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)

Angiotensin II (Ang II) is a vasoactive hormone with critical roles in vascular smooth muscle cell growth, an important feature of hypertension and atherosclerosis. Many of these effects are dependent on the production of reactive oxygen species (ROS). Ang II induces phosphorylation of the epidermal growth factor (EGF) receptor (EGF-R), which serves as a scaffold for various signaling molecules. Here, we provide novel evidence that ROS are critical mediators of EGF-R transactivation by Ang II. Pretreatment of vascular smooth muscle cells with the antioxidants diphenylene iodonium, Tiron, N-acetylcysteine, and ebselen significantly inhibited ( approximately 80% to 90%) tyrosine phosphorylation of the EGF-R by Ang II but not by EGF. Of the 5 autophosphorylation sites on the EGF-R, Ang II mainly phosphorylated Tyr1068 and Tyr1173 in a redox-sensitive manner. The Src family kinase inhibitor PP1, overexpression of kinase-inactive c-Src, or chelation of intracellular Ca(2+) attenuated EGF-R transactivation. Although antioxidants had no effects on the Ca(2+) mobilization or phosphorylation of Ca(2+)-dependent tyrosine kinase Pyk2, they inhibited c-Src activation by Ang II, suggesting that c-Src is 1 signaling molecule that links ROS and EGF-R phosphorylation. Furthermore, Ang II-induced tyrosine phosphorylation of the autophosphorylation site and the SH2 domain of c-Src was redox sensitive. These findings emphasize the importance of ROS in specific Ang II-stimulated growth-related signaling pathways and suggest that redox-sensitive EGF-R transactivation may be a potential target for antioxidant therapy in vascular disease.
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PMID:Epidermal growth factor receptor transactivation by angiotensin II requires reactive oxygen species in vascular smooth muscle cells. 2436 72

Acceleration of the polyol pathway and enhanced oxidative stress are implicated in the pathogenesis of diabetic complications. We and others recently reported that aldose reductase (AR), the rate-limiting enzyme in the polyol pathway, was upregulated by reactive oxygen and nitrogen species in vascular smooth muscle cells. To clarify the molecular mechanisms underlying these findings, we investigated the signal transduction pathways mediating AR expression using the rat vascular smooth muscle cell line A7r5. A selective epidermal growth factor (EGF) receptor kinase inhibitor, tyrphostin AG1478, significantly suppressed the hydrogen peroxide (H2O2)-induced increase in AR mRNA and enzyme activity. Activation of extracellular signal-regulated protein kinase (ERK) by H2O2 was blunted by AG1478. PD98059, a specific inhibitor of ERK kinase (MEK1), reduced H2O2-induced AR expression. EGF alone elicited activation of ERK and induction of AR expression. Increased level of AR transcript was demonstrated in cells treated with oxidized low-density lipoprotein, and this increase was also suppressed by AG1478. Inhibition of p38 MAP kinase by SB203580 also partially suppressed the H2O2-initiated AR induction. The presence of ponalrestat, an AR inhibitor, significantly accelerated H2O2-induced cell death. These results suggested that AR may act as a survival factor in these cells and that the EGF receptor-ERK pathway is the major signaling pathway involved in the upregulation of AR expression under oxidative stress.
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PMID:EGF receptor-ERK pathway is the major signaling pathway that mediates upregulation of aldose reductase expression under oxidative stress. 1144 Aug 32

Angiotensin II (Ang II)-stimulated hypertrophy of vascular smooth muscle cells is mediated by reactive oxygen species (ROS) derived from NAD(P)H oxidases. The upstream signaling mechanisms by which Ang II activates these oxidases are unclear but may include protein kinase C, tyrosine kinases, phosphatidylinositol-3-kinase, and Rac, a small molecular weight G protein. We found that Ang II-stimulated ROS production is biphasic. The first phase occurs rapidly (peak at 30 seconds) and is dependent on protein kinase C activation. The larger second phase of ROS generation (peak at 30 minutes) requires Rac activation, because inhibition of Rac by either Clostridium difficile toxin A or dominant-negative Rac significantly inhibits Ang II-induced ROS production. Phosphatidylinositol-3-kinase inhibitors (wortmannin or LY294002) and the epidermal growth factor (EGF) receptor kinase blocker AG1478 attenuate both Rac activation and ROS generation. The upstream activator of EGF receptor transactivation, c-Src, is also required for ROS generation, because PP1, an Src kinase inhibitor, abrogates the Ang II stimulation of both responses. These results suggest that c-Src, EGF receptor transactivation, phosphatidylinositol-3-kinase, and Rac play important roles in the sustained Ang II-mediated activation of vascular smooth muscle cell NAD(P)H oxidases and provide insight into the integrated signaling mechanisms whereby Ang II stimulation leads to activation of the growth-related NAD(P)H oxidases.
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PMID:Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators. 1221 89

Bainiku-ekisu, the fruit-juice concentrate of the Oriental plum (Prunus mume) has recently been shown to improve human blood fluidity. We have shown that angiotensin II (AngII) stimulates growth of vascular smooth muscle cells (VSMCs) through epidermal growth factor (EGF) receptor transactivation that involves reactive oxygen species (ROS) production. To better understanding the possible cardiovascular protective effect of Bainiku-ekisu, we have studied whether Bainiku-ekisu inhibits AngII-induced growth promoting signals in VSMCs. Bainiku-ekisu markedly inhibited AngII-induced EGF receptor transactivation. H(2)O(2)-induced EGF receptor transactivation was also inhibited by Bainiku-ekisu. Thus, Bainiku-ekisu markedly inhibited AngII-induced extracellular signal-regulated kinase (ERK) activation. However, EGF-induced ERK activation was not affected by Bainiku-ekisu. AngII stimulated leucine uptake in VSMCs that was significantly inhibited by Bainiku-ekisu. Also, Bainiku-ekisu possesses a potent antioxidant activity. Since the activation of EGF receptor, ERK and the production of ROS play central roles in mediating AngII-induced vascular remodeling, these data suggest that Bainiku-ekisu could exert a powerful cardiovascular protective effect with regard to cardiovascular diseases.
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PMID:Fruit-juice concentrate of Asian plum inhibits growth signals of vascular smooth muscle cells induced by angiotensin II. 1246 6

Reactive oxygen species (ROS) are implicated in cardiovascular diseases. ROS, such as H2O2, act as second messengers to activate diverse signaling pathways. Although H2O2 activates several tyrosine kinases, including the epidermal growth factor (EGF) receptor, JAK2, and PYK2, in vascular smooth muscle cells (VSMCs), the intracellular mechanism by which ROS activate these tyrosine kinases remains unclear. Here, we identified two distinct signaling pathways required for receptor and nonreceptor tyrosine kinase activation by H2O2 involving a metalloprotease-dependent generation of heparin-binding EGF-like growth factor (HB-EGF) and protein kinase C (PKC)-delta activation, respectively. H2O2-induced EGF receptor tyrosine phosphorylation was inhibited by a metalloprotease inhibitor, whereas the inhibitor had no effect on H2O2-induced JAK2 tyrosine phosphorylation. HB-EGF neutralizing antibody inhibited H2O2-induced EGF receptor phosphorylation. In COS-7 cells expressing an HB-EGF construct tagged with alkaline phosphatase, H2O2 stimulates HB-EGF production through metalloprotease activation. By contrast, dominant negative PKC-delta transfection inhibited H2O2-induced JAK2 phosphorylation but not EGF receptor phosphorylation. Dominant negative PYK2 inhibited H2O2-induced JAK2 activation but not EGF receptor activation, whereas dominant negative PKC-delta inhibited PYK2 activation by H2O2. These data demonstrate the presence of distinct tyrosine kinase activation pathways (PKC-delta/PYK2/JAK2 and metalloprotease/HB-EGF/EGF receptor) utilized by H2O2 in VSMCs, thus providing unique therapeutic targets for cardiovascular diseases.
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PMID:Distinct mechanisms of receptor and nonreceptor tyrosine kinase activation by reactive oxygen species in vascular smooth muscle cells: role of metalloprotease and protein kinase C-delta. 1258 78

Her-2/neu (erbB-2) oncogene overexpression is associated with increased tumor progression and metastasis. Fatty acid synthase (FAS), the key lipogenic enzyme responsible for the endogenous synthesis of fatty acids, has been shown to be one of the genes regulated by Her-2/neu at the level of transcription, translation, and biosynthetic activity. Interestingly, we recently established that both pharmacological inhibition of FAS activity and silencing of FAS gene expression specifically suppress Her-2/neu oncoprotein expression and tyrosine-kinase activity in breast and ovarian Her-2/neu overexpressors. Unraveling the functional organization of this novel bi-directional molecular connection between Her-2/neu and FAS-dependent neoplastic lipogenesis is a major challenge that the field is only beginning to take on. Considering that Her-2/neu overexpression correlates with increased expression of the hypoxia inducible factor-1alpha (HIF-1alpha), which, in a mitogen-activated protein kinase (MAPK)-dependent manner, plays a key role in the expression of several genes including cytokines such as vascular endothelial growth factor (VEGF), we hypothesized that FAS blockade should result in a concomitant down-regulation of VEGF. Unexpectedly, the specific inhibition of the de novo fatty acid synthesis with the small-molecule inhibitor of FAS activity C75 resulted in a dramatic dose-dependent enhancement (up to 500% increase) of VEGF secretion in Her-2/neu-overexpressing SK-Br3, BT-474, and SKOV3 cancer cells. Concurrently, FAS blockade drastically activated MAPK and promoted further a prominent accumulation of HIF-1alpha in Her-2/neu overexpressors. Moreover, U0126-induced inhibition of MAPK activity completely abolished C75-induced up-regulation of HIF-1alpha expression and VEGF secretion, whereas it did not modulate C75-induced down-regulation of Her-2/neu oncogene. Importantly, RNA interference (RNAi)-mediated silencing of the FAS gene recapitulated C75's effects by up-regulating VEGF secretion, MAPK activation and HIF-1alpha expression. Therefore, it appears that perturbation of cancer-associated endogenous fatty metabolism triggers a "hypoxia-like" (oxygen-independent) condition that actively rescues Her-2/neu-dependent MAPK --> HIP-1alpha --> VEGF cascade. It is tempting to suggest that an intact FAS-catalyzed endogenous fatty acid metabolism is a necessary metabolic adaptation to support the enhanced ability of Her-2/neu-overexpressing cancer cells to survive cellular hypoxia in a HIF-alpha-dependent manner.
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PMID:Does endogenous fatty acid metabolism allow cancer cells to sense hypoxia and mediate hypoxic vasodilatation? Characterization of a novel molecular connection between fatty acid synthase (FAS) and hypoxia-inducible factor-1alpha (HIF-1alpha)-related expression of vascular endothelial growth factor (VEGF) in cancer cells overexpressing her-2/neu oncogene. 1566 79

A G protein-coupled receptor agonist, angiotensin II (AngII), induces epidermal growth factor (EGF) receptor (EGFR) transactivation possibly through metalloprotease-dependent, heparin-binding EGF (HB-EGF) shedding. Here, we have investigated signal transduction of this process by using COS7 cells expressing an AngII receptor, AT1. In these cells AngII-induced EGFR transactivation was completely inhibited by pretreatment with a selective HB-EGF inhibitor, or with a metalloprotease inhibitor. We also developed a COS7 cell line permanently expressing a HB-EGF construct tagged with alkaline phosphatase, which enabled us to measure HB-EGF shedding quantitatively. In the COS7 cell line AngII stimulated release of HB-EGF. This effect was mimicked by treatment either with a phospholipase C activator, a Ca2+ ionophore, a metalloprotease activator, or H2O2. Conversely, pretreatment with an intracellular Ca2+ antagonist or an antioxidant blocked AngII-induced HB-EGF shedding. Moreover, infection of an adenovirus encoding an inhibitor of G(q) markedly reduced EGFR transactivation and HB-EGF shedding through AT1. In this regard, AngII-stimulated HB-EGF shedding was abolished in an AT1 mutant that lacks G(q) protein coupling. However, in cells expressing AT1 mutants that retain G(q) protein coupling, AngII is still able to induce HB-EGF shedding. Finally, the AngII-induced EGFR transactivation was attenuated in COS7 cells overexpressing a catalytically inactive mutant of ADAM17. From these data we conclude that AngII stimulates a metalloprotease ADAM17-dependent HB-EGF shedding through AT1/G(q)/phospholipase C-mediated elevation of intracellular Ca2+ and reactive oxygen species production, representing a key mechanism indispensable for EGFR transactivation.
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PMID:G protein coupling and second messenger generation are indispensable for metalloprotease-dependent, heparin-binding epidermal growth factor shedding through angiotensin II type-1 receptor. 1590 75

Air pollution particles (PM) are known to elicit an acute inflammatory response in vivo that is mediated in part through PM-induced activation of the NF-kappaB signaling pathway. Many of the details of this process and particularly where in the cell it occurs are unclear. To determine whether contact of PM particles with an epithelial cell surface activates NF-kappaB, rat tracheal explants were exposed to Ottawa Urban Air Particles or iron-loaded fine TiO2, a model PM particle, for up to 2 h. During this period, there was no evidence of particle entry into the tracheal epithelial cells by light or electron microscopy, but both types of particle activated NF-kappaB as assayed by gel shifts. NF-kappaB activation could be inhibited by the active oxygen species scavenger, tetramethylthiourea; the redox-inactive metal chelator, deferoxamine; the Src inhibitor, PP2; and the epidermal growth factor (EGF) receptor inhibitor AG1478. An iron-containing citrate extract of both dusts also produced NF-kappaB activation. Both dusts and a citrate extract caused phosphorylation of the EGF receptor on tyrosine 845, an indicator of Src activity. We conclude that iron-containing PM particles can activate NF-kappaB via a pathway involving Src and the EGF receptor. This process does not require entry of particles into the airway epithelial cells but is dependent on the presence of iron and generation of active oxygen species by the dusts. These findings imply that even brief contact of PM with a pulmonary epithelial cell surface may produce deleterious effects in vivo.
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PMID:Air pollution particles activate NF-kappaB on contact with airway epithelial cell surfaces. 1616 60

Acetylcholine (ACh) and opioid receptor agonists trigger the preconditioned phenotype through sequential activation of the epidermal growth factor (EGF) receptor, phosphatidylinositol 3-kinase (PI3-K), Akt, and nitric oxide synthase (NOS), and opening of mitochondrial (mito) K(ATP) channels with the generation of reactive oxygen species (ROS). Although extracellular signal-regulated kinase (ERK) has recently been reported to be part of this pathway, its location has not been determined. To address this issue, we administered a 5-min pulse of ACh (550 microM) prior to 30 min of ischemia in isolated rabbit hearts. It reduced infarction from 30.4 +/- 2.2% of the risk zone in control hearts to 12.3 +/- 2.8% and co-administration of the MEK, and, therefore, downstream ERK inhibitor U0126 abolished protection (29.1 +/- 4.6% infarction) con.rming ERK's involvement. MitoK(ATP) opening was monitored in adult rabbit cardiomyocytes by measuring ROS production with MitoTracker Red. ROS production was increased by each of three G protein-coupled agonists: ACh (250 microM), bradykinin (BK) (500 nM), and the delta-opioid agonist DADLE (20 nM). Co-incubation with the MEK inhibitors U0126 (500 nM) or PD 98059 (10 microM) blocked the increased ROS production seen with all three agonists. Direct activation of its receptor by EGF increased ROS production and PD 98059 blocked that increase, thus placing ERK downstream of the EGF receptor. Desferoxamine (DFO) which opens mitoK(ATP) through direct activation of NOS also increased ROS. PD 98059 could not block DFO-induced ROS production, placing ERK upstream of NOS. In isolated hearts, ACh caused phosphorylation of both Akt and ERK. U0126 blocked phosphorylation of ERK but not of Akt. The PI3-K inhibitor wortmannin blocked both. Together these data indicate that ERK is located between Akt and NOS.
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PMID:Localizing extracellular signal-regulated kinase (ERK) in pharmacological preconditioning's trigger pathway. 1628 91

We previously showed that ANG II induces mesangial cell (MC) proliferation via the JNK-activator protein-1 pathway. The present study attempted to determine the upstream mediators of JNK activation, with emphasis on reactive oxygen species (ROS) and the epidermal growth factor (EGF) receptor (EGFR). In cultured human MCs (HMCs), as early as 3 min, ANG II time dependently increased intracellular ROS production, which was sensitive to 10 microM diphenyleneiodonium sulfate and 500 microM apocynin, two structurally distinct NADPH oxidase inhibitors. In contrast, inhibitors of other oxidant-producing enzymes, including the mitochondrial complex I inhibitor rotenone, the xanthine oxidase inhibitor allopurinol, the cyclooxygenase inhibitor indomethacin, the lipoxygenase inhibitor nordihydroguiaretic acid, the cytochrome P-450 oxygenase inhibitor ketoconazole, and the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester, were without effect. ANG II-induced ROS generation was inhibited by the angiotensin type 1 receptor antagonist losartan (10 muM) but not the angiotensin type 2 receptor antagonist PD-123319 (10 microM). ANG II induced translocation of p47(phox) and p67(phox) from the cytosol to the membrane. The antioxidants almost abolished the ANG II mitogenic response, as assessed by [(3)H]thymidine incorporation and cell number, associated with a remarkable blockade of the activation of EGFR (90% inhibition) and JNK (83% inhibition). The EGFR inhibitor AG-1478 was able to mimic the effect of antioxidants, in that it inhibited the mitogenic response and the JNK activation following ANG II treatment. Together, these data suggest that the ROS-EGFR-JNK pathway is involved in transducing the proliferative effect of ANG II in cultured HMCs.
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PMID:ANG II induces c-Jun NH2-terminal kinase activation and proliferation of human mesangial cells via redox-sensitive transactivation of the EGFR. 1788 65


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