Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: DrugBank:APRD00369 (ROS)
 19,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Osteoblast-like cells, such as UMR 106 osteosarcoma cells, are known to be growth stimulated by growth factors such as EGF. In contrast, factors such as PTH and prostaglandin E2 inhibit their growth. The exact signal transduction mechanisms by which these latter factors act remain to be elucidated. Here we show that simultaneous treatment of UMR 106 cells with EGF and PTH-(1-34) resulted in a level of DNA synthesis intermediate between the levels of treatment with epidermal growth factor (EGF) and PTH alone. This correlated with the interference of PTH-(1-34) early in an EGF receptor-linked signal transduction pathway, i.e. the EGF-induced activation of p42 mitogen-activated protein (MAP) kinase. This effect was also found for prostaglandin E2, and could be potentiated by the phosphodiesterase inhibitor isobutyl-methylxanthine and mimicked by forskolin and 8-bromo-cAMP. There was a strict correlation between the lowest concentration of PTH-(1-34) required to enhance protein kinase A (PKA) activity and that required to inhibit MAP kinase activation, whereas saturating amounts of PTH-(3-34), a PTH analog unable to elevate PKA activity, had no effect. Lysophosphatidic acid- and 12-O-tetracanoylphorbol-13-acetate-induced MAP kinase activation were also inhibited by PTH-(1-34) and forskolin in these cells. Similar effects were seen on basic fibroblast growth factor-mediated MAP kinase activation in ROS 17/2.8 cells, indicating that this mechanism is a general feature of PTH in osteosarcoma cells. The inhibition of this mitogenic pathway through activation of PKA might play an important role in PTH-induced changes in proliferation and differentiation of osteoblasts.
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PMID:Parathyroid hormone inhibits mitogen-activated protein kinase activation in osteosarcoma cells via a protein kinase A-dependent pathway. 762 68

We examined the effect of estrogen on mitogen-activated protein kinase (MAPK) in osteoblastic cells. Rat ROS 17/2.8 cells were exposed to 17beta-estradiol (E2) and MAPK activity in the cells was measured by an in vitro phosphorylation assay. E2 treatment caused a rapid and transient MAPK activation within 5 min. Insulin-like growth factor-I, which acts via their membrane receptors, caused a similar effect, but it required 10 min to reach the maximum level. Western blot analyses with anti-MAPK and anti-phosphotyrosine antibodies demonstrated that the E2 activation of MAPK was accompanied by phosphorylation of the enzyme. The concentration range (10 nM-1 pM) of E2 needed for this MAPK activation was less than that (1 microM-0.1 nM) needed for the transcriptional activation via the nuclear estrogen receptor (ER). These data provide the first evidence of MAPK activation by E2 through phosphorylation, which may be mediated through a putative plasma membrane receptor in the cultured bone cells.
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PMID:Rapid activation of MAP kinase by estrogen in the bone cell line. 919 43

Interstitial collagenases participate in the remodeling of skeletal matrix and are regulated by fibroblast growth factor (FGF). A 0.2-kb fragment of the proximal human interstitial collagenase [matrix metalloproteinase (MMP1)] promoter conveys 4- to 8-fold induction of a luciferase reporter in response to FGF2 in MC3T3-E1 osteoblasts. By 5'-deletion, this response maps to nucleotides -100 to -50 relative to the transcription initiation site. The 63- bp MMP1 promoter fragment -123 to -61 confers this FGF2 response on the rous sarcoma virus minimal promoter. Intact Ets and AP1 cognates in this element are both required for responsiveness. The AP1 site supports basal and FGF-inducible promoter activity. The intact Ets cognate represses basal transcriptional activity in both heterologous and native promoter contexts and is also required for FGF activation. FGF2 up-regulates a DNA-binding activity that recognizes the MMP1 AP1 cognate and contains immunoreactive Fra1 and c-Jun. Both constitutive and FGF-inducible DNA-binding activities are present in MC3T3-E1 cells that recognize the MMP1 Ets cognate; prototypic Ets transcriptional activators are not present in these complexes. Inhibitors of protein kinase C, phosphatidyl inositol 3-OH kinase, and calmodulin-dependent protein kinase do not attenuate MMP1 promoter activation. FGF2 activates ERK1/ERK2 signaling in osteoblasts; however, 25 microM MAPK-ERK kinase (MEK) inhibitor PD98059 (inhibits by > 85% the phosphorylation of ERK1/ERK2) has no effect on MMP1 promoter activation by FGF2. Ligand-activated and constitutively active FGF receptors initiate MMP1 induction. Dominant negative Ras abrogates MMP1 induction by constitutively active FGFR2-ROS, but dominant negative Rho and Rac do not inhibit induction. The mitogen-activated protein kinase (MAPK) phosphatase MKP2 [inactivates extracellular regulated kinase (ERK) = Jun N-terminal kinase (JNK) > p38 MAPK] completely abrogates MMP1 activation, whereas PAC1 (inactivates ERK = p38 > JNK) attenuates but does not completely prevent induction. Thus, a Ras- and MKP2-regulated MAPK pathway, independent of ERK1/ERK2 MAPK activity, mediates FGF2 transcriptional activation of MMP1 in MC3T3-E1 osteoblasts, converging upon the bipartite Ets-AP1 element. The DNA-protein interactions and signal cascades mediating FGF induction of the MMP1 promoter are distinct from two other recently described FGF response elements: the MMP1 promoter (-123 to -61) represents a third FGF-activated transcriptional unit.
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PMID:Fibroblast growth factor receptor signaling activates the human interstitial collagenase promoter via the bipartite Ets-AP1 element. 921 60

We recently demonstrated that basic fibroblast growth factor (FGF-2) and platelet-derived growth factor-BB (PDGF-BB) mainly activated extracellular signal-regulated kinase 2 (ERK2) in normal human osteoblastic (HOB) and bone marrow stromal (HBMS) cells by an "in-gel" MAP kinase assay, although both ERK1 and ERK2 proteins were present. In the present study, we examined whether ERK1 is also activated by growth factors by using three different MAPK assay procedures, an "in-gel MAP kinase assay," an immune-complex kinase assay, and western blotting with anti-active MAPK antibody which recognizes specifically activated forms of both ERK1 and ERK2. Results have demonstrated that in addition to ERK2, ERK1 is activated by FGF-2 and PDGF-BB in normal HOB and HBMS cells. The human ERK1 moved faster on SDS-polyacrylamide gel compared to rat and mouse, revealing differences in the apparent molecular weight of FRK1 in normal human osteoblastic and bone marrow osteoprogenitor cells, human (TE-85) and rat (ROS 17/2.8 and UMR-106) osteosarcoma, and mouse (MC3T3E1) osteoblastic cells. ERK1 is less stable in the in-gel renaturation process compared to ERK2; thus, in-gel MAP kinase assay does not provide an accurate estimation of ERK1 activity. Results also showed that anti-active MAPK antibody can be used reliably and accurately to measure the activation of ERK1 and ERK2 in osteoblastic cells.
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PMID:Activation of extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) by FGF-2 and PDGF-BB in normal human osteoblastic and bone marrow stromal cells: differences in mobility and in-gel renaturation of ERK1 in human, rat, and mouse osteoblastic cells. 929 66

The mitogen-activated protein (MAP) kinases (p44mapk and p42mapk), also known as extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), are activated in response to a variety of extracellular signals, including growth factors, hormones and, neurotransmitters. We have investigated MAP kinase signal transduction pathways in normal human osteoblastic cells. Normal human bone marrow stromal (HBMS), osteoblastic (HOB), and human (TE85, MG-63, SaOS-2), rat (ROS 17/2.8, UMR-106) and mouse (MC3T3-E1) osteoblastic cell lines contained immunodetectable p44mapk/ERK1 and p42mapk/ERK2. MAP kinase activity was measured by 'in-gel' assay using myelin basic protein as the substrate. Mainly ERK2 was rapidly activated (within 10 min) by bFGF, IGF-I and PDGF-BB in normal HOB, HBMS and human osteosarcoma cells, whereas both ERK1 and ERK2 were activated by growth factors in rat osteoblast-like cell lines, ROS 17/2.8 and UMR-106. The ERK1 activation was greater than the ERK2 in ROS 17/2.8 cells. Furthermore, ERK2 was also activated by bFGF and PDGF-BB in the mouse osteoblastic cell line, MC3T3-E1. This is the first demonstration of inter-species differences in the activation of MAP kinases in osteoblastic cells. Cyclic AMP derivatives or cAMP generating agents such as PTH and forskolin inhibited ERK2 activation by bFGF and PDGF-BB suggesting a 'cross-talk' between the two different signalling pathways activated by receptor tyrosine kinases and cAMP-dependent protein kinase. The accumulated results also suggest that the MAP kinases may be involved in mediating mitogenic and other biological actions of bFGF, IGF-I and PDGF-BB in normal human osteoblastic and bone marrow stromal cells.
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PMID:Identification and activation of mitogen-activated protein (MAP) kinase in normal human osteoblastic and bone marrow stromal cells: attenuation of MAP kinase activation by cAMP, parathyroid hormone and forskolin. 954 82

The hormone 1alpha,25(OH)2vitamin D3 (1,25-D) produces biological responses via both genomic and rapid mechanisms. The genomic responses are linked to a nuclear receptor, while the rapid responses are believed to utilize other signal transduction pathways that are likely linked to a putative cell membrane receptor for 1,25-D. The natural seco-steroid, 1,25-D, is capable of facile rotation about its 6,7 single carbon bond to permit generation of a continuum of potential ligand shapes extending from the 6-s-cis (6C) to the 6-s-trans (6T). To identify the shape of the conformer(s) that can serve as agonists for the genomic and rapid responses, we synthesized two families of analogs that were locked in either the 6T or 6C conformation. We found that 6T-locked analogs were inactive or significantly less active than 1,25-D in both rapid responses (transcaltachia or the rapid stimulation of intestinal Ca2+ absorption in perfused chick intestine, stimulation of whole cell chloride currents in osteoblastic ROS 17/2.8 cells, and stimulation of phosphorylation of mitogen-activated protein kinase in promyelocytic NB4 leukemic cells) and in genomic responses (induction of osteocalcin in human MG-63 osteoblastic cells). For genomic responses, the 6C-locked analogs bound poorly to the nuclear receptor and were much less potent than 1,25-D. In contrast, the 6C-locked analogs were potent agonists of the three rapid responses studied and had activities equivalent to 1,25-D. These results demonstrate that the signal transduction pathways that support rapid and genomic responses can discriminate between different shapes of the conformationally flexible 1,25-D.
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PMID:Rapid and genomic biological responses are mediated by different shapes of the agonist steroid hormone, 1alpha,25(OH)2vitamin D3. 1032 80

Transforming growth factor beta (TGFbeta) family members are known for their important role in bone physiology. TGFbeta(1) and, to a smaller extent, bone morphogenetic protein 2 (BMP-2) have been reported to regulate the gene expression of different osteoblast markers in vitro. However, little is known about the molecular mechanisms involved in these actions. Here we report that BMP-2, like TGFbeta(1), up-regulated alpha1(I) collagen mRNA expression in ROS 17/2.8 osteoblastic cells. This was mediated through an increase in the transcriptional rate of the gene rather than through the stabilization of alpha1(I) collagen mRNA, and required new protein synthesis. In addition, TGFbeta(1)- and BMP-2-induced increases in alpha1(I) collagen mRNA levels were both dependent on protein kinase C and protein tyrosine kinase activities. Furthermore, the mitogen-activated protein kinase (MAPK) [MAPK/extracellular signal-regulated protein kinase kinase 1/extracellular signal-regulated protein kinase (MEK-1/ERK)] pathway participated in the up-regulation of alpha1(I) collagen gene expression by TGFbeta(1) and BMP-2. In response to either TGFbeta(1) or BMP-2, the stimulation of alpha1(I) collagen mRNA levels was paralleled by an early increase in extracellular signal-regulated kinase protein activity. Moreover, the effects of both TGFbeta(1) and BMP-2 on alpha1(I) collagen gene expression were markedly decreased in transfected ROS 17/2.8 cells expressing a dominant-negative MEK-1. Our findings therefore show that TGFbeta(1) and BMP-2, which signal through discrete cell-surface receptors, are able to trigger analogous, if not identical, protein-phosphorylation-transducing cascades leading to comparable actions on the transcription of the alpha1(I) collagen gene in osteoblastic cells.
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PMID:Protein kinase signalling pathways involved in the up-regulation of the rat alpha1(I) collagen gene by transforming growth factor beta1 and bone morphogenetic protein 2 in osteoblastic cells. 1049 7

Multiple enzymes may stimulate ROS production in VSMC and endothelial cells. These include NADH/NADPH oxidase, xanthine oxidase, lipoxygenases, cyclooxygenase, P-450 monooxygenases, and the enzymes of mitochondrial oxidative phosphorylation. In addition to generation of intracellular O2- by these enzymes, extracellular stimuli including lipophilic substrates, membrane permeant oxidants (e.g., H2O2), cytokines, and growth factors may modulate cellular redox state. Both intracellular and extracellular ROS act as second-messengers to activate tyrosine and serine-threonine kinases, such as the MAP kinase family. As discussed in the previous sections, regulation of the MAP kinases is one example of the complexity of ROS-dependent signal transduction. Although the complexity of ROS-mediated signal transduction is daunting, the diversity offers multiple therapeutic targets for pharmacologic intervention.
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PMID:Redox signals that regulate the vascular response to injury. 1060 87

Although the acceleration of bone regeneration by radiation has been reported, the mechanisms of action of radiation on bone are unclear. The present results indicate that ionizing radiation-stimulated differentiation could result from the generation of reactive oxygen species during radiation exposure. The free radical release is considered as the most important mechanism of bone effect by radiation treatment. In addition, we report that radiation induced transient activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activation and the transcription factor, AP-1. The JNK and AP-1 activation is mediated with radiation-released free radicals in ROS 17/2.8 osteoblasts. These results indicate that ionizing radiation at a single dose of up to 5 Gray stimulates differentiation of ROS 17/2.8 osteoblasts via free radial release which may affect JNK/SAPK and AP-1 activities.
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PMID:Effect of ionizing radiation on the differentiation of ROS 17/2.8 osteoblasts through free radicals. 1074 78

Serotonin (5-HT) stimulates mitogenesis in rat renal mesangial cells through a G protein-coupled 5-HT(2A) receptor. We tested the hypothesis that oxidants might be involved in the signal transduction pathway linking the receptor to extracellular signal-regulated protein kinase (ERK). 5-HT rapidly increased the activity and phosphorylation of ERK. These effects were blocked by the 5-HT(2A) receptor antagonist ketanserin. The peak effect was noted at 5-10 min, and half-maximal stimulation was achieved at 10-30 nM 5-HT. Chemical inhibitor and activator studies supported the involvement of phospholipase C, protein kinase C (PKC), and reactive oxygen species (ROS, i.e., H(2)O(2) and superoxide) generated by an NAD(P)H oxidase-like enzyme in the ERK activation cascade. Mapping studies supported a location for the NAD(P)H oxidase enzyme and the ROS downstream from PKC. Our studies are most consistent with an ERK activation pathway as follows: 5-HT(2A) receptor --> G(q) protein --> phospholipase C --> diacylglycerol --> classical PKC --> NAD(P)H oxidase --> superoxide --> superoxide dismutase --> H(2)O(2) --> mitogen-activated extracellular signal-regulated kinase --> ERK. These studies demonstrate a role for the 5-HT(2A) receptor in rapid, potent, and efficacious activation of ERK in rat renal mesangial cells. They support a role for oxidants in conveying the stimulatory signal from 5-HT, because 1) chemical antioxidants attenuate the 5-HT signal, 2) oxidants and 5-HT selectively activate ERK to a similar degree, 3) 5-HT produces superoxide and H(2)O(2) in these cells, and 4) a specific enzyme [NAD(P)H oxidase] has been implicated as the source of the ROS, which react selectively downstream of classical PKC.
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PMID:5-HT(2A) receptors stimulate mitogen-activated protein kinase via H(2)O(2) generation in rat renal mesangial cells. 1075 Dec 27


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