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)

Irradiation of HeLa cells with short-wavelength ultraviolet light (UVC) induces the modification and activation of the preexisting transcription factors c-Fos-c-Jun (AP-1) and TCF/Elk-1, as well as the protein synthesis independent transcriptional activation of the c-fos and c-jun genes. This response to UVC is mediated via obligatory cytoplasmic signal transduction, involving Ras and Raf, Src, and MAP kinases. The UVC response is inhibited by prior down-modulation of growth factor receptor signaling upon growth factor prestimulation, by suramin (an inhibitor of receptor activation) or by expression of a dominant negative epidermal growth factor (EGF) receptor mutant. These data suggest the involvement of several growth factor receptors in the UVC response. Indeed, UVC induces the suramin-inhibitable immediate tyrosine phosphorylation of the EGF receptor.
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PMID:Involvement of growth factor receptors in the mammalian UVC response. 792 65

To understand the mechanisms regulating the transactivating activity of Jun/AP-1, we analyzed alterations in c-Jun induced by growth stimulation and cell transformation. Serum stimulation of quiescent NIH3T3 cells induced a marked increase in phosphorylation of c-Jun in its amino-terminal activation domain. On the other hand, this domain was highly phosphorylated, in a serum-independent manner, in cells transformed with various oncogenes, including active c-raf-1, v-src, active Ha-ras, and active erbB-2. There were no obvious differences in the phosphorylation states of c-Jun in exponentially growing normal and transformed cells. However, in the exponentially growing state, the TRECAT activity in transformed cells was markedly higher than that in normal cells. Gel retardation analysis indicated that the AP-1 components in transformed cells were significantly different from those in normal cells. These results suggest that some other alterations besides phosphorylation of c-Jun are involved in enhancement of AP-1 activity in exponentially growing transformed cells.
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PMID:Serum-independent phosphorylation of c-Jun and alterations in AP-1 components by transformation with various oncogenes. 830 27

Members of the epidermal growth factor (EGF) receptor family are known to be specifically involved in mammary carcinogenesis. As a nuclear target of activated receptors, we examined c-Jun in mammary epithelial cells. For this, we used a c-JunER fusion protein which was tightly controlled by estrogen. Activation of the JunER by hormone resulted in the transcriptional regulation of a variety of AP-1 target genes. Hormone-activated JunER induced the loss of epithelial polarity, a disruption of intercellular junctions and normal barrier function and the formation of irregular multilayers. These changes were completely reversible upon hormone withdrawal. Loss of epithelial polarity involved redistribution of both apical and basolateral proteins to the entire plasma membrane. The redistribution of E-cadherin and beta-catenin was accompanied by a destabilization of complexes formed between these two proteins, leading to an enrichment of beta-catenin in the detergent-soluble fraction. Uninduced cells were able to form three-dimensional tubular structures in collagen I gels which were disrupted upon JunER activation, leading to irregular cell aggregates. The JunER-induced disruption of tubular structures was dependent on active signaling by growth factors. Moreover, the effects of JunER could be mimicked in normal cells by the addition of acidic fibroblast growth factor (aFGF). These data suggest that a possible function of c-Jun in epithelial cells is to modulate epithelial polarity and regulate tissue organization, processes which may be equally important for both normal breast development and as initiating steps in carcinogenesis.
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PMID:The estrogen-dependent c-JunER protein causes a reversible loss of mammary epithelial cell polarity involving a destabilization of adherens junctions. 860 89

Overexpression of the erbB-2 gene contributes to aggressive behavior of various human adenocarcinomas, including breast cancer, through an unknown molecular mechanism. The erbB-2-encoded protein is a member of the ErbB family of growth factor receptors, but no direct ligand of ErbB-2 has been reported. We show that in various cells ErbB-2 can form heterodimers with both EGF receptor (ErbB-1) and NDF receptors (ErbB-3 and ErbB-4), suggesting that it may affect the action of heterologous ligands without the involvement of a direct ErbB-2 ligand. This possibility was addressed in breast cancer cells through either overexpression of ErbB-2 or by blocking its delivery to the cell surface by means of an endoplasmic reticulum-trapped antibody. We report that ErbB-2 overexpression enhanced binding affinities to both EGF and NDF, through deceleration of ligand dissociation rates. Likewise, removal of ErbB-2 from the cell surface almost completely abolished ligand binding by accelerating dissociation of both growth factors. The kinetic effects resulted in enhancement and prolongation of the stimulation of two major cytoplasmic signaling pathways, namely: MAP kinase (ERK) and c-Jun kinase (SAPK), by either ligand. Our results imply that ErbB-2 is a pan-ErbB subunit of the high affinity heterodimeric receptors for NDF and EGF. Therefore, the oncogenic action of ErbB-2 in human cancers may be due to its ability to potentiate in trans growth factor signaling.
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PMID:ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. 861 1

We have reported that angiotensin II induces the epidermal growth factor (EGF) receptor transactivation leading to extracellular signal-regulated kinase (ERK) activation in rat vascular smooth muscle cells. Here, we report that the EGF receptor kinase inhibitor AG1478 and the ERK kinase inhibitor PD98059 markedly inhibited angiotensin II-induced c-Fos expression and protein synthesis but not c-Jun expression in these cells. These data suggest that the EGF receptor transactivation and subsequent ERK activation are indispensable for angiotensin II-mediated growth promotion of vascular smooth muscle cells providing a new mechanistic insight whereby angiotensin II contributes abnormal vascular remodeling.
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PMID:Epidermal growth factor receptor is indispensable for c-Fos expression and protein synthesis by angiotensin II. 1044 Jan 5

Multiple lines of evidence suggest that cyclooxygenase-2 (COX-2) is an important target for preventing epithelial malignancies. Little is known, however, about the expression of COX-2 in gynecological malignancies. By immunoblot analysis, COX-2 was detected in 12 of 13 cases of cervical cancer but was undetectable in normal cervical tissue. Immunohistochemistry revealed COX-2 in malignant epithelial cells. COX-2 was also expressed in cervical intraepithelial neoplasia. The mechanism by which COX-2 is up-regulated in cervical cancer is unknown. Because the epidermal growth factor (EGF) receptor is commonly overexpressed in cervical cancer, we investigated whether EGF could induce COX-2 in cultured human cervical carcinoma cells. Treatment with EGF markedly induced COX-2 protein, COX-2 mRNA, and stimulated COX-2 promoter activity. The induction of COX-2 by EGF was suppressed by inhibitors of tyrosine kinase activity, phosphatidylinositol 3-kinase, mitogen-activated protein kinase kinase, and p38 mitogen-activated protein kinase. Moreover, overexpressing dominant-negative forms of extracellular signal-regulated kinase 1, c-Jun NH2-terminal kinase, p38, and c-Jun blocked EGF-mediated induction of COX-2 promoter activity. Taken together, these findings suggest that deregulation of the EGF receptor signaling pathway may lead to enhanced COX-2 expression in cervical cancer.
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PMID:Cyclooxygenase-2 is overexpressed in human cervical cancer. 1123

Markedly increased levels of cyclooxygenase-2 (COX-2) mRNA, protein, and prostaglandin E(2) synthesis were detected in HER-2/neu-transformed human mammary epithelial cells (184B5/HER) compared with its nontransformed partner cell line (184B5). HER-2/neu stimulated COX-2 transcription via the Ras --> Raf --> MAPK pathway. The inductive effects of HER-2/neu were mediated, in part, by enhanced binding of AP-1 (c-Jun, c-Fos, and ATF-2) to the cyclic AMP-response element (-59/-53) of the COX-2 promoter. The potential contribution of the transcription factor PEA3 was also investigated. Elevated levels of PEA3 were detected in 184B5/HER cells. A PEA3 site (-75/-72) was identified juxtaposed to the cyclic AMP-response element. HER-2/neu-mediated activation of the COX-2 promoter was blocked by mutagenizing the PEA3 site or overexpressing antisense to PEA3. To determine whether HER-2/neu status was also a determinant of COX-2 expression in vivo, we compared levels of COX-2 protein in HER-2/neu-positive and -negative human breast cancers. Increased amounts of COX-2 were detected in HER-2/neu-positive tumors. Taken together, these results suggest that closely spaced PEA3 and cyclic AMP-response elements are required for HER-2/neu-mediated induction of COX-2 transcription. The clear relationship between HER-2/neu status and COX-2 expression in human breast tumors suggests that this mechanism is likely to be operative in vivo.
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PMID:Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA3. 1190 Nov 51

The epidermal growth factor (EGF) receptor (EGFR) family consists of four transmembrane tyrosine kinases that undergo homodimerization and heterodimerization. Pancreatic cancers overexpress these receptors. To examine the effects of EGFR blockade on pancreatic cancer cell mitogenesis in relation to activation of specific signaling pathways, four pancreatic cancer cell lines were infected with an adenoviral vector encoding a truncated EGFR (AdtrEGFR), and activation of signaling was assessed with the mitogen-activated protein kinase (MAPK) kinase inhibitors PD98059 and U0126, the p38 MAPK inhibitor SB203580, and the c-Jun NH2-terminal kinase inhibitor SP600125. In all four cell lines, AdtrEGFR markedly attenuated EGF and heparin-binding EGF-dependent cell growth, EGFR family tyrosine phosphorylation, and phosphorylation of MAPK, c-Jun NH2-terminal kinase, p38 MAPK, and activating transcription factor 2. AdtrEGFR did not alter fibroblast growth factor 2 actions on mitogenesis. In ASPC-1, PANC-1, and T3M4 cells, PD98059 and U0126 inhibited MAPK kinase activation but not EGF-stimulated mitogenesis, whereas SB203580 inhibited EGF-stimulated mitogenesis, p38 MAPK activation, and MAPK-activated protein kinase 2 activation, without attenuating the mitogenic effect of insulin-like growth factor 1. In contrast, in COLO-357 cells, PD98059, and U0126, but not SB203580, inhibited EGF-stimulated mitogenesis, whereas SP600125 did not alter the mitogenic actions of EGF in any of the cell lines. Thus, EGF promotes proliferation via the MAPK in COLO-357 cells but via p38 MAPK in ASPC-1, PANC-1, and T3M4 cells, and whereas EGFR activation leads to the activation of all four members of the EGFR family in these cells, downstream signaling is efficiently blocked by AdtrEGFR.
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PMID:Multiple mitogenic pathways in pancreatic cancer cells are blocked by a truncated epidermal growth factor receptor. 1235 75

The epidermal growth factor (EGF) receptor plays an important role in epithelial cells by controlling cell proliferation and survival. Keratinocytes also express another class of receptor tyrosine kinases, the neurotrophin receptors. To analyze the biological role of the neurotrophin brain-derived neurotrophic factor (BDNF) in keratinocytes, we expressed the BDNF receptor TrkB in immortalized human HaCaT keratinocytes. Stimulation of HaCaT-TrkB cells with BDNF induced DNA synthesis and increased mitochondrial reduction capacities, both indications of proliferating cells. An analysis of the signal transduction cascade revealed that the activated TrkB receptor effectively utilized components of the EGF receptor signaling pathway to control cell proliferation. Mitogenic signaling induced by BDNF or EGF was completely abrogated by the MAP kinase kinase inhibitor PD-98059, whereas inhibition of phosphatidylinositol 3-kinase by wortmannin only delayed the proliferative response. The importance of the extracellular signal-regulated kinase signaling pathway for growth of HaCaT keratinocytes was further demonstrated with HaCaT cells engineered to express an inducible A-Raf-estrogen receptor fusion protein (DeltaA-Raf:ER). Despite differences in the amplitude and duration of extracellular signal-regulated kinase activation, HaCaT cells expressing DeltaA-Raf:ER proliferated after activation of mutant A-Raf protein kinase. Proliferation was completely inhibited by PD-98059. Proliferation of HaCaT cells induced by EGF, BDNF, or DeltaA-Raf:ER was also accompanied by biosynthesis of the transcription factors Egr-1 and c-Jun, suggesting that these proteins may be part of the mitogenic signaling cascade.
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PMID:Brain-derived neurotrophic factor-, epidermal growth factor-, or A-Raf-induced growth of HaCaT keratinocytes requires extracellular signal-regulated kinase. 1507 11

Arsenite is a human carcinogen that may induce cancer in skin, liver, kidney, bladder or lung. Arsenite executes its toxic effects by the induction of signaling cascades. In particular, the activation of the stress-induced protein kinase c-Jun N-terminal protein kinase and p38 and the phosphorylation and activation of the transcription factor c-Jun have been linked to the biological effects of arsenite. We analyzed whether arsenite has an impact on the biosynthesis of the zinc finger transcription factor Egr-1. Egr-1 transcription is upregulated following treatment of cells with hormones, cytokines or toxic chemicals, and thus Egr-1 integrates many signaling cascades with changes in gene expression patterns. Here, we show by Western blot experiments that arsenite induces a transient synthesis of Egr-1 in human HaCaT keratinocytes. Egr-1 biosynthesis was activated by arsenite concentrations insufficient for the induction of c-Jun biosynthesis. This arsenite-triggered Egr-1 biosynthesis was completely inhibited by the mitogen-activated protein kinase kinase inhibitor PD98059 and by AG1487, an epidermal growth factor (EGF) receptor-specific tyrosine kinase inhibitor. These results indicate that activation of the EGF receptor as well as stimulation of the mitogen activated/extracellular signal-regulated protein kinase is essential for arsenite-induced upregulation of Egr-1. Moreover, we detected an elevated transcriptional activation potential of the ternary complex factor Elk1, a key transcriptional regulator of serum response element-driven gene transcription. The Egr-1 5'-flanking region contains five serum response elements. Accordingly, we observed an increase in Egr-1 promoter activity as a result of arsenite treatment. The fact that low concentrations of arsenite are sufficient to induce Egr-1 biosynthesis suggests that Egr-1 may be an integral part of arsenite-triggered signaling cascades leading to tumor formation or cell death via alterations of the cellular genetic program.
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PMID:The zinc finger transcription factor Egr-1 is upregulated in arsenite-treated human keratinocytes. 1529 61


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