Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arsenic produces a variety of stress responses in mammalian cells, including metabolic abnormalities accompanied by growth inhibition and eventually apoptosis. Morphological alterations in cells exposed to arsenic often suggest underlying disruption of cytoskeletal structural elements responsible for cellular integrity, shape, and locomotion. However, specifics of the ultrastructural changes produced by arsenic remain poorly understood. Various tissues and organs differ in their sensitivity to arsenic, with the liver and skin being the most studied. Characteristic skin pathology related to arsenic exposure ranges from hyperkeratotic lesions to squamous-cell carcinomas. However, molecular events in the arsenic-exposed skin still remain to be elucidated. Although mutagenicity of arsenic has not been unequivocally established, recent evidence supports the view that oncogenic mutations do occur, and that only selected enzymes related to DNA replication and repair are affected by arsenic. Sensitivity of the mitotic spindle to arsenic, particularly its organic compounds, underlies the well-documented chromosomal aberrations in arsenic-exposed populations. Arsenite-induced stress at the molecular level shares many features with the heat shock response. This includes the differential sensitivity of the stress signal pathway elements to the magnitude of the stress, stressor-specific activation of the response elements, and the protective role of the heat shock response. Oxidative stress, the central component of heat shock response, is typical of arsenic-related effects that are, in fact, regarded as the chemical paradigm of heat stress. Similar to heat stress, arsenite induces heat shock proteins (HSPs) of various sizes. The signal cascade triggered by arsenite-like heat stress induces the activity of the mitogen-activated protein (MAP) kinases, extracellular regulated kinase (ERK), c-jun terminal kinase (JNK), and p38. Through the JNK and p38 pathways, arsenite activates the immediate early genes c-fos, c-jun, and egr-1, usually activated by various growth factors, cytokines, differentiation signals, and DNA-damaging agents. Like other oxygen radical-producing stressors, arsenic induces nitric oxide production at the level of transcriptional activation along with induction of poly(ADP)-ribosylation, NAD depletion, DNA strand breaks, and formation of micronuclei. This review presents an overview of current research on molecular aspects of arsenic stress with an emphasis on the tissue-specific events in humans. It deals with current progress on the understanding of the signal transduction pathways and mechanisms underlying the sensitivity of various species, organs, and tissues to arsenic.
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PMID:Molecular aspects of arsenic stress. 1105 8

For understanding the mechanism(s) relating inflammation to corticosteroid action, the effect of tumour necrosis factor-alpha (TNF-alpha) on 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the enzyme regulating access of 11beta-hydroxycorticosteroids to receptors, was studied in LLC-PK(1) cells. We observed (i) NAD-dependent enzyme activity and mRNA for 11beta-HSD2, but not 11beta-HSD1, (ii) increasing 11beta-HSD2 activity with increasing degree of differentiation and (iii) a concentration-dependent down-regulation by TNF-alpha, phorbol myristate acetate (PMA) or glucose of activity and mRNA of 11beta-HSD2. The decrease of activity and mRNA by glucose and PMA, but not that by TNF-alpha, was abrogated by the protein kinase C inhibitor GF-109203X. The effect of TNF-alpha on 11beta-HSD2 was reversed by inhibiting the mitogen-activated protein kinases ERK with PD-098050 and p38 by SB-202190, or by activating protein kinase A with forskolin. Overexpression of MEK1, an ERK activator, down-regulated the 11beta-HSD2 activity. In conclusion, TNF-alpha decreases 11beta-HSD2 activity and thereby enhances glucocorticoid access to glucocorticoid receptors to modulate the inflammatory response.
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PMID:TNF-alpha enhances intracellular glucocorticoid availability. 1169 70

Benzo(a)pyrene (BP) is a polyaromatic hydrocarbon generated from the combustion of fossil fuel. Human exposure results primarily through dietary sources and smoking. Little is known about the effect of BP on mitogen-activated protein (MAP) kinases, which include extracellular signal-related kinase (ERK), Jun N-terminal kinase (JNK), and p38. We investigated the participation of BP-induced MAP kinase activation in cell growth and increases in activity of the detoxification enzyme NAD(P)H:quinone reductase (QR). In HT29 human colon carcinoma cells, 10 nM BP activated ERK and p38 but not JNK after 24 h. Treatment with 10 nM BP increased QR activity within 24 h and tritiated thymidine ([(3)H]thyd) incorporation after 48 h and reduced cell viability after 72 h. Using the MAP kinase inhibitors PD98059 and SB203580, we investigated the relative contributions of ERK and p38 to QR activity and [(3)H]thyd cell incorporation. Inhibition of ERK eliminated BP-induced QR activity, whereas inhibition of p38 had no effect on QR activity. Treatment of cells with 10 nM BP increased [(3)H]thyd incorporation by 50% after 48 h. This increase was eliminated by ERK but not p38 inhibition. In conclusion, 10 nM BP activates ERK and p38, but only ERK contributes to BP-induced QR activity. ERK, but not p38 activation participated in [(3)H]thyd incorporation. In summary, BP influences cellular signaling pathways at concentrations present in routine human exposures.
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PMID:Benzo(a)pyrene activates extracellular signal-related and p38 mitogen-activated protein kinases in HT29 colon adenocarcinoma cells: involvement in NAD(P)H:quinone reductase activity and cell proliferation. 1238 7

Activation of vascular NAD(P)H oxidases and the production of reactive oxygen species (ROS) by these enzyme systems are common in cardiovascular disease. In the past several years, a new family of NAD(P)H oxidase subunits, known as the non-phagocytic NAD(P)H oxidase (NOX) proteins, have been discovered and shown to play a role in vascular tissues. Recent studies make clearer the mechanisms of activation of the endothelial and vascular smooth muscle NAD(P)H oxidases. ROS produced following angiotensin II-mediated stimulation of NAD(P)H oxidases signal through pathways such as mitogen-activated protein kinases, tyrosine kinases and transcription factors, and lead to events such as inflammation, hypertrophy, remodeling and angiogenesis. Studies in mice that are deficient in p47(phox) and gp91(phox) (also known as NOX2) NAD(P)H oxidase subunits show that ROS produced by these oxidases contribute to cardiovascular diseases including atherosclerosis and hypertension. Recently, efforts have been devoted to developing inhibitors of NAD(P)H oxidases that will provide useful experimental tools and might have therapeutic potential in the treatment of human diseases.
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PMID:The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. 1296 72

Reactive oxygen species (ROS) are important signaling molecules in the vasculature. However, when there is imbalance between their occurrence and antioxidant defense mechanisms, ROS can contribute to the vascular abnormalities that lead to hypertension. Evidence accumulated in the last decade strongly supports the notion that ROS are generated in the vasculature mainly by NAD(P)H oxidase in a mechanism that is angiotensin II-dependent. Activation of this enzyme leads to superoxide production and uncouples endothedial NO synthase (eNOS), which sustains oxidative stress while increasing the levels of tissue-damaging peroxynitrite. The latter can result in vascular dysfunction. NAD(P)H-dependent ROS formation, in particular H(2)O(2), could also contribute to vascular injury by sustaining NAD(P)H oxidase activation, promoting inflammatory gene expression, extracellular matrix reorganization, and growth (hypertrophy/hyperplasia) of vascular smooth muscle cells. The effect of ROS appears to be mediated by redox-sensitive targets such as tyrosine kinases and phosphatases, mitogen-activated protein kinases, transcription factors, matrix metalloproteinases, peroxisome proliferator activated receptor-alpha, poly(ADP-ribose)polymerase-1, Ca(2+) signaling mechanisms and secreted factors such as cyclophilin A and heat shock protein 90-alpha. Redox-sensitive targets appear to play a central role in normal vascular function, but can also lead to remodeling of the vascular wall, increasing vascular reactivity and hypertension. Polymorphisms in the p22phox gene promoter could determine susceptibility to NAD(P)H-mediated oxidative stress in humans and animals with hypertension. Although ROS are strongly implicated in the etiology of hypertension, clinical trials with antioxidants are inconclusive regarding their effectiveness in treating the disease. New drugs with both antihypertensive action and antioxidant properties (Celiprolol, Carvedilol) offer promising results in the management of hypertension.
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PMID:Oxidative-nitrosative stress in hypertension. 1602 20

One of the most prominent strategies of cancer chemoprevention might be protecting cells or tissues against various carcinogens and carcinogenic metabolites derived from exogenous or endogenous sources. This protection could be achieved through the induction of phase 2 detoxifying enzymes and antioxidant enzymes such as glutathione S-transferase, NAD(P)H quinone oxidoreductase 1, and heme oxygenase-1, a process that is mediated mainly by the antioxidant response elements (ARE) within the promoter regions of these genes. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a member of the Cap 'n' collar (CNC) family of basic region-leucine zipper transcription factors, plays a key role in ARE-mediated gene expression. Under normal condition, Nrf2 is sequestered in the cytoplasm by an actin-binding protein, Kelch-like ECH associating protein 1 (Keap1), and upon exposure of cells to inducers such as oxidative stress and certain chemopreventive agents, Nrf2 dissociates from Keap1, translocates to the nucleus, binds to AREs, and transactivates phase 2 detoxifying and antioxidant genes. Several upstream signaling pathways including mitogen-activated protein kinases, protein kinase C, phosphatidylinositol 3-kinase, and transmembrane kinase are implicated in the regulation of Nrf2/ARE activity. Furthermore, many natural chemopreventive agents are known to induce Nrf2/ARE-dependent gene expression, also in part by regulating the turnover of the Nrf2 protein itself. This review discusses our current understanding of the Nrf2/ARE pathway as a potential molecular target for cancer chemoprevention, as well as the feasibility of screening natural compounds for activation of this pathway and as potential cancer preventive agents for human use.
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PMID:Nrf2: a potential molecular target for cancer chemoprevention by natural compounds. 1648 42

Yeast Sir2 plays critical roles in gene silencing, stress resistance and longevity. Mammalian Sirt1 NAD(+)-dependent protein deacetylase, the closest homolog of Sir2, regulates cell cycle, cellular senescence, apoptosis and metabolism, by functional interactions with a number of biological molecules such as p53. To investigate a role of Sirt1 in endothelial dysfunction and premature senescence, we examined the effects of Sirt1 inhibition in human umbilical vein endothelial cells (HUVEC). Sirt1 inhibition by sirtinol, which is a 2-hydroxy-1-napthaldehyde derivative, or siRNA for Sirt1-induced premature senescence-like phenotype, as judged by increased senescence-associated beta-galactosidase (SA-beta-gal) activity, sustained growth arrest and enlarged and flattened cell morphology at 10 days after the treatment. Sixty-four percent of sirtinol (60 mumol/L)-treated HUVEC was SA-beta-gal-positive, whereas only 17% of vehicle-treated cells were positive. Sirt1 inhibition by sirtinol or Sirt1 siRNA increased PAI-1 expression and decreased both protein expression and activity of eNOS. Treatment with sirtinol or Sirt1 siRNA increased acetylation of p53, while p53 expression was unaltered. Impaired epidermal growth factor-induced activation of mitogen-activated protein kinases was associated with Sirt1 inhibition-induced senescence-like growth arrest. Conversely, overexpression of Sirt1 prevented hydrogen peroxide-induced SA-beta-gal activity, morphological changes and deranged expression of PAI-1 and eNOS. These results showed that Sirt1 inhibition increased p53 acetylation and induced premature senescence-like phenotype in parallel with increased PAI-1 and decreased eNOS expression. Our data suggest that Sirt1 may exert protective effects against endothelial dysfunction by preventing stress-induced premature senescence and deranged expression of PAI-1 and eNOS.
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PMID:Sirt1 modulates premature senescence-like phenotype in human endothelial cells. 1791 62

Improving endothelial nitric oxide synthase (eNOS) bioactivity and endothelial function is important to limit native, vein graft, and transplant atherosclerosis. Visfatin, a NAD biosynthetic enzyme, regulates the activity of the cellular survival factor, Sirt1. We hypothesized that visfatin may improve eNOS expression, endothelial function, and postnatal angiogenesis. In human umbilical vein (HUVEC) and coronary artery endothelial cells, we evaluated the effects of recombinant human visfatin on eNOS protein and transcript expression and mRNA stability, in the presence and absence of visfatin RNA silencing. We also assessed visfatin-induced protein kinase B (Akt) activation and its association with src-tyrosine kinases, phosphorylation of Ser(1177) within eNOS in the presence and absence of phosphatidylinositol 3-kinase (PI 3-kinase) inhibition with LY-294002, and evaluated the contributory role of extracellular signal-regulated kinase 1/2. Finally, we determined the impact of visfatin on HUVEC migration, proliferation, inflammation-induced permeability, and in vivo angiogenesis. Visfatin (100 ng/ml) upregulated and stabilized eNOS mRNA and increased the production of nitric oxide and cGMP. Visfatin-treated HUVEC demonstrated greater proliferation, migration, and capillary-like tube formation but less tumor necrosis factor-alpha-induced permeability; these effects were decreased in visfatin gene-silenced cells. Visfatin increased total Akt and Ser(473)-phospho-Akt expression with concomitant rises in eNOS phosphorylation at Ser(1177); these effects were blocked by LY-2940002. Studies with PP2 showed that the nonreceptor tyrosine kinase, src, is an upstream stimulator of the PI 3-kinase-Akt pathway. Visfatin also activated mitogen-activated protein (MAP) kinase through PI 3-kinase, and mitogen/extracellular signal-regulated kinase inhibition attenuated visfatin-elicited Akt and eNOS phosphorylation. Visfatin-filled Matrigel implants showed an elevated number of infiltrating vessels, and visfatin treatment produced significant recovery of limb perfusion following hindlimb ischemia. These results indicate a novel effect of visfatin to stimulate eNOS expression and function in endothelial cells, via a common upstream, src-mediated signaling cascade, which leads to activation of Akt and MAP kinases. Visfatin represents a translational target to limit endothelial dysfunction, native, vein graft and transplant atherosclerosis, and improve postnatal angiogenesis.
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PMID:Visfatin activates eNOS via Akt and MAP kinases and improves endothelial cell function and angiogenesis in vitro and in vivo: translational implications for atherosclerosis. 1935 6

Hypertension is associated with vascular changes characterised by remodelling, endothelial dysfunction and hyperreactivity. Cellular processes underlying these perturbations include altered vascular smooth muscle cell growth and apoptosis, fibrosis, hypercontractility and calcification. Inflammation, associated with macrophage infiltration and increased expression of redox-sensitive pro-inflammatory genes, also contributes to vascular remodelling. Many of these features occur with ageing, and the vascular phenotype in hypertension is considered a phenomenon of 'premature vascular ageing'. Among the many factors involved in the hypertensive vascular phenotype, angiotensin II (Ang II) is especially important. Ang II, previously thought to be the sole effector of the renin-angiotensin system (RAS), is converted to smaller peptides [Ang III, Ang IV, Ang-(1-7)] that are biologically active in the vascular system. Another new component of the RAS is the (pro)renin receptor, which signals through Ang-II-independent mechanisms and might influence vascular function. Ang II mediates effects through complex signalling pathways on binding to its G-protein-coupled receptors (GPCRs) AT1R and AT2R. These receptors are regulated by the GPCR-interacting proteins ATRAP, ARAP1 and ATIP. AT1R activation induces effects through the phospholipase C pathway, mitogen-activated protein kinases, tyrosine kinases/phosphatases, RhoA/Rhokinase and NAD(P)H-oxidase-derived reactive oxygen species. Here we focus on recent developments and new research trends related to Ang II and the RAS and involvement in the hypertensive vascular phenotype.
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PMID:Angiotensin II and the vascular phenotype in hypertension. 2145 Jan 23

To understand the roles of purinergic receptors and cellular molecules below the receptors in the vascular inflammatory response, we determined if extracellular nucleotides up-regulated chemokine expression in vascular smooth muscle cells (VSMCs). Human aortic smooth muscle cells (AoSMCs) abundantly express P2Y(1), P2Y(6), and P2Y(11) receptors, which all respond to extracellular nucleotides. Exposure of human AoSMCs to NAD(+), an agonist of the human P2Y(11) receptor, and NADP(+) as well as ATP, an agonist for P2Y(1) and P2Y(11) receptors, caused increase in chemokine (C-C motif) ligand 2 gene (CCL2) transcript and CCL2 release; however, UPT did not affect CCL2 expression. CCL2 release by NAD(+) and NADP(+) was inhibited by a concentration dependent manner by suramin, an antagonist of P2-purinergic receptors. NAD(+) and NADP(+) activated protein kinase C and enhanced phosphorylation of mitogen-activated protein kinases and Akt. NAD(+)- and NADP(+)-mediated CCL2 release was significantly attenuated by SP6001250, U0126, LY294002, Akt inhibitor IV, RO318220, GF109203X, and diphenyleneiodium chloride. These results indicate that extracellular nucleotides can promote the proinflammatory VSMC phenotype by up-regulating CCL2 expression, and that multiple cellular elements, including phosphatidylinositol 3-kinase, Akt, protein kinase C, and mitogen-activated protein kinases, are involved in that process.
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PMID:Extracellular Nucleotides Can Induce Chemokine (C-C motif) Ligand 2 Expression in Human Vascular Smooth Muscle Cells. 2146 Dec 38


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