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)

Transforming growth factor-beta 1 (TGF beta 1) is a multifunctional regulator of cell growth and differentiation. We report here that TGF beta 1 decreased the proliferation of nontransformed bovine anterior pituitary-derived cells grown in culture. We have previously demonstrated that these cells express both TGF alpha and its receptor [the epidermal growth factor (EGF) receptor] and that expression can be stimulated by phorbol ester (TPA) and EGF. TGF beta 1 treatment over a 2-day period decreased the proliferation of pituitary cells. This decreased growth rate was accompanied by a decrease in the TGF alpha mRNA level. The effect of TGF beta 1 on TGF alpha mRNA down-regulation was both dose dependent (maximal effect observed at 1.0 ng/ml TGF beta 1) and time dependent (minimum of 2-day treatment with TGF beta 1 was required before a decrease in TGF alpha mRNA was observed). Studies on TGF alpha mRNA stability indicated that TGF beta 1 did not alter the TGF alpha mRNA half-life. Treatment of the TGF beta 1 down-regulated cells with EGF resulted in the stimulation of TGF alpha mRNA levels; thus, the TGF beta 1-treated cells remained responsive to EGF. The decreased proliferation in response to TGF beta 1 could be only partially reversed by simultaneous treatment of the cells with EGF (10(-9)M) and TGF beta 1 (3.0 ng/ml). Qualitatively, the TGF beta 1-induced reduction of TGF alpha mRNA content was independent of cell density. TGF beta 1 treatment of the anterior pituitary-derived cells also reduced the levels of c-myc and EGF receptor mRNA. These results represent the first demonstration of the down-regulation of TGF alpha synthesis by a polypeptide growth factor and suggest that TGF beta 1 may be a physiological regulator of TGF alpha production in vivo.
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PMID:Transforming growth factor-beta (TGF beta) inhibits TGF alpha expression in bovine anterior pituitary-derived cells. 172 43

We have investigated the actions of transforming growth factor (TGF) type alpha on epidermal growth factor (EGF) receptor mRNA expression in MDA-468 human mammary carcinoma cells in serum-free media. We found that exposure of MDA-468 cells to TGF alpha results in elevated levels of EGF receptor mRNA. This increase in mRNA accumulation showed time and dose dependence. Addition of TGF beta 1 enhanced the accumulation of EGF receptor mRNA induced by TGF alpha in a time- and dose-dependent manner. We also found that triiodothyronine at physiological concentrations exerts synergistic control on the action of TGF alpha alone, or in association with TGF beta 1, on EGF receptor mRNA expression. Similarly, retinoic acid treatment also enhanced in a time- and dose-dependent manner the TGF alpha-dependent response of EGF receptor mRNA and acted synergistically with TGF beta 1. The results described here suggest that optimum regulation of EGF receptor gene expression by TGF alpha is a complex process involving synergistic interactions with heterologous growth factors and hormones.
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PMID:Modulation of transforming growth factor alpha-dependent expression of epidermal growth factor receptor gene by transforming growth factor beta, triiodothyronine, and retinoic acid. 261 50

Some human neoplasms show aberrant expression or overexpression of epidermal growth factor (EGF) receptor, and the degree of the receptor expression is correlated with the malignant phenotype in certain epithelial tumors including squamous carcinoma cells. Since phenotypic transformation of cells could involve quantitative and qualitative alteration of integrin function, the effects of EGF on cell-matrix interactions were studied using HSC-1 cells, a human squamous carcinoma cell line showing EGF receptor overexpression. The EGF-treated HSC-1 cells interacted with matrix proteins differently from the untreated cells, as shown by cell adhesion and phagokinetic track assays. Among fibronectin, laminin, fibrinogen, and type I collagen, fibronectin was the most efficient substratum to promote untreated HSC-1 cell adhesion and migration. Pretreatment of the cells with 50 ng/ml EGF for 18 h selectively increased the number of spread cells and the size of the individual cell migration area on type I collagen by 250 and 400%, respectively. The same pretreatment diminished cell adhesion and migration on other substrata so that the EGF treatment converted type I collagen as the most efficient substratum for cell adhesion and migration of the HSC-1 cells. ELISA and immunoprecipitation studies showed that EGF up-regulated the expression of alpha 2 beta 1 integrin collagen receptor in a time- and dose-dependent manner by stimulating biosynthesis of alpha 2 subunit, but did not up-regulate those of the alpha 3 beta 1, alpha 5 beta 1, or alpha v beta 3 integrins. These results suggest that EGF preferentially enhances HSC-1 cell interaction with type I collagen, leading to the enhanced cellular migratory activity on the substratum, as a result of selective up-regulation of alpha 2 beta 1 integrin expression.
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PMID:Epidermal growth factor enhancement of HSC-1 human cutaneous squamous carcinoma cell adhesion and migration on type I collagen involves selective up-regulation of alpha 2 beta 1 integrin expression. 752 89

Heregulin (HRG) is a pluripotent growth factor that can stimulate the growth of some human mammary tumor cells and the differentiation of others. Two members of the epidermal growth factor receptor family of receptor/tyrosine kinases, p180erbB3 and p180erbB4, serve as receptors for the HRG ligand. While HRG appears to be capable of stimulating the autophosphorylation activity of p180erbB4, the co-expression of p185erbB2/neu with p180erbB3 is necessary for the HRG-stimulated tyrosine phosphorylation of both of these receptors. On the basis of the sequences surrounding their putative tyrosine phosphorylation sites, we predict that the different HRG-responsive receptors couple to different intracellular SH2 domain-containing proteins. Hence, the different receptors may mediate different cellular responses to the HRG ligand. In the present study we show that HRG beta 1 is mitogenic for erbB3-transfected DHFR/G8 cells, an NIH3T3 mouse fibroblast derivative that over-expresses p185erbB2/neu. HRG stimulated the incorporation of [3H]thymidine into the DNA of these cells with an EC50 of 70 +/- 7 pM. HRG was not mitogenic for parental DHFR/G8 cells that do not express the ErbB3 protein. Phosphatidylinositol (PI) 3-kinase, an enzyme believed to be important in cellular growth regulation by growth factors and oncogenes, is predicted to couple to tyrosine-phosphorylated ErbB3. We observed that HRG stimulated the association of PI 3-kinase with both p185erbB2/neu and ErbB3 in transfected DHFR/G8 cells, but not in the parental cell line. We conclude that the ErbB3 protein is capable of mediating a proliferative response of fibroblasts to HRG, and that the activation of PI 3-kinase is an integral part of the growth signaling mechanism.
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PMID:Heregulin stimulates mitogenesis and phosphatidylinositol 3-kinase in mouse fibroblasts transfected with erbB2/neu and erbB3. 753 67

beta 1,4-Galactosyltransferase (GalTase) is unusual among the glycosyltransferases in that it is localized both in the Golgi complex and on the cell surface. Most studies of surface GalTase function have focused on its role in cellular interactions; however, surface GalTase has also been suggested to function during cellular proliferation. Consistent with this hypothesis, a variety of GalTase-specific perturbants inhibit cell growth in vitro and in vivo. However, all of these studies have been limited to the use of exogenous reagents to perturb GalTase function. Furthermore, all of these perturbants inhibit cell growth, irrespective of whether they stimulate or inhibit GalTase enzyme activity. Therefore, it remains unclear whether surface GalTase delivers a growth inhibitory or growth stimulatory signal. In this study, we took a more direct approach to defining surface GalTase function during growth by examining its expression during the cell cycle and by molecularly altering its expression in stably transfected cell lines. The expression of GalTase was shown to be cell cycle specific, with the cell surface and intracellular GalTase pools displaying independent expression patterns. Furthermore, multiple, independent, stably transfected cell lines with reduced levels of cytoskeletally associated surface GalTase grew faster than control cells, whereas cell lines that over-expressed surface GalTase grew slower than controls. These observations directly support the concept that surface GalTase delivers a growth inhibitory signal. Evidence is presented suggesting that surface GalTase interacts with the epidermal growth factor (EGF) receptor, as suggested by others. The activity of the EGF receptor was shown to be directly proportional to the growth rate of the various GalTase-transfected cell lines. Thus, the expression of surface GalTase directly affects cell proliferation rate and may do so by modulating the ability of the EGF receptor to transduce EGF-dependent signals.
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PMID:Altering the expression of cell surface beta 1,4-galactosyltransferase modulates cell growth. 764 15

Neu differentiation factor (NDF) is a 44-kD glycoprotein which was isolated from ras-transformed rat fibroblasts and indirectly induces tyrosine phosphorylation of the HER-2/neu receptor via binding to either the HER-3 or HER-4 receptor. NDF contains a receptor binding epidermal growth factor (EGF)-like domain and is a member of the EGF family. There are multiple different isoforms of NDF which arise by alternative splicing of a single gene. To date, in vivo biologic activities have not been demonstrated for any NDF isoform. Since NDF, HER-2/neu, and HER-3 are present in skin, and other EGF family members can influence wound keratinocytes in vivo, we investigated whether NDF would stimulate epidermal migration and proliferation in a rabbit ear model of excisional wound repair. In this model, recombinant human NDF-alpha 2 (rhNDF-alpha 2), applied once at the time of wounding, induced a highly significant increase in both epidermal migration and epidermal thickness at doses ranging from 4 to 40 micrograms/cm2. In contrast, rhNDF-alpha 1, rhNDF-beta 1, and rhNDF-beta 2 had no apparent biologic effects in this model. rhNDF-alpha 2 also induced increased neoepidermal expression of alpha 5 and alpha 6 integrins, two of the earliest integrins to appear during epidermal migration. In addition, rhNDF-alpha 2-treated wounds exhibited increased neoepidermal expression of cytokeratin 10 and filaggrin, both epidermal differentiation markers. NDF alpha isoforms were expressed in dermal fibroblasts of wounded and unwounded skin, while both HER-2/neu and HER-3 were expressed in unwounded epidermis and dermal adnexa. In wounds, HER-2/neu expression was markedly decreased in the wound neoepidermis while neoepidermal HER-3 expression was markedly upregulated. Taken together, these results suggest that endogenous NDF-alpha 2 may function as a paracrine mediator directing initial epidermal migration during cutaneous tissue repair.
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PMID:Neu differentiation factor upregulates epidermal migration and integrin expression in excisional wounds. 786 Jul 68

The ability of sensory axons to stimulate Schwann cell proliferation by contact was established in the 1970s. Although the mitogen responsible for this proliferation has been localized to the axon surface and biochemically characterized, it has yet to be identified. Recently a family of proteins known as heregulins (HRGs) has been isolated, characterized, and shown to interact with a number of class 1 receptor tyrosine kinases, including the erbB2, erbB3, and erbB4 gene products. These factors include glial growth factor, a Schwann cell mitogen. We have tested the effects of antibodies against components of this system (HRG beta 1 and p185erbB2) in cocultures of rat sensory neurons and human (or rat) Schwann cells to elucidate the role of these proteins in axon-induced Schwann cell proliferation. 2C4, a monoclonal antibody specific for the human p185erbB2 receptor tyrosine kinase, bound to the surface of human Schwann cells and reduced human Schwann cell incorporation of [3H]thymidine by > 90% compared with untreated controls in this coculture system. This antibody had no effect on rat Schwann cell incorporation of [3H]thymidine under similar conditions. A polyclonal antibody raised against HRG beta 1 reduced human and rat Schwann cell incorporation of [3H]thymidine by nearly 80% and up to 49%, respectively, relative to controls. These results imply that a HRG, or a HRG-like molecule, is a component of the axonal mitogen. This mitogen is presented to Schwann cells by axons and induces proliferation through an interaction that involves p185erbB2 on Schwann cells.
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PMID:Axon-induced mitogenesis of human Schwann cells involves heregulin and p185erbB2. 787 96

Transforming growth factor beta (TGF-beta) is a potent modulator of cell growth in many systems. In normal rat kidney fibroblasts, TGF-beta 1 increases epidermal growth factor (EGF) receptor gene transcription and synergizes with EGF to stimulate growth in soft agar, a characteristic of the transformed phenotype. In order to identify the target of TGF-beta 1 action, we have used a series of 5' deletion mutants of the EGF receptor promoter linked to a chloramphenicol acetyltransferase reporter gene (ERCAT). The TGF-beta response element(s) was localized to a cis-regulatory region which resides between positions -919 and -860 relative to the ATG translation initiation codon of the EGF receptor promoter. This 60-base pair region contains a repressor of the EGF receptor promoter and a TGF-beta inhibitory element that mediates TGF-beta 1 suppression of transin/stromelysin gene transcription through binding of a Fos-containing protein complex. Cotransfection of c-fos, c-jun, or both expression vectors with the intact or 5'-deleted ERCAT constructs identified several Fos-responsive inhibitory regions within the EGF receptor promoter, but these did not localize to the -919 to -860 promoter region. Mobility shift assays showed binding of the 60-base pair DNA fragment to proteins in extracts from untreated normal rat kidney cells; the binding was specifically competed by oligonucleotides containing a CAGATG sequence but not by oligonucleotides containing the EGF receptor repressor or the TGF-beta inhibitory element. TGF-beta 1 treatment but not anti-Fos antibody caused a decrease in specific 60-base pair DNA-protein complex formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Induction of epidermal growth factor receptor gene transcription by transforming growth factor beta 1: association with loss of protein binding to a negative regulatory element. 798 46

ErbB3 is a member of the epidermal growth factor (EGF) receptor subfamily of receptor tyrosine kinases and is believed to be a receptor for an unknown ligand. We have tested the possibility that heregulin, a growth factor possessing an EGF-like domain, is a ligand for ErbB3. We have found that the iodinated recombinant EGF-like domain of heregulin-beta 1 (125I-rHRG beta 1(177-244) bound specifically to insect cell-expressed bovine ErbB3 with a dissociation constant of 0.85 nM. Moreover, 125I-rHRG beta 1(177-244) bound to NIH3T3 fibroblasts stably transfected with bovine erbB3 with a dissociation constant of 60 pM, but did not bind to parental cells. 125I-rHRG beta 1(177-244) could be chemically cross-linked to a 170-180 kDa protein in erbB3-transfected fibroblasts, and the cross-linked product could be immunoprecipitated with antibodies specific for ErbB3. Finally, rHRG beta 1 stimulated the tyrosine phosphorylation of both ErbB3 and endogenous p185erbB2/neu in transfectants but not in parental cells. We conclude that ErbB3 is a receptor for HRG and is capable of mediating HRG-stimulated tyrosine phosphorylation of itself and p185erbB2/neu in cells that express both receptors.
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PMID:The erbB3 gene product is a receptor for heregulin. 818 16

In murine keratinocytes, Ca(++)-induced terminal differentiation is accompanied by a rapid and sustained increase of inositol phosphates and diacylglycerol. Based on Western blotting analysis, basal keratinocytes cultured in 0.05 mM Ca++ medium express phospholipase C (PLC)-gamma 1 predominantly and no detectable PLC-beta 1. Differentiating keratinocytes cultured in 1.4 mM Ca++ express two- to threefold more PLC-gamma 1 protein and PLC-delta 1, but no detectable PLC-beta 1. Although the amount of PLC-gamma 1 and -delta 1 protein increased, PLC-gamma 1 and -delta 1 mRNA decreased in differentiating cells. Thus the sustained rise of PLC activity induced by Ca++ in differentiating keratinocytes may be associated with higher amounts of both PLC-gamma 1 and -delta 1 in maturing cells, determined by a posttranscriptional mechanism. Tyrosine phosphate content in PLC-gamma 1 was low in basal cells and did not change in cells exposed to 1.4 mM Ca++. However, genistein inhibited the increase in PLC activity induced by 1.4 mM Ca++. In contrast, transforming growth factor (TGF)alpha, which stimulates both PLC activity and growth in basal keratinocytes, increased tyrosine phosphorylation of PLC-gamma 1. These results suggest that tyrosine phosphorylation of PLC-gamma 1 by the epidermal growth factor (EGF) receptor is linked to stimulated proliferation, whereas stimulation of PLC activity by Ca++ is linked to keratinocyte differentiation and involves the action of a tyrosine kinase but not tyrosine phosphorylation of PLC-gamma 1. Based on studies using the intracellular free Ca++ chelator BAPTA, a rise in intracellular free Ca++ was not required for stimulation of PLC activity by raising extracellular Ca++. Phorbol esters inhibited PLC stimulation by 1.4 mM Ca++ medium and increased serine phosphorylation of PLC-gamma 1. Exogenous phosphatidylinositol-specific and phosphatidylcholine-specific bacterial PLC also inhibited endogenous inositol phosphate formation and increased endogenous diacylglycerol (DAG). Thus, direct serine phosphorylation of PLC-gamma 1 by protein kinase C is associated with the inhibition of Ca(++)-mediated PLC stimulation. These results show that keratinocytes have multiple mechanisms to regulate PLC activity in response to a specific signal.
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PMID:Keratinocyte differentiation is associated with changes in the expression and regulation of phospholipase C isoenzymes. 822 34


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