactivation. Using pharmacological inhibitors and transient transfections, we identified signaling pathways required for suppression of integrin function by c-erbB2. Among these was the MEK-ERK pathway, previously implicated in integrin inactivation. However, we could also show that downstream of phosphoinositide-3-kinase (PI3K), protein kinase B (PKB) acted as a previously unknown, potent inhibitor of integrin function and mediator of the disruptive effects of c-erbB2 on adhesion and morphogenesis. The integrin-linked kinase, previously identified as a PKB coactivator, was also found to be required for integrin inactivation by c-erbB2. In addition, the PI3K-dependent mTOR/S6 kinase pathway was shown to mediate c-erbB2-induced inhibition of adhesion (but not spreading) independently of PKB. Overexpression of MEK1 or PKB suppressed adhesion without requirement for c-erbB2 activation, suggesting that these two pathways partake in integrin inhibition by targeting common downstream effectors. These results demonstrate a major novel role for PI3K and PKB in regulation of integrin function.
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PMID:c-erbB2-induced disruption of matrix adhesion and morphogenesis reveals a novel role for protein kinase B as a negative regulator of alpha(2)beta(1) integrin function. 1218 54

MUC1 mucin is a heavily O-glycosylated transmembrane protein that is aberrantly expressed in many carcinomas, including breast cancer. In the present study, the effect of signaling generated from the Erb-B2 homodimer as a result of transcription of the MUC1 gene was investigated in human mammary epithelial cell lines (MTSV1-7 and Hb2) stably transfected with a pBAT/trk-neu construct in which the extracellular domain of Erb-B2 was replaced with the corresponding domain from the nerve growth factor (NGF) receptor. In this system, NGF stimulated homodimerization of Erb-B2 and phosphorylation of its intracellular domain. MTSV1-7/trk-neu and Hb2/trk-neu cells were transiently transfected with a construct in which the MUC1 promoter caused expression of a CAT reporter gene, and were then treated with NGF. These studies showed that MUC1 expression was inhibited by NGF treatment in both cell lines, suggesting that its expression can be regulated by signals resulting from the homodimerization of Erb-B2.
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PMID:Erb-B2 homodimerization inhibits MUC1 transcription in cultured human mammary epithelial cells. 1279 75