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)

Signaling from the epidermal growth factor (EGF) receptor is triggered by the binding of ligands such as EGF or transforming growth factor alpha (TGF-alpha) and subsequent receptor dimerization. An understanding of these processes has been hindered by the lack of structural information about the ligand-bound, dimerized EGF receptor. Using an NMR-derived structure of EGF and a homology model of the major ligand binding domain of the EGF receptor and experimental data, we modeled the binding of EGF to this EGF receptor fragment. In this low resolution model of the complex, EGF sits across the second face of the EGF receptor L2 domain and EGF residues 10-16, 36-37, 40-47 bind to this face. The structural model is largely consistent with previously published NMR data describing the residues of TGF-alpha which interact strongly with the EGF receptor. Other EGF residues implicated in receptor binding are accounted by our proposal that the ligand binding is a two-step process with the EGF binding to at least one other site of the receptor. This three-dimensional model is expected to be useful in the design of ligand-based antagonists of the receptor.
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PMID:Modeling the epidermal growth factor -- epidermal growth factor receptor l2 domain interaction: implications for the ligand binding process. 1202 99

Fibroblast growth factor (FGF)-2 and transforming growth factor alpha (TGFalpha) promote astroglial proliferation during brain development and reactive processes. The mitogenic potential of both growth factors is attenuated by increasing intracellular cAMP levels, an effect currently assumed to depend on the inhibition of the mitogen-activated protein kinase cascade. In the present study, we sought to determine whether cAMP interferes with the mitogenic potential of FGF-2 and TGFalpha on astroglia by affecting the expression of respective growth factor receptors. Treatment of highly enriched cultures of cortical astrocytes with dibutyryl cAMP accelerated the TGFalpha-induced internalization and subsequent functional inactivation of epidermal growth factor (EGF) receptor by transiently inhibiting EGF receptor mRNA synthesis. In apparent contrast, both short- and long-term activation of cAMP-dependent signaling pathways robustly promoted the expression of FGF receptors 1 and 2, whereas expression levels of FGF receptor 3 remained unaffected. Moreover, elevation of intracellular cAMP levels did not prevent translocation of FGF receptor 1 to the cell nucleus, a mechanism thought to be essential for FGF-2-induced cell proliferation. We propose that cAMP controls the mitogenic effects of TGFalpha and FGF-2 on astroglial cells by distinctly different mechanisms. Whereas cAMP seems to interfere with the mitogenic effects of TGFalpha on astroglial cells by affecting both the expression level and signaling of the EGF receptor, the modulatory effects of cAMP on FGF-2-induced astroglial proliferation seem to solely result from an inhibition of FGF receptor-activated signaling pathways.
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PMID:Cyclic AMP differentially regulates the expression of fibroblast growth factor and epidermal growth factor receptors in cultured cortical astroglia. 1220 56

The multifunctional cytokine interleukin 6 (IL-6) is expressed in a wide variety of disease states and pathologic processes. Mice deficient in IL-6 display abnormal and delayed liver regeneration and repair. Currently, IL-6 is thought to influence liver growth indirectly by priming hepatocytes to respond to growth factors such as hepatocyte growth factor (HGF) by inducing expression of HGF and by inhibiting hepatocyte apoptosis, as distinct from the direct mitotic effects of IL-6 on myeloid and other cell types. Here, we show that systemic administration of IL-6 using CHO cell tumors in nude mice results in dramatic hepatomegaly and hepatocyte hyperplasia in the absence of liver injury. Liver mass and liver to body mass ratios increased to 2 to 3 times normal because of proliferation of hepatocytes. Liver growth was associated with high levels of serum IL-6 and with activation of the IL-6-signaling pathway, including increased expression of IL-6 receptor-alpha/gp80, activation of the signal transducer and activator of transcription-3 (STAT-3), and mitogen-activated protein kinase (MAPK/ERK)-signaling pathways and induction of downstream target genes, including c-myc. HGF receptor and transforming growth factor alpha (TGF-alpha)/epidermal growth factor (EGF) receptor activation were decreased in hypertrophied livers, suggesting that IL-6-induced liver growth was independent of these known hepatocyte mitotic pathways. In conclusion, we suggest that IL-6 may function as a direct hepatic mitogen in vivo and, furthermore, that IL-6 warrants closer examination as a potent liver growth factor with potential clinical utility for increasing liver mass following injury.
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PMID:Massive liver growth in mice induced by systemic interleukin 6 administration. 1288 76

The activation of transforming growth factor alpha (TGFalpha)-erbB-1 and neuregulin-erbB-4 signaling pathways in hypothalamic astrocytes has been shown to play a key role in the process by which the neuroendocrine brain controls luteinizing hormone-releasing hormone (LHRH) secretion. Earlier studies suggested that tanycytes, an ependymoglial cell type of the median eminence, regulate LHRH release during the estrous cycle by undergoing plastic changes that alternatively allow or prevent direct access of the LHRH nerve terminals to the portal vasculature. Neither the molecules responsible for these plastic changes nor the underlying controlling mechanisms have been identified. Here we show that cultured tanycytes express erbB-1 and erbB-2, two of the four members of the erbB receptor family, and respond to TGFalpha with receptor phosphorylation, release of prostaglandin E2 (PGE2), and a PGE2-dependent increase in the release of TGFbeta1, a growth factor previously implicated in the glial control of LHRH secretion. Blockade of either erbB-1 receptor signal transduction or prostaglandin synthesis prevented the stimulatory effect of TGFalpha on both PGE2 and TGFbeta1 release. Time-lapse studies revealed that TGFalpha and TGFbeta1 have dramatically opposite effects on tanycyte plasticity. Whereas TGFalpha promotes tanycytic outgrowth, TGFbeta1 elicits retraction of tanycytic processes. Blockade of metalloproteinase activity abolished the effect of TGFbeta1, suggesting that TGFbeta1 induces tanycytic retraction by facilitating dissolution of the extracellular matrix. Prolonged (>12 hr) exposure of tanycytes to TGFalpha resulted in focal tanycytic retraction, an effect that was abolished by immunoneutralization of TGFbeta1 action, indicating that the retraction was attributable to TGFalpha-induced TGFbeta1 formation. These in vitro results identify tanycytes as targets of TGFalpha action and demonstrate that activation of erbB-1-mediated signaling in these cells results in plastic changes that, involving PGE2 and TGFbeta1 as downstream effectors, mimic the morphological plasticity displayed by tanycytes during the hours encompassing the preovulatory surge of LHRH.
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PMID:Activation of erbB-1 signaling in tanycytes of the median eminence stimulates transforming growth factor beta1 release via prostaglandin E2 production and induces cell plasticity. 1462 47

In synthetic phenotype vascular smooth muscle cells (VSMC), activation of epidermal growth factor (EGF) receptor (EGFR) induces a sustained increase in intermediate conductance K(Ca) (int-K(Ca); K(Ca)3.1) channels that is essential for proliferation. However, a comparable mechanism has not been identified in native contractile phenotype VSMC, which express large conductance K(Ca) (maxi-K(Ca); K(Ca)1.1) channels, not int-K(Ca) channels. Using patch clamp of freshly isolated contractile VSMC from rat basilar artery, we found that EGF (100 ng ml(-1)) caused hyperpolarization (7.9 +/- 3.9 mV) due to activation of iberiotoxin-sensitive, maxi-K(Ca) channels. The EGFR ligands EGF (100 ng ml(-1)), transforming growth factor alpha (0.4 ng ml(-1)) and heparin-binding EGF (100 ng ml(-1)) all caused a 20% increase in maxi-K(Ca) channel current that was blocked by AG-1478 or by knock-down of EGFR expression using cisterna magna infusion of antisense oligodeoxynucleotide (AS-ODN). In controls, EGFR knock-down, and EGFR gain-of-expression (angiotensin II hypertension), the increase in maxi-K(Ca) current correlated with the abundance of EGFR protein expressed. The EGFR-mediated increase in maxi-K(Ca) channel activity was blocked by inhibiting cAMP-dependent protein kinase (cAK) using KT-5720 or Rp-cAMP, or by inhibiting adenylate cyclase type 5 (AC-5) using 2',5'-dideoxyadenosine or knock-down of AC-5 expression by intracisternal AS-ODN. Direct infusion of EGF into cisterna magna caused up-regulation of proliferating cell nuclear antigen (PCNA) in VSMC that was prevented by coinfusion of iberiotoxin or of AG-1478. Our data, which are consistent with the hypothesis that hyperpolarization is critical for a proliferative response, are the first to implicate AC-5 and maxi-K(Ca) channels in gene activation related to EGFR signalling in native contractile VSMC.
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PMID:Adenylate cyclase 5 and KCa1.1 channel are required for EGFR up-regulation of PCNA in native contractile rat basilar artery smooth muscle. 1629 43

In the developing neocortex, brain-derived neurotrophic factor (BDNF) exerts a trophic activity to increase the expression and channel activity of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor subunits. Here, we demonstrate that the epidermal growth factor (EGF) receptor (ErbB1) ligands exert the opposite biological activity in cultured neocortical neurons. Subchronic stimulation of ErbB1 with transforming growth factor alpha (TGFalpha), EGF, or heparin-binding EGF (HB-EGF) down-regulated protein expression of the GluR1 AMPA receptor subunit in cultured neocortical neurons. In agreement, TGFalpha treatment decreased the Bmax of [3H] AMPA binding and GluR1 mRNA levels. Immunocytochemistry revealed that the decrease in GluR1 was most pronounced in multipolar GABAergic neurons. To examine the physiological consequences, we recorded AMPA-evoked currents as well as miniature excitatory postsynaptic currents in morphologically identified putative GABAergic neurons in culture. Subchronic TGFalpha treatment decreased AMPA-triggered currents as well as the amplitude and frequency of miniature excitatory postsynaptic currents. An ErbB1 tyrosine kinase inhibitor, PD153035, inhibited the TGFalpha effect. Moreover, TGFalpha counteracted the neurotrophic activity of BDNF on AMPA receptor expression. Co-application of TGFalpha with BDNF blocked the BDNF-triggered up-regulation of AMPA receptor expression and currents. These observations reveal a negative regulatory activity of the ErbB1 ligand, TGFalpha, which reduces the input sensitivity of cortical GABAergic neurons to attenuate their inhibitory function.
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PMID:Transforming growth factor alpha attenuates the functional expression of AMPA receptors in cortical GABAergic neurons. 1644 72

Ligands for epidermal growth factor (EGF) receptor (ErbB1), such as EGF, transforming growth factor alpha (TGFalpha), and epiregulin, are enriched in body fluids and blood and regulate development of various peripheral organs. It remains however how such circulating polypeptide growth factors influence brain development and function. Here, we performed peripheral injections of TGFalpha and epiregulin to mouse neonates and evaluated immediate physical and neurochemical development and later behavioral consequences. Subcutaneous administration of TGFalpha and epiregulin increased phosphorylation of brain ErbB1, suggesting their effects on brain development. Repeated their injections similarly enhanced physical development of eyelid opening and tooth eruption during early postnatal stage and resulted in abnormal behavioral traits in the adult stage. Acoustic startle responses of mice treated with these growth factors as neonates were enhanced and prepulse inhibition was decreased without an apparent correlation between prepulse inhibition level and startle intensity. Locomotor activity and fear-learning performance with tone and context cues were not altered, however. These results suggest that circulating ErbB1 ligands in the periphery of neonates have some common influences on later behavioral traits. Abnormal ErbB1 ligand production at neonatal and potentially prenatal stages might therefore associate with neurodevelopmental disorders such as schizophrenia.
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PMID:Common behavioral influences of the ErbB1 ligands transforming growth factor alpha and epiregulin administered to mouse neonates. 1831 47

The potential mechanisms involving the genesis and growth of androgen-independent prostate cancer include super-expression of the androgen receptor (AR), in an attempt to compensate for the low androgenic plasma levels and mutations of this specific receptor, which could determine resistance to anti-androgenic therapy. However, most advanced prostate tumors have no mutations or amplifications of the AR, suggesting a potential role of non-androgenic growth factors, including epidermal growth factor (EGF), transforming growth factor alpha, insulin-like growth factor (IGF-1) and fibroblast growth factor. More specifically, these factors, and their receptors like EGFR (HER-1) and HER-2/neu, through paracrine and autocrine mechanisms, may contribute to the proliferation and growth of prostate cancer.
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PMID:Molecular oncogenesis of prostate adenocarcinoma: role of the human epidermal growth factor receptor 2 (HER-2/neu). 2130 6

MCF-10A cells are a spontaneously immortalized, nontransformed human mammary epithelial cell line that contains two normal p53 alleles and produces a normal p53 protein. We have recently shown that overexpression of several genes that are important for normal mammary gland development and for neoplastic transformation, such as transforming growth factor alpha, c-Ha-rns or c-erbB-2, leads to in vitro transformation of these cells (Ciardiello et al: Mol Carcinogen 6: 43-52, 1992). To investigate the neoplastic potential of mutated forms of the p53 gene on MCF-10A cells, we have constructed two expression vector plasmids containing two p53 mutants that were isolated from human primary breast carcinomas. Overexpression of either mutant p53 gene confers on MCF-10A cells the ability to grow in serum-free medium in monolayer culture and to form colonies in semi-solid medium. Furthermore, to determine whether a mutated p53 gene may cooperate with a point mutated c-Ha-ras and/or the normal c-erbB-2 protooncogenes in the transformation of these cells, we generated clones of MCF-10A cells that overexpress a combination of these gene pruducts. Although these cells were able to grow with a higher cloning efficiency in soft agar, none of the cell lines was tumorigenic when injected subcutaneously into immunodeficient mice.
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PMID:Effects of mutant p53 genes on transformation of human mammary epithelial-cells. 2156 22


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