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)

Increasing interest in anhydrobiosis ('life without water') has prompted the use of mammalian cells as a model in which candidate adaptations suspected of conferring desiccation tolerance can be tested. Despite this, there is no information on whether mammalian cells are able to sense and respond to desiccation. We have therefore examined the effect of desiccation on stress signalling pathways and on genes which are proposed to be expressed in response to water loss through osmotic stress. Depending on the severity of the drying regime, human cells survived for at least 24 h. Both SAPK/JNK and p38 mitogen-activated protein kinases (MAPKs) were activated within 30 min by desiccation as well as by all osmotica tested, and therefore MAPK pathways probably play an important role in both responses. Gene induction profiles differed under the two stress conditions, however: quantitative polymerase chain reaction (PCR) experiments showed that AR, BGT-1 and SMIT, which encode proteins governing organic osmolyte accumulation, were induced by hypersalinity but not by desiccation. This was surprising, since these genes have been proposed to be regulated by ionic strength and cell volume, both of which should be significantly affected in drying cells. Further investigation demonstrated that AR, BGT-1 and SMIT expression was dependent on the nature of the osmolyte. This suggests that their regulation involves factors other than intracellular ionic strength and cell volume changes, consistent with the lack of induction by desiccation. Our results show for the first time that human cells react rapidly to desiccation by MAPK activation, and that the response partially overlaps with that to hyperosmotic stress.
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PMID:Response of human cells to desiccation: comparison with hyperosmotic stress response. 1519 35

Exposure to particulate matter (PM) is associated with acute cardiovascular mortality and morbidity, but the mechanisms are not entirely clear. In this study, we hypothesized that PM may activate the angiotensin type 1 receptor (AT1R), a G protein-coupled receptor that regulates inflammation and vascular function. We investigated the acute effects of St. Louis, Missouri, urban particles (UPs; Standard Reference Material 1648) on the constriction of isolated rat pulmonary artery rings and the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 mitogen-activated protein kinases (MAPKs) in human pulmonary artery endothelial cells with or without losartan, an antagonist of AT1R. UPs at 1-100 microg/mL induced acute vasoconstriction in pulmonary artery. UPs also produced a time- and dose-dependent increase in phosphorylation of ERK1/2 and p38 MAPK. Losartan pretreatment inhibited both the vasoconstriction and the activation of ERK1/2 and p38. The water-soluble fraction of UPs was sufficient for inducing ERK1/2 and p38 phosphorylation, which was also losartan inhibitable. Copper and vanadium, two soluble transition metals contained in UPs, induced pulmonary vasoconstriction and phosphorylation of ERK1/2 and p38, but only the phosphorylation of p38 was inhibited by losartan. The UP-induced activation of ERK1/2 and p38 was attenuated by captopril, an angiotensin-converting enzyme inhibitor. These results indicate that activation of the local renin-angiotensin system may play an important role in cardiovascular effects induced by PM.
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PMID:Pollutant particles produce vasoconstriction and enhance MAPK signaling via angiotensin type I receptor. 1607 71

Signaling mechanisms in aniline-induced fibrogenic and/or tumorigenic response in the spleen are not known. Previous studies have shown that aniline exposure leads to iron accumulation and oxidative stress in the spleen, which may cause activation of redox-sensitive transcription factors and regulate the transcription of genes involved in fibrosis and/or tumorigenesis. To test this, male SD rats were treated with 0.5 mmol/kg/day aniline via drinking water for 30 days, and activation of transcription factor AP-1 was determined in the splenocyte nuclear extracts (NEs). AP-1 DNA-binding activity in the NEs of freshly isolated splenocytes from aniline-treated rats increased in comparison to the controls, as determined by electrophoretic mobility shift assay (EMSA). AP-1 binding was also determined in the NEs of cultured splenocytes (2 h and 24 h), which showed even a greater increase in binding activity at 2 h. The specificity of AP-1 binding for relevant DNA motifs was confirmed by competition EMSA and by supershift EMSA using antibodies specific to c-Jun and c-Fos. To further explore the signaling mechanisms in the AP-1 activation, phosphorylation patterns of mitogen-activated protein kinases (MAPKs) were pursued. Aniline exposure induced increases in the phosphorylation of the three classes of MAPKs: extracellular-signal-regulated kinase (ERK 1/2), c-Jun N-terminal kinase (JNK 1/2), and p38 MAPKs. Furthermore, TGF-beta1 mRNA expression showed a 3-fold increase in the spleens of aniline-treated rats. These observations suggest a strong association among MAPK phosphorylation, AP-1 activation, and enhanced TGF-beta1 gene expression. The observed sequence of events subsequent to aniline exposure could regulate genes that lead to fibrogenic and/or tumorigenic response in the spleen.
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PMID:Activation of transcription factor AP-1 and mitogen-activated protein kinases in aniline-induced splenic toxicity. 1616 68

Interleukin-1alpha (IL-1alpha) plays an important role in the regulation of immune responses as well as in non-inflammatory events in different types of cells. Here we have investigated the involvement of the extracellular signal-regulated kinase (ERK) cascade in IL-1alpha-induced steroidogenesis by primary cultures of immature rat Leydig cells. Our findings indicate that protein kinase C functions as an upstream component of signal transduction from the IL-1 receptor type I (IL-1RI) to the ERK cascade. It was observed that IL-1alpha upregulated both steroidogenic acute regulatory (StAR) protein expression and its phosphorylation when compared with controls. Selective inhibition of these mitogen-activated protein kinases (MAPKs) by UO126 enhanced both the expression and phosphorylation of the StAR protein, but suppressed androgen production by the immature Leydig cells as well as dissipating the mitochondrial electrochemical potential (Psim) in these cells. The evidence that water-soluble cholesterol but not 22R-hydroxycholesterol-stimulated steroidogenesis was inhibited by UO126 suggested that an intact Psim across the inner mitochondrial membrane is required for cholesterol translocation and is positively regulated by the ERK cascade. We propose that activation of ERKs by IL-1alpha plays a dual role in the regulation of steroidogenesis in immature Leydig cells: these MAPKs downregulate StAR expression and phosphorylation, while at the same time they support an intact Psim across the inner mitochondrial membrane, thereby promoting translocation of cholesterol into the mitochondria of the Leydig cell.
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PMID:Induction of steroidogenesis in immature rat Leydig cells by interleukin-1alpha is dependent on extracellular signal-regulated kinases. 1659 3

The expression of mitogen-activated protein kinases (MAPK) in DBA/2-pcy/pcy (pcy) mice, a murine model of polycystic kidney disease was investigated. Proliferating cell nuclear antigen-positive cells were recognized in cyst epithelium from embryonic day 14.5 to 25 wk of age. Extracellular signal-regulated kinase (ERK) was expressed in the renal tubules of control and pcy mice, but stronger immunostaining was observed in cyst epithelium. Phosphorylated ERK was detected only in pcy mice and was localized predominantly in the cysts. p38 MAPK (p38) was no longer expressed after birth in controls but was detected in the cyst epithelium and in occasional tubular cells of pcy mice at all stages examined. c-Jun N-terminal kinase (JNK) was expressed in all tubular segments of controls after neonatal day 7, whereas in pcy kidneys, tubules became positive for JNK after 8 wk, and the cysts expressed little JNK. Administration of an oral MAP/ERK kinase inhibitor, PD184352, 400 mg/kg per d, to 10-wk-old pcy mice daily for the first week and then every third day for 6 additional weeks significantly decreased BP, kidney weight, serum creatinine level, and water intake and significantly increased urine osmolality. The cystic index and expression of phosphorylated ERK and ERK were significantly lower in PD184352-treated pcy mice. These results demonstrate that the expression of MAPK is dysregulated in cyst epithelium and that inhibition of ERK slowed the progression of renal disease in pcy mice.
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PMID:Extracellular signal-regulated kinase inhibition slows disease progression in mice with polycystic kidney disease. 1668 24

Stomata are specialized epidermal structures that regulate gas (CO(2) and O(2)) and water vapor exchange between plants and their environment. In Arabidopsis thaliana, stomatal development is preceded by asymmetric cell divisions, and stomatal distribution follows the one-cell spacing rule, reflecting the coordination of cell fate specification. Stomatal development and patterning are regulated by both genetic and environmental signals. Here, we report that Arabidopsis MITOGEN-ACTIVATED PROTEIN KINASE3 (MPK3) and MPK6, two environmentally responsive mitogen-activated protein kinases (MAPKs), and their upstream MAPK kinases, MKK4 and MKK5, are key regulators of stomatal development and patterning. Loss of function of MKK4/MKK5 or MPK3/MPK6 disrupts the coordinated cell fate specification of stomata versus pavement cells, resulting in the formation of clustered stomata. Conversely, activation of MKK4/MKK5-MPK3/MPK6 causes the suppression of asymmetric cell divisions and stomatal cell fate specification, resulting in a lack of stomatal differentiation. We further establish that the MKK4/MKK5-MPK3/MPK6 module is downstream of YODA, a MAPKKK. The establishment of a complete MAPK signaling cascade as a key regulator of stomatal development and patterning advances our understanding of the regulatory mechanisms of intercellular signaling events that coordinate cell fate specification during stomatal development.
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PMID:Stomatal development and patterning are regulated by environmentally responsive mitogen-activated protein kinases in Arabidopsis. 1725 59

Artemisinin and its derivatives exhibit potent immunosuppressive activity. The aim of this study was to investigate the suppressive effects of SM905, a new water-soluble artemisinin derivative, on T lymphocytes both in vitro and in vivo, and explore its potential mode of action. The results showed that SM905 had a high inhibitory activity in Concanavalin A (ConA)-induced splenocyte proliferation and mixed lymphocyte reaction, and a relatively low cytotoxicity in vitro. In ovalbumin-immunized mice, oral administration of SM905 dose-dependently suppressed T cell proliferative response to ovalbumin, and inhibited anti-ovalbumin interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) production by T cells. Further studies showed that SM905 inhibited TCR (T cell receptor)/CD3 plus CD28-mediated primary T cell proliferation and cytokine production (IL-2 and IFN-gamma), and exerted an inhibitory action on the phosphorylation of mitogen-activated protein (MAP) kinases including extracellular signal-regulated kinase (ERK), p38 and Jun N-terminal kinase (JNK), and the activation of Ras. The results of this study provided experimental evidence that the new artemisinin derivative SM905 had immunosuppressive effects both in vitro and in vivo. SM905 suppressed T cell activation, which was associated with the inhibition of MAP kinases and Ras activation. Our results suggested a potential of SM905 to be developed as a new type agent for treating T cell-mediated immune disorder.
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PMID:Suppressive effect of a novel water-soluble artemisinin derivative SM905 on T cell activation and proliferation in vitro and in vivo. 1734 93

To develop novel mechanism-based preventive approaches for lung cancer, we examined the effect of oral consumption of a human achievable dose of pomegranate fruit extract (PFE) on growth, progression, angiogenesis, and signaling pathways in two mouse lung tumor protocols. Benzo(a)pyrene [B(a)P] and N-nitroso-tris-chloroethylurea (NTCU) were used to induce lung tumors, and PFE was given in drinking water to A/J mice. Lung tumor yield was examined on the 84th day and 140 days after B(a)P dosing and 240 days after NTCU treatment. Mice treated with PFE and exposed to B(a)P and NTCU had statistically significant lower lung tumor multiplicities than mice treated with carcinogens only. Tumor reduction was 53.9% and 61.6% in the B(a)P + PFE group at 84 and 140 days, respectively, compared with the B(a)P group. The NTCU + PFE group had 65.9% tumor reduction compared with the NTCU group at 240 days. Immunoblot analysis and immunohistochemistry were used to determine effect on cell survival pathways and markers of cellular proliferation and angiogenesis. PFE treatment caused inhibition of (a) activation of nuclear factor-kappaB and IkappaBalpha kinase, (b) degradation and phosphorylation of IkappaBalpha, (c) phosphorylation of mitogen-activated protein kinases (extracellular signal-regulated kinase 1/2, c-Jun NH(2)-terminal kinase 1/2, and p38), (d) phosphatidylinositol 3-kinase (p85 and p110), (e) phosphorylation of Akt at Thr(308), (f) activation of mammalian target of rapamycin signaling, (g) phosphorylation of c-met, and (h) markers of cell proliferation (Ki-67 and proliferating cell nuclear antigen) and angiogenesis (inducible nitric oxide synthase, CD31, and vascular endothelial growth factor) in lungs of B(a)P- and NTCU-treated mice. Thus, our data show that PFE significantly inhibits lung tumorigenesis in A/J mice and merits investigation as a chemopreventive agent for human lung cancer.
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PMID:Oral consumption of pomegranate fruit extract inhibits growth and progression of primary lung tumors in mice. 1738 58

Osmoregulation is the active control of the cellular water balance and encompasses homeostatic mechanisms crucial for life. The osmoregulatory system in the yeast Saccharomyces cerevisiae is particularly well understood. Key to yeast osmoregulation is the production and accumulation of the compatible solute glycerol, which is partly controlled by the high osmolarity glycerol (HOG) signaling system. Genetic analyses combined with studies on protein-protein interactions have revealed the wiring scheme of the HOG signaling network, a branched mitogen-activated protein (MAP) kinase (MAPK) pathway that eventually converges on the MAPK Hog1. Hog1 is activated following cell shrinking and controls posttranscriptional processes in the cytosol as well as gene expression in the nucleus. HOG pathway activity can easily and rapidly be controlled experimentally by extracellular stimuli, and signaling and adaptation can be separated by a system of forced adaptation. This makes yeast osmoregulation suitable for studies on system properties of signaling and cellular adaptation via mathematical modeling. Computational simulations and parallel quantitative time course experimentation on different levels of the regulatory system have provided a stepping stone toward a holistic understanding, revealing how the HOG pathway can combine rigorous feedback control with maintenance of signaling competence. The abundant tools make yeast a suitable model for an integrated analysis of cellular osmoregulation. Maintenance of the cellular water balance is fundamental for life. All cells, even those in multicellular organisms with an organism-wide osmoregulation, have the ability to actively control their water balance. Osmoregulation encompasses homeostatic processes that maintain an appropriate intracellular environment for biochemical processes as well as turgor of cells and organism. In the laboratory, the osmoregulatory system is studied most conveniently as a response to osmotic shock, causing rapid and dramatic changes in the extracellular water activity. Those rapid changes mediate either water efflux (hyperosmotic shock), and hence cell shrinkage, or influx (hypoosmotic shock), causing cell swelling. The yeast S. cerevisiae, as a free-living organism experiencing both slow and rapid changes in extracellular water activity, has proven a suitable and genetically tractable experimental system in studying the underlying signaling pathways and regulatory processes governing osmoregulation. Although far from complete, the present picture of yeast osmoregulation is both extensive and detailed (de Nadal et al., 2002; Hohmann, 2002; Klipp et al., 2005). Simulations using mathematical models combined with time course measurements of different molecular processes in signaling and adaptation have allowed elucidation of the first system properties on the yeast osmoregulatory network.
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PMID:Yeast osmoregulation. 1787 10

Mume Fructus (Family Rosaceae) is used as a traditional drug and health food in Asian countries. However, its therapeutic mechanisms and effects on macrophage-mediated inflammation remain unknown. In this study we examined the effect of Mume Fructus water extract (MFWE) on pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. The investigation focused on whether MFWE inhibited nitric oxide (NO) and prostaglandin (PG) E2 productions, as well as the expressions of inducible NO synthase (iNOS), cyclooxygenase (COX)-2, interleukin (IL)-6, nuclear factor-kappaB (NF-kappaB), and mitogen-activated protein kinases (MAPKs) in LPS-stimulated RAW 264.7 cells. We found that MFWE inhibited LPS-induced NO, PGE(2), and IL-6 productions as well as the expressions of iNOS and COX-2. Furthermore, MFWE suppressed the LPS-induced phosphorylations of p38 MAPK and extracellular signal-regulated kinase MAPK, as well as IkappaBalpha degradation and NF-kappaB activation. These results suggest that MFWE has inhibitory effects on LPS-induced PGE2, NO, and IL-6 production, as well as the expressions of iNOS and COX-2 in the murine macrophage. These inhibitory effects occur through blockades on the phosphorylation of MAPKs following IkappaBalpha degradation and NF-kappaB activation.
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PMID:Mume Fructus water extract inhibits pro-inflammatory mediators in lipopolysaccharide-stimulated macrophages. 1788 39


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