Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator composed of HIF-1alpha and HIF-1beta subunits. Several dozen HIF-1 targets are known, including the gene encoding vascular endothelial growth factor (VEGF). Under hypoxic conditions, HIF-1alpha expression increases as a result of decreased ubiquitination and degradation. The tumor suppressors VHL (von Hippel-Lindau protein) and p53 target HIF-1alpha for ubiquitination such that their inactivation in tumor cells increases the half-life of HIF-1alpha. Increased phosphatidylinositol 3-kinase (PI3K) and AKT or decreased PTEN activity in prostate cancer cells also increases HIF-1alpha expression by an undefined mechanism. In breast cancer, increased activity of the HER2 (also known as neu) receptor tyrosine kinase is associated with increased tumor grade, chemotherapy resistance, and decreased patient survival. HER2 has also been implicated as an inducer of VEGF expression. Here we demonstrate that HER2 signaling induced by overexpression in mouse 3T3 cells or heregulin stimulation of human MCF-7 breast cancer cells results in increased HIF-1alpha protein and VEGF mRNA expression that is dependent upon activity of PI3K, AKT (also known as protein kinase B), and the downstream kinase FRAP (FKBP-rapamycin-associated protein). In contrast to other inducers of HIF-1 expression, heregulin stimulation does not affect the half-life of HIF-1alpha but instead stimulates HIF-1alpha synthesis in a rapamycin-dependent manner. The 5'-untranslated region of HIF-1alpha mRNA directs heregulin-inducible expression of a heterologous protein. These data provide a molecular basis for VEGF induction and tumor angiogenesis by heregulin-HER2 signaling and establish a novel mechanism for the regulation of HIF-1alpha expression.
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PMID:HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. 1135 7

Advanced glycation end products (AGEs) are generated during long term diabetes and are correlated with the development of diabetic complications, such as retinopathy. Diabetic retinopathy is characterized by an increased retinal neovascularization due to the action of the angiogenic factor, vascular endothelial growth factor (VEGF). In this report, we show that injection of insulin and glycated albumin (Alb-AGE) to mice increases VEGF mRNA expression in eyes. Insulin and Alb-AGE stimulate VEGF mRNA and protein expression in retinal epithelial cells (ARPE-19). Alb-AGE-induced VEGF expression is not modulated by the use of antioxidants, N-acetyl-l-cysteine or pyrrolidinedithiocarbamate, or by an inhibitor of phosphatidylinositol 3-kinase (PI3K), wortmannin. However, using an inhibitor of ERK activation, U0126, we show that Alb-AGE stimulates VEGF expression through an ERK-dependent pathway. Accordingly, we found that Alb-AGE activated mitogen-activate protein kinase, ERK1/2, JNK1/2, but not p38, and that Alb-AGE did not activate PI3K and PKB. Moreover, Alb-AGE activated the transcription factor, hypoxia inducible factor-1 (HIF-1) DNA binding activity. This activation is mediated by an increase in accumulation of the HIF-1alpha protein through an ERK-dependent pathway. Thus, stimulation of VEGF expression by Alb-AGE, through the activation of HIF-1, could play an important role in the development of diabetic retinopathy.
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PMID:Regulation of vascular endothelial growth factor expression by advanced glycation end products. 1157 Dec 95

Oxygen-dependent regulation of HIF-1 activity occurs at multiple levels in vivo. The mechanisms regulating HIF-1alpha protein expression have been most extensively analyzed but the ones modulating HIF-1 transcriptional activity remain unclear. Changes in the phosphorylation and/or redox status of HIF-1alpha certainly play a role. Here, we show that ionomycin could activate HIF-1 transcriptional activity in a way that was additive to the effect of hypoxia without affecting HIF-1alpha protein level. In addition, a calmodulin dominant negative mutant and W7, a calmodulin antagonist, as well as BAPTA, an intracellular calcium chelator, inhibited the hypoxia-induced HIF-1 activation. These results indicate that elevated calcium in hypoxia could participate in HIF-1 activation. Furthermore, ERK but not JNK phosphorylation was evidenced in both conditions, ionomycin and hypoxia. PD98059, an inhibitor of the ERK pathway as well as a ERK1 dominant negative mutant also blocked HIF-1 activation by hypoxia and by ionomycin. A MEKK1 (a kinase upstream of JNK) dominant negative mutant had no effect. In addition, BAPTA, calmidazolium, a calmodulin antagonist and PD98059 inhibited VEGF secretion by hypoxic HepG2. All together, these results suggest that calcium and calmodulin would act upstream of ERK in the hypoxia signal transduction pathway.
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PMID:Role of ERK and calcium in the hypoxia-induced activation of HIF-1. 1244 87

HIF-1 (hypoxia-inducible factor-1) is the main transcription factor responsible for increased gene expression in hypoxia. The oxygen-dependent regulation of HIF-1 activity occurs at multiple levels in vivo. The mechanisms regulating HIF-1alpha protein expression have been most extensively analyzed, but the ones modulating HIF-1 transcriptional activity remain unclear. Changes in the phosphorylation and/or redox status of HIF-1alpha certainly play a role. Here, we show that ionomycin could activate HIF-1 transcriptional activity in a way that is additive to the effect of hypoxia without affecting HIF-1alpha protein level and HIF-1 DNA binding capacity. In addition, a calmodulin dominant-negative mutant as well as BAPTA, an intracellular calcium chelator, inhibited the hypoxia-induced HIF-1 activation. These results indicate that elevated calcium in hypoxia could participate in HIF-1 activation. PD98059, an inhibitor of the ERK pathway, but not KN-93, an inhibitor of calmodulin kinases II and IV, also blocked HIF-1 activation by hypoxia and by ionomycin. Altogether, these results suggest that calcium and calmodulin would act upstream of ERK in the hypoxia signal transduction pathway leading to enhanced HIF-1 transcriptional activity.
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PMID:ERK and calcium in activation of HIF-1. 1248 9

Mitogen-activated protein kinases (MAPKs) and protein kinase B (PKB) mediate growth and stress signals and have been implicated in the hypoxic response. Under hypoxic conditions, the expression of plasminogen activator inhibitor-1 (PAI-1) is mainly controlled by the hypoxia-inducible factor HIF-1. However, the role of MAPKs and PKB in HIF-1-mediated PAI-1 regulation is not clear. Treatment with the p38 inhibitor SB203580 and the PI3K inhibitor LY294002, but not with the MEK1 inhibitor PD98059, abrogated hypoxia-dependent PAI-1 induction in HepG2 cells. Consistently, overexpression of PKB or of the p38 upstream kinases MKK6 and MKK3 and of JNK, but not of ERK, enhanced PAI-1 mRNA levels. In MKK3-, MKK6- and PKB-expressing cells luciferase (Luc) activities from a hypoxia-inducible PAI-1-Luc construct or from a HIF-dependent Luc construct and, concomitantly, HIF-1alpha protein levels were enhanced. These findings indicate that p38- and PKB-dependent signalling pathways contribute to enhanced PAI-1 levels in the hypoxic response.
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PMID:Regulation of the hypoxia-dependent plasminogen activator inhibitor 1 expression by MAP kinases. 1266 21

Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for stability and function of multiple mutated, chimeric, and over-expressed signaling proteins that promote cancer cell growth and/or survival. Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, Akt, HER2/Neu (ErbB2), and HIF-1alpha. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the destabilization and eventual degradation of Hsp90 client proteins, and they have also shown promising anti-tumor activity in preclinical model systems. One Hsp90 inhibitor, 17-AAG, is currently in Phase I clinical trial. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signaling pathways on which cancer cells depend for growth and survival. Benzoquinone ansamycin binding to Hsp90 led to the identification of radicicol as an additional Hsp90 inhibitor. Additional target-based screening uncovered novobiocin as a third structurally distinct small molecule with Hsp90 inhibitory properties. Use of novobiocin, in turn, led to identification of a previously uncharacterized C-terminal ATP binding site in the chaperone. Small molecule inhibitors of Hsp90 have been very useful in understanding Hsp90 biology and in validating this protein as a molecular target for anti-cancer drug development.
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PMID:Development of small molecule Hsp90 inhibitors: utilizing both forward and reverse chemical genomics for drug identification. 1267 76

The pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA) remains obscure, although angiogenesis appears to play an important role. We recently confirmed an overexpression of two angiogenic factors, namely vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF), by the lining and stromal cells of the synovium in both conditions. Because hypoxia inducible factor (HIF)-1alpha and HIF-2alpha are essential in regulating transcription of the VEGF gene, active participation of HIF-alpha molecules in the pathogenesis of these arthritides is anticipated. We investigated the immunohistochemical expression of HIF-1alpha and HIF-2alpha in the synovium of 22 patients with RA, 34 patients with OA and 22 'normal' nonarthritic individuals, in relation to VEGF, VEGF/KDR (kinase insert domain protein receptor) vascular activation, PD-ECGF and bcl-2. A significant cytoplasmic and nuclear overexpression of HIF-1alpha and HIF-2alpha was noted in the synovial lining and stromal cells of both diseases relative to normal. Overexpression of HIF-alphas was related to high microvessel density, high PD-ECGF expression and high VEGF/KDR receptor activation, suggesting HIF-alpha-dependent synovial angiogenesis in OA. By contrast, the activation of the angiogenic VEGF/KDR pathway was persistently increased in RA, as indeed was microvessel density and the expression of PD-ECGF, irrespective of the extent of HIF-alpha expression, indicating a cytokine-dependent angiogenesis. In all cases, the VEGF/KDR vascular activation was significantly lower in OA than in RA, suggesting a relative failure of the HIF-alpha pathway to effectively produce a viable vasculature for OA, which is consistent with the degenerative nature of the disease. The activation of the HIF-alpha pathway occurs in both RA and OA, although for unrelated reasons.
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PMID:Upregulated hypoxia inducible factor-1alpha and -2alpha pathway in rheumatoid arthritis and osteoarthritis. 1282 54

Hypoxia-inducible factor 1 (HIF-1) is a phosphorylated protein and its phosphorylation is involved in HIF-1alpha subunit stabilization as well as in the regulation of HIF-1 transcriptional activity. In a variety of cell lines, the phosphorylation of HIF-1alpha is dependent on ERK or p38, two members of the mitogen-activated protein kinase (MAPK) superfamily. In addition, active MAPK could be inactivated through dephosphorylation by mitogen-activated protein kinase phosphatase-1 (MKP-1). MKP-1 has been identified as a hypoxia responsive gene, but its role in the response of cells to hypoxia is poorly understood. Here we found that hypoxia induces MKP-1 expression in human hepatoma cells HepG2 in a time-dependent manner. Inhibition of MKP-1 expression using siRNA technique could enhance HIF-1alpha phosphorylation, accompanied by an increase in transcriptionally active HIF-1 as well as a rise in the levels of HIF-1-induced erythropoietin expression.
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PMID:Suppression of the dual-specificity phosphatase MKP-1 enhances HIF-1 trans-activation and increases expression of EPO. 1468 Aug 33

Vascular endothelial growth factor (VEGF) released by osteoblasts plays an important role in angiogenesis and endochondral ossification during bone formation. In animal studies, we have reported that shock waves (SW) can promote osteogenic differentiation of mesenchymal stem cells through superoxide-mediated signal transduction (Wang, F. S., Wang, C. J., Sheen-Chen, S. M., Kuo, Y. R., Chen, R. F., and Yang, K. D. (2002) J. Biol. Chem. 277, 10931-10937) and vascularization of the bone-tendon junction. Here, we found that SW elevation of VEGF-A expression in human osteoblasts to be mediated by Ras-induced superoxide and ERK-dependent HIF-1alpha activation. SW treatment (0.16 mJ/mm(2), 1 Hz, 500 impulses) rapidly activated Ras protein (15 min) and Rac1 protein (30 min) and increased superoxide production in 30 min and VEGF mRNA expression in 6 h. Early scavenging of superoxide, but not nitric oxide, peroxide hydrogen, or prostaglandin E(2), reduced SW-augmented VEGF-A levels. Inhibition of superoxide production by diphenyliodonium, an NADPH oxidase inhibitor, was found to suppress VEGF-A expression. Transfection of osteoblasts with a dominant negative (S17N) Ras mutant abrogated the SW enhancement of Rac1 activation, superoxide synthesis, and VEGF expression. Further studies demonstrated that SW significantly promoted ERK activation in 1 h and HIF-1alpha phosphorylation and HIF-1alpha binding to VEGF promoter in 3 h. In support of the observation that superoxide mediated the SW-induced ERK activation and HIF-1alpha transactivation, we further demonstrated that scavenging of superoxide by superoxide dismutase and inhibition of ERK activity by PD98059 decreased HIF-1alpha activation and VEGF-A levels. Moreover, culture medium harvested from SW-treated osteoblasts increased vessel number of chick chorioallantoic membrane. Superoxide dismutase pretreatment and anti-VEGF-A antibody neutralization reduced the promoting effect of conditioned medium on angiogenesis. Thus, modulation of redox reaction by SW may have some positive effect on angiogenesis during bone regeneration.
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PMID:Ras induction of superoxide activates ERK-dependent angiogenic transcription factor HIF-1alpha and VEGF-A expression in shock wave-stimulated osteoblasts. 1468 Dec 37

We proposed a model in which myocardial hypoxia triggers the apoptosis-dependent remodeling of the avian outflow tract (OFT) in the transition of the embryo to a dual circulation. In this study, we examined hypoxia-dependent signaling in cardiomyocyte apoptosis and outflow tract remodeling. The hypoxia-inducible transcription factor HIF-1alpha was specifically present in the nuclei of OFT cardiomyocytes from stages 25-32, the period of hypoxia-dependent OFT remodeling. HIF-1alpha expression was sensitive to changes in ambient oxygen concentrations, while its dimerization partner HIF-1beta was constitutively expressed. There was not a simple relationship between HIF-1alpha expression and apoptosis. Apoptotic cardiomyocytes were detected in HIF-1alpha-positive and -negative regions, and a hypoxic stimulus sufficient to induce nuclear accumulation of HIF-1alpha did not induce cardiomyocyte apoptosis. The hypoxia-dependent expression of the vascular endothelial growth factor receptor (VEGFR2) in the distal OFT myocardium may be protective as cardiomyocyte apoptosis in the early stages (25-30) of OFT remodeling was absent from this region. Furthermore, recombinant adenoviral-mediated expression of dominant negative Akt, an inhibitor of tyrosine kinase receptor signaling, augmented cardiomyocyte apoptosis in the OFT and constitutively active Akt suppressed it. Adenovirus-mediated forced expression of VEGF165 induced conotruncal malformation such as double outlet right ventricle (DORV) and ventricular septal defect (VSD), similar to defects observed when apoptosis-dependent remodeling of the OFT was specifically targeted. We conclude that normal developmental remodeling of the embryonic avian cardiac OFT involves hypoxia/HIF-1-dependent signaling and cardiomyocyte apoptosis. Autocrine signaling through VEGF/VEGFR2 and Akt provides survival signals for the hypoxic OFT cardiomyocytes, and regulated VEGF signaling is required for the normal development of the OFT.
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PMID:Hypoxia-responsive signaling regulates the apoptosis-dependent remodeling of the embryonic avian cardiac outflow tract. 1532 13


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