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: UNIPROT:P51812 (mitogen-activated protein)
10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor cells frequently have pronounced effects on the skeleton including bone destruction, bone pain, hypercalcemia, and depletion of bone marrow cells. Despite the serious sequelae associated with skeletal metastasis, the mechanisms by which tumor cells alter bone homeostasis remain largely unknown. In this study, we tested the hypothesis that the disruption of bone homeostasis by tumor cells is due in part to the ability of tumor cells to upregulate osteopontin (OPN) mRNA in osteoblasts. Conditioned media were collected from tumor cells that elicit either osteolytic (MCF-7, PC-3) or osteoblastic responses (LNCaP) in animal models and their effects on OPN gene expression were compared using an osteoblast precursor cell line, MC3T3-E1 cells. Secretory products from osteolytic but not osteoblastic tumor cell lines were demonstrated to upregulate OPN in osteoblasts while inhibiting osteoblast proliferation and differentiation. Signal transduction studies revealed that regulation of OPN was dependent on both protein kinase C (PKC) and the mitogen-activated protein (MAP) kinase cascade. These results suggest that the upregulation of OPN may play a key role in the development of osteolytic lesions. Furthermore, these results suggest that drugs that prevent activation of the MAP kinase pathway may be efficacious in the treatment of osteolytic metastases.
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PMID:Secretory products from PC-3 and MCF-7 tumor cell lines upregulate osteopontin in MC3T3-E1 cells. 1086 58

We examined the effect of hypoxia on proliferation and osteopontin (OPN) expression in cultured rat aortic vascular smooth muscle (VSM) cells. In addition, we determined whether hypoxia-induced increases in OPN and cell proliferation are altered under hyperglycemic conditions. Quiescent cultures of VSM cells were exposed to hypoxia (3% O(2)) or normoxia (18% O(2)) in a serum-free medium, and cell proliferation as well as the expression of OPN was assessed. Cells exposed to hypoxia for 24 h exhibited a significant increase in [(3)H]thymidine incorporation followed by a significant increase in cell number at 48 h in comparison with respective normoxic controls. Exposure to hypoxia produced significant increases in OPN protein and mRNA expression at 2 h followed by a gradual decline at 6 and 12 h, with subsequent significant increases at 24 h. Neutralizing antibodies to either OPN or its receptor beta3 integrin but not neutralizing antibodies to beta5 integrin prevented the hypoxia-induced increase in [(3)H]thymidine incorporation. Inhibitors of protein kinase C (PKC) and p38 mitogen-activated protein (MAP) kinase also reduced the hypoxia-induced stimulation of proliferation and OPN synthesis. Exposure to high-glucose (HG) (25 mmol/l) medium under normoxic conditions also resulted in significant increases in OPN protein and mRNA levels as well as the proliferation of VSM cells. Under hypoxic conditions, HG further stimulated OPN synthesis and cell proliferation in an additive fashion. In conclusion, hypoxia-induced proliferation of cultured VSM cells is mediated by the stimulation of OPN synthesis involving PKC and p38 MAP kinase. In addition, hypoxia also enhances the effect of HG conditions on both OPN and proliferation of cultured VSM cells, which may have important implications in the development of diabetic atherosclerosis associated with arterial wall hypoxia.
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PMID:Hypoxia stimulates osteopontin expression and proliferation of cultured vascular smooth muscle cells: potentiation by high glucose. 1137 51

Using spontaneously hypertensive and aortic banded rats, we have shown that expression of myocardial osteopontin, an extracellular matrix protein, coincides with the development of heart failure and is inhibited by captopril, suggesting a role for angiotensin II (ANG II). This study tested whether ANG II induces osteopontin expression in adult rat ventricular myocytes and cardiac microvascular endothelial cells (CMEC), and if so, whether induction is mediated via activation of mitogen-activated protein kinases (p42/44 MAPK) and involves reactive oxygen species (ROS). ANG II (1 microM, 16 h) increased osteopontin expression (fold increase 3.3+/-0.34, n = 12, P < 0.01) in CMEC as measured by northern analysis, but not in ARVM. ANG II stimulated osteopontin expression in CMEC in a time- (within 4 h) and concentration-dependent manner, which was prevented by the AT1 receptor antagonist, losartan. ANG II elicited robust phosphorylation of p42/44 MAPK as measured using phospho-specific antibodies, and increased superoxide production as measured by cytochrome c reduction and lucigenin chemiluminescence assays. These effects were blocked by diphenylene iodonium (DPI), an inhibitor of the flavoprotein component of NAD(P)H oxidase. PD98059, an inhibitor of p42/44 MAPK pathway, and DPI each inhibited ANG II-stimulated osteopontin expression. Northern blot analysis showed basal expression of p22phox, a critical component of NADH/NADPH oxidase system, which was increased 40-60% by exposure to ANG II. These results suggest that p42/44 MAPK is a critical component of the ROS-sensitive signaling pathways activated by ANG II in CMEC and plays a key role in the regulation of osteopontin gene expression. Published 2001 Wiley-Liss, Inc.
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PMID:Regulation of angiotensin II-stimulated osteopontin expression in cardiac microvascular endothelial cells: role of p42/44 mitogen-activated protein kinase and reactive oxygen species. 1138 29

Previous work shows that osteopontin has a role during matrix reorganization after tissue injury including vascular conditions such as atherosclerosis and restenosis following angioplasty. In vitro, osteopontin promotes activities such as adhesion and migration but the mechanisms that regulate the expression of this matrix protein remain essentially unknown. This study examined if the ERK signaling pathway is involved in injury-induced osteopontin expression in cultured rat aortic smooth muscle cells. Northern and Western blotting demonstrated a marked activation of osteopontin expression in response to injury. Treating the cells with PD98059, a specific MEK1 inhibitor, prior to injury, blocked this upregulation. MEK1 phosphorylates ERK1/ERK2, which belong to the family of mitogen-activated protein kinases. We conclude that ERK1/ERK2 are involved in the regulation of osteopontin expression in cultured vascular smooth muscle cells.
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PMID:Injury-induced osteopontin gene expression in rat arterial smooth muscle cells is dependent on mitogen-activated protein kinases ERK1/ERK2. 1171 72

Many factors have been shown to be involved in the development of hyperplasic lesions of vessels, but the role of extracellular nucleotides remains largely unknown. The presence of P2Y and P2X nucleotide receptors on arterial endothelial and smooth muscle cells suggests a potential role for nucleotides in the vessel pathophysiology. Although the role of P2X in physiology of vessels is well documented, that of P2Y is not completely understood. We recently demonstrated that extracellular nucleotides, and particularly UTP, induced migration of cultured arterial smooth muscle cells (ASMCs). This migration is dependent on osteopontin expression and involves the Rho and mitogen-activated protein (MAP) kinase pathways. An important question is to determine the specific role of the different P2Y receptors of rat ASMCs in the UTP-induced migration process. Therefore, we first quantified mRNA levels of P2Y(2), P2Y(4), and P2Y(6) nucleotide receptors in cultured rat ASMCs by a competitive RT-PCR approach and demonstrated that P2Y(2) is the most highly expressed among these receptors potentially involved in the UTP-mediated response. In addition to UTP, UDP also induced ASMC migration even when UTP regeneration was inhibited, suggesting the involvement of UDP receptor P2Y(6). Moreover, suramin, a specific antagonist of rat P2Y(2) receptor, acted as an inhibitor of UTP-induced migration. Taken together, these results suggest a prominent role for the UTP receptor, P2Y(2), and for the UDP receptor, P2Y(6), in UTP-induced rat ASMC migration.
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PMID:Nucleotide receptors involved in UTP-induced rat arterial smooth muscle cell migration. 1193 35

The hydrophobicity of biomaterials has been recognized as a limitation to the adequate function of anchorage-dependent cells when hydrophobic biomaterials are used for tissue engineering. This is due to flawed solid-state signals from cell adhesion. In this study, a recombinant osteopontin (rOPN17-169) fragment containing the cell adhesion motifs was expressed in E. coli and was precoated on the hydrophobic surface prior to osteoblastic MG63 cell culture. Precoating the hydrophobic surface with rOPN17-169 improved osteoblastic cell adhesion, which was blocked by soluble RGDS. The adhesion of MG63 cells to rOPN17-169 pre-coated surface-activated mitogen-activated protein kinases (MAPK) such as extracellular signal-receptor kinase 1/2, p38, and c-Jun N-terminal kinase (JNK). In addition, p38 MAPK was activated in response to a soluble factor of transforming growth factor-beta in the cells adhered to the hydrophobic surface via rOPN17-169. This suggests that rOPN17-169 precoated on the hydrophobic surface can allow osteoblastic cells to generate adhesion signals sufficient for cell adhesion, MAPK activation, and the cytokine activation of osteoblastic cells.
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PMID:MG63 osteoblastic cell adhesion to the hydrophobic surface precoated with recombinant osteopontin fragments. 1250 28

Osteopontin (OPN), also called cytokine Eta-1, expressed in the myocardium co-incident with heart failure plays an important role in post myocardial infarction (MI) remodeling by promoting collagen synthesis and accumulation. Angiotensin II (Ang II) and inflammatory cytokines are increased in the heart following MI. We studied the involvement of mitogen-activated protein kinases (ERK1/2, JNKs, p38 kinase) and reactive oxygen species (ROS) in Ang II- and cytokine-induced OPN gene expression in adult rat cardiac fibroblasts. Ang II alone increased OPN mRNA (3.3 +/- 0.3-folds; P < 0.05; n = 7), while interleukin-1beta (IL-1beta), tumor necrosis factor (TNF-alpha), and interferon-gamma (IFN-gamma) had no effect. A combination of Ang II with IL-1beta or TNF-alpha, not IFN-gamma, increased OPN mRNA more than Ang II alone. Nitric oxide donor, S-nitrosoacetylpenicillamine (SNAP), alone or in combination with Ang II had no effect. Diphenylene iodonium (DPI), inhibitor of NAD(P)H oxidase, and tiron, superoxide scavenger, inhibited Ang II- and Ang II+ IL-1beta-stimulated increases in OPN mRNA. Ang II activated ERK1/2 within 5 min of treatment, not JNKs. IL-1beta activated ERK1/2 and JNKs within 15 min of treatment. A combination of Ang II and IL-1beta activated ERK1/2 within 5 min of treatment. None of these stimuli activated p38 kinase. DPI almost completely inhibited Ang II + IL-1beta-stimulated activation of ERK1/2, while partially inhibiting JNKs. PD98059, ERK1/2 pathway inhibitor, and SP600125, JNKs inhibitor, partially inhibited Ang II + IL-1beta-stimulated increases in OPN mRNA. A combination of PD98059 and SP600125 almost completely inhibited Ang II + IL-1beta-stimulated increases in OPN mRNA. Thus, Ang II alone increases OPN expression, while IL-1beta and TNF-alpha act synergistically with Ang II to increase OPN mRNA possibly via NO independent mechanisms. The synergistic increase in OPN mRNA involves ROS-mediated activation of ERK1/2 and JNKs, not P38 kinase, pathways in cardiac fibroblasts.
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PMID:ERK1/2 and JNKs, but not p38 kinase, are involved in reactive oxygen species-mediated induction of osteopontin gene expression by angiotensin II and interleukin-1beta in adult rat cardiac fibroblasts. 1475 45

We investigated the effects of oscillatory flow in regulating the gene expressions of type I collagen (COL1, the main component of human bone tissues) and osteopontin (OPN, the key gene for calcium deposition) in human osteoblast-like (MG-63) cells, and the roles of mitogen-activated protein kinases (MAPKs) in this regulation. The cells were subjected to oscillatory flow (0.5 +/- 4 dyn/cm(2)) or kept under static condition for various time periods (15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 16 h). Oscillatory flow caused significant up-regulations of both COL1 and OPN gene expressions over the 16 h of study, and a transient activation of MAPKs was starting at 15 min and declining to basal level in 2 h. The flow-induction of COL1 was blocked by an ERK inhibitor (PD98059) and reduced by a JNK inhibitor (SP600125), whereas that of OPN was abolished by PD98059. Analysis of the cis-elements in the COL1 and OPN promoters suggests the involvement of transacting factors Elk-1 and AP-1 in the transcription regulation. The ERK inhibitor (PD98059) blocked Elk-1 phosphorylation, as well as COL1 and OPN gene expression. The JNK inhibitor (SP600125) abolished c-jun phosphorylation and COL1 expression. These results suggest that the flow-induction of OPN was mediated through the ERK-Elk1-OPN pathway, and that COL1 was regulated by both the ERK-Elk1-COL1 and JNK-c-JUN-COL1 pathway.
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PMID:Roles of MAP kinases in the regulation of bone matrix gene expressions in human osteoblasts by oscillatory fluid flow. 1644 Mar 9

Localized acidification of the osteoclast-bone interface is driven by a vacuolar-type H+-ATPase (V-ATPase) in the plasma membrane in a process thought to be associated with bone resorption. The present study investigated the mechanism underlying the roles of V-ATPase-induced acidosis in osteoclastogenesis. Active proton pumping due to increased V-ATPase activity during RANKL-induced osteoclastogenesis induced intracellular and extracellular acidification of osteoclast precursors. Subsequent analysis revealed blockage of extracellular acidification and induction of intracellular acidification by bafilomycin A1, a specific inhibitor of V-ATPase, indicating that extracellular acidification is mostly induced by V-ATPase-mediated proton pumping into extracellular space. Low-pH media controlled by HEPES-buffered conditions to mimic metabolic acidosis led to synergistic activation of RANKL-stimulated signals, including mitogen-activated protein kinases and transcription factor NF-kappaB, resulting in enhanced osteoclastogenesis. Low-pH media also upregulated the expression of osteopontin secreted into extracellular space, which is required for cell migration by binding to cell surface integrin alphavbeta3. Osteoclast precursor migration was significantly inhibited by treatment of antibodies to integrin alphavbeta3, resulting in the retardation of osteoclastogenesis. Taken together, these findings indicate that V-ATPase-driven acidosis modulates osteoclastogenesis.
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PMID:Vacuolar-type H+-ATPase-mediated acidosis promotes in vitro osteoclastogenesis via modulation of cell migration. 1727 86

Recently, natural products have gained more interest as alternative treatments for metabolic bone disorders and for the maintenance of bone health. In this study, the anabolic activities of 89 natural compounds were evaluated by measuring the amount of newly synthesized calcium in the differentiation process of mouse osteoblastic MC3T3-E1 subclone 4 cells. Of these compounds, a low concentration (up to 5 microm) of 3-carene, which is a bicyclic monoterpene in essential oils extracted from pine trees, was shown to stimulate significantly the activity and expression of alkaline phosphatase, an early phase marker of osteoblastic differentiation, on differentiation day 9. On day 15, it dramatically promoted the induction of calcium in a dose-dependent manner. The stimulatory effect of 3-carene on mineralization might be associated with its potential to induce the protein expression/activation of the mitogen-activated protein kinases and the transcript levels of osteoblast mineralization-related genes such as osteopontin and type I collagen. Further studies are needed to determine the precise mechanism, but the anabolic activity of 3-carene in bone metabolism suggested that the use of natural additives to the diet including essential oils could have a beneficial effect on bone health.
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PMID:Low concentration of 3-carene stimulates the differentiation of mouse osteoblastic MC3T3-E1 subclone 4 cells. 1768 87


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