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)

Identification of the factors controlling transcription of the epidermal growth factor (EGF) receptor gene is essential for understanding regulation of the EGF receptor and its overexpression in human carcinomas. In this study, we have identified a 60-base pair (bp) region (-919 to -860) relative to the AUG translation initiation codon in the EGF receptor 5' promoter that functions as a cis-acting EGF receptor transcriptional repressor (ETR). This fragment also acted as a repressor when linked to the thymidine kinase promoter. Gel mobility shift assays demonstrated that trans-acting factors bind to 60- and 19-bp fragments. Competition and chloramphenicol acetyltransferase assays with oligonucleotides containing mutations and deletions in this region indicate that the TTCGAGGG sequence (-877 to -870) is required for binding as well as repressor activity. While the ETR-protected region contains consensus sequences for the E2F binding site, no competition was observed with an E2F binding fragment. However, DNA-protein blot analysis indicates that both the 60- and 19-bp fragments specifically bind a 128-kDa polypeptide in extracts from HeLa or A431 human epidermoid carcinoma cells. These results suggest that a novel transcription factor(s) negatively regulates EGF receptor gene expression through binding to the ETR element.
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PMID:Identification of an epidermal growth factor receptor transcriptional repressor. 830 97

To create a universal system for the control of gene expression, we have studied methods for the construction of novel polydactyl zinc finger proteins that recognize extended DNA sequences. Elsewhere we have described the generation of zinc finger domains recognizing sequences of the 5'-GNN-3' subset of a 64-member zinc finger alphabet. Here we report on the use of these domains as modular building blocks for the construction of polydactyl proteins specifically recognizing 9- or 18-bp sequences. A rapid PCR assembly method was developed that, together with this predefined set of zinc finger domains, provides ready access to 17 million novel proteins that bind the 5'-(GNN)6-3' family of 18-bp DNA sites. To examine the efficacy of this strategy in gene control, the human erbB-2 gene was chosen as a model. A polydactyl protein specifically recognizing an 18-bp sequence in the 5'-untranslated region of this gene was converted into a transcriptional repressor by fusion with Kr uppel-associated box (KRAB), ERD, or SID repressor domains. Transcriptional activators were generated by fusion with the herpes simplex VP16 activation domain or with a tetrameric repeat of VP16's minimal activation domain, termed VP64. We demonstrate that both gene repression and activation can be achieved by targeting designed proteins to a single site within the transcribed region of a gene. We anticipate that gene-specific transcriptional regulators of the type described here will find diverse applications in gene therapy, functional genomics, and the generation of transgenic organisms.
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PMID:Toward controlling gene expression at will: specific regulation of the erbB-2/HER-2 promoter by using polydactyl zinc finger proteins constructed from modular building blocks. 984 40

The paucity of tools that control expression of specific genes in vivo represents a major limitation of functional genomics in mammals; most available small-molecule regulators of transcription-e.g. histone deacetylase inhibitors-exert pan-genomic effects. Recent developments in understanding the role of chromatin in regulating the genome, and of protein-DNA interactions have allowed the development of designed transcription factors that regulate specific genes in vivo (Reik et al., Curr Opin Genet Dev 2002;12:233). These proteins contain two modules: (i) a zinc finger protein (ZFP)-based DNA-binding domain (DBD) designed to recognize a specific sequence (for example, a motif in the promoter of a certain gene); (ii) a functional module (for example, a transcriptional activation or repression domain). Recent data describe the use of such designed transcription factors to regulate a variety of clinically relevant gene targets in human cells: these include MDR1, erythropoietin, erbB-2 and erbB-3, VEGF, and PPARgamma. In the case of VEGF (Liu et al., J Biol Chem 2001;276:11323), proportional upregulation by the designed transcription factor of all three distinct splice isoforms generated by this locus was observed, illuminating the utility of endogenous gene control in therapeutic settings (proper isoform ratio is essential for the proangiogenic function of VEGF). In the case of PPARgamma, use of a transcriptional repressor designed to downregulate the expression of two PPARgamma isoforms allowed "mutation-free reverse genetics" analysis that illuminated a unique role for the PPARgamma2 isoform in adipogenesis (Ren et al., Genes Dev 2002;16:27). The ability to selectively activate or repress specific mammalian genes in vivo using designed transcription factors thus has considerable promise in clinical and in basic science settings.
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PMID:Designed transcription factors as tools for therapeutics and functional genomics. 1221 87

Fatty acid synthase (FAS) activity is a potential therapeutic target to treat cancer and obesity. Here, we have identified a molecular link between FAS and HER2 (erbB-2) oncogene, a marker for poor prognosis that is overexpressed in 30% of breast and ovarian cancers. Pharmacological FAS inhibitors cerulenin and C75 were found to suppress p185(HER2) oncoprotein expression and tyrosine-kinase activity in breast and ovarian HER2 overexpressors. Similarly, p185(HER2) expression was dramatically down-regulated when FAS gene expression was silenced by using the highly sequence-specific mechanism of RNA interference (RNAi). Pharmacological and RNAi-mediated silencing of FAS specifically down-regulated HER2 mRNA and, concomitantly, caused a prominent up-regulation of PEA3, a transcriptional repressor of HER2. A cytoplasmic redistribution of p185(HER2) was associated with marked morphological changes of FAS RNAi-transfected cells, whereas chemical inhibitors of FAS promoted a striking nuclear accumulation of p185(HER2). The simultaneous targeting of FAS and HER2 by chemical FAS inhibitors and the humanized antibody directed against p185(HER2) trastuzumab, respectively, was synergistically cytotoxic toward HER2 overexpressors. Similarly, concurrent RNAi-mediated silencing of FAS and HER2 genes synergistically stimulated apoptotic cell death in HER2 overexpressors. p185(HER2) was synergistically down-regulated after simultaneous inhibition of FAS and HER2 by either pharmacological inhibitors or small interfering RNA. These findings provide evidence of an active role of FAS in cancer evolution by specifically regulating oncogenic proteins closely related to malignant transformation, strongly suggesting that HER2 oncogene may act as the key molecular sensor of energy imbalance after the perturbation of tumor-associated FAS hyperactivity in cancer cells.
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PMID:Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. 1523 25

The omega-6 polyunsaturated fatty acid gamma-linolenic acid (GLA; 18:3n-6), which is found in several plant oils and is used as an herbal medicine, has antitumor activity in vitro. We examined the effect of GLA on the expression of the Her-2/neu (erbB-2) oncogene, which is involved in development of numerous types of human cancer. Flow cytometric and immunoblotting analyses demonstrated that GLA treatment substantially reduced Her-2/neu protein levels in the Her-2/neu-overexpressing cell lines BT-474, SK-Br3, and MDA-MB-453 (breast cancer), SK-OV3 (ovarian cancer), and NCI-N87 (gastrointestinal tumor derived). GLA exposure led to a dramatic decrease in Her-2/neu promoter activity and a concomitant increase in the levels of polyomavirus enhancer activator 3 (PEA3), a transcriptional repressor of Her-2/neu, in these cell lines. In transient transfection experiments, a Her-2/neu promoter bearing a PEA3 site-mutated sequence was not subject to negative regulation by GLA in Her-2/neu-overexpressing cell lines. Concurrent treatments of Her-2/neu-overexpressing cancer cells with GLA and the anti-Her-2/neu antibody trastuzumab led to synergistic increases in apoptosis and reduced growth and colony formation.
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PMID:Effect of gamma-linolenic acid on the transcriptional activity of the Her-2/neu (erbB-2) oncogene. 1670 27

The final proof about the specific mechanisms by which the different components of olive oil, the principal source of fat in a typical "Mediterranean diet", exert their potential protective effects on the promotion and progression of several human cancers requires further investigations. A recent discovery that dietary fatty acids can interact with the human genome by regulating the amount and/or activity of transcription factors has opened a whole new line of research aimed to molecularly corroborate the ant-cancer benefits of the olive oil-based Mediterranean diet and the underlying mechanisms. Our most recent findings reveal that oleic acid (OA; 18:1n-9), the main olive oil's monounsaturated fatty acid, can suppress the overexpression of HER2 (erbB-2), a well-characterized oncogene playing a key role in the etiology, invasive progression and metastasis in several human cancers. First, exogenous supplementation with physiological concentrations of OA significantly down-regulates HER2-coded p185(Her-2/neu) oncoprotein in human cancer cells naturally harboring amplification of the HER gene. Second, OA exposure specifically represses the transcriptional activity of the human HER2 gene promoter in tumor-derived cell lines naturally exhibiting HER2 gene amplification and p185(Her-2/neu) protein overexpression but not in cancer cells expressing physiological levels of HER2. Third, OA treatment induces the up-regulation of the Ets protein PEA3 (a transcriptional repressor of the HER2 gene promoter) solely in cancer cells naturally displaying HER2 gene amplification. Fourth, HER2 gene promoter bearing a PEA3 site-mutated sequence cannot be negatively regulated by OA, while treatment with OA fails to repress the expression of a human full-length HER2 cDNA controlled by a SV40 viral promoter. Fifth, OA-induced inhibition of HER2 promoter activity does not occur if HER2 gene-amplified cancer cells do no concomitantly exhibit high levels of Fatty Acid Synthase (FASN; Oncogenic antigen-519) as specific depletion of FASN, which itself similarly suppresses HER2 overexpression by inducing PEA3-dependent repression of HER2 gene promoter, strongly antagonizes the inhibitory effects of OA on HER2 gene promoter activity. Considering that OA treatment efficiently blocks FASN activity and down-regulates FASN protein expression, it is reasonable to suggest that an accumulation of supra-physiological concentrations of the FASN substrate malonyl-CoA, due to its reduced utilization by FASN in the presence of exogenous OA, appears to act as an indicator of "cell fuel" availability capable to suppress HER2 expression via formation of inhibitory "PEA3 protein-PEA3 DNA binding site" complexes on the endogenous HER2 promoter. Indeed, malonyl-CoA on its own dramatically decreases HER2 promoter activity, while OA or malonyl-CoA similarly up-regulates PEA3 gene promoter activity. This previously unrecognized ability of OA to directly affect the expression of a cluster of interrelated human cancer genes (i.e., HER2, FASN and PEA3) should open a new line of research aimed to explore the anti-cancer effects of OA. Certainly, an appropriate dietary intervention reproducing this prominent anti-oncogenic feature of the "Mediterranean diet" must be carried out in animal models and human pilot studies in the future. Only then we will know whether the old "Mediterranean dietary traditions" will become a new molecular approach in the management of cancer disease.
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PMID:Mediterranean dietary traditions for the molecular treatment of human cancer: anti-oncogenic actions of the main olive oil's monounsaturated fatty acid oleic acid (18:1n-9). 1716 66

CD4 T cells express the epidermal growth factor (EGF) receptor ligand, heparin-binding EGF (HB-EGF), with no defined immuno-pathophysiological function. Therefore, we wished to elucidate the function of HB-EGF synthesized by CD4 T cells in the context of allergic pulmonary inflammation and the asthma surrogate, airway hyperresponsiveness, in a murine acute model of asthma. In this study, we show how knocking out HB-EGF expression in CD4 T cells in vivo attenuates IL-5 synthesis in the lung that is accompanied by diminished eosinophilic inflammation and airway hyperresponsiveness. HB-EGF coimmunoprecipitates with the transcriptional repressor B cell lymphoma 6 (Bcl-6) in CD4 T cells. Knocking out HB-EGF in CD4 T cells resulted in increased Bcl-6 binding to the IL-5 gene and decreased IL-5 mRNA expression. Thus, these findings suggest an immunoregulatory function for intrinsic HB-EGF expressed by CD4 T cells in TH2 inflammation and airway dysfunction by modulating IL-5 expression via binding to and inhibiting the repressive function of Bcl-6.
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PMID:HB-EGF Synthesized by CD4 T Cells Modulates Allergic Airway Eosinophilia by Regulating IL-5 Synthesis. 3112 30