UNIPROT:P51812 - FACTA Search

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

Studies from our laboratory have shown that epigallocatechin-3-gallate, the major polyphenol present in green tea, inhibits ultraviolet (UV)B-exposure-mediated phosphorylation of mitogen-activated protein kinases (MAPKs) (Toxicol. Appl. Pharmacol. 176: 110-117, 2001) and activation of nuclear factor kappa B (NF-kappaB) (Oncogene 22: 1035-1044, 2003) pathways in normal human epidermal keratinocytes. This study was designed to investigate the relevance of these findings to the in vivo situations in SKH-1 hairless mouse model, which is regarded to have relevance to human situations. SKH-1 hairless mice were topically treated with GTP (5 mg/0.2 ml acetone/mouse) and were exposed to UVB 30 min later (180 mJ/cm2). These treatments were repeated every alternate day for 2 weeks, for a total of seven treatments. The animals were killed 24 h after the last UVB exposure. Topical application of GTP resulted in significant decrease in UVB-induced bifold-skin thickness, skin edema and infiltration of leukocytes. Employing Western blot analysis and immunohistochemical studies, we found that GTP resulted in inhibition of UVB-induced: (i) phosphorylation of extracellular-signal-regulated kinases (ERK1/2), (ii) c-Jun N-terminal kinases, and (iii) p38 protein expression. Since NF-kappaB plays a major role in inflammation and cell proliferation, we assessed the effect of GTP on UVB-mediated modulations in the NF-kappaB pathway. Our data demonstrated that GTP inhibited UVB-induced: (i) activation of NF-kappaB, (ii) activation of IKKalpha, and (iii) phosphorylation and degradation of IkappaBalpha. Our data suggest that GTP protects against the adverse effects of UV radiation via modulations in MAPK and NF-kappaB signaling pathways, and provides molecular basis for the photochemopreventive effect of GTP in an in vivo animal model system.
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PMID:Suppression of UVB-induced phosphorylation of mitogen-activated protein kinases and nuclear factor kappa B by green tea polyphenol in SKH-1 hairless mice. 1468 84

In addition to their inhibitory effects, cannabinoids also exert stimulatory activity which can be detected at the cellular level. In a previous study, we demonstrated a stimulatory effect of the synthetic cannabinoid receptor agonist desacetyllevonantradol (DALN) on Ca(2+) flux into N18TG2 neuroblastoma cells, and suggested a dual mechanism: one pathway mediated by PKA and the other one by protein kinase C (PKC). Here we studied the PKC-mediated effect of DALN on Ca(2+) influx. The stimulatory effect of DALN on Ca(2+) influx was partially blocked by the PKC inhibitor chelerythrine, by the metalloprotease inhibitor o-phenanthroline and by the MEK (mitogen-activated protein-kinase kinase, MAPK kinase) inhibitor PD98059. Immunobloting of ERK1/2 MAPK demonstrated phosphorylation by DALN, and indicated the involvement of vascular endothelial growth factor (VEGF) receptor tyrosin kinases (RTKs) in MAPK activation as it was blocked by oxindole-1. Transactivation of the VEGFR-MAPK cascade by DALN involved CB1 cannabinoid receptors coupled to Gi/Go GTP-binding proteins as it was blocked by SR141716A and by pertussis toxin (PTX). The pharmacological implications of this novel mechanism of cannabinoid activity are discussed.
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PMID:The involvement of VEGF receptors and MAPK in the cannabinoid potentiation of Ca2+ flux into N18TG2 neuroblastoma cells. 1474 3

We present an analysis of over 1,100 of the approximately 10,000 predicted proteins encoded by the genome sequence of the filamentous fungus Neurospora crassa. Seven major areas of Neurospora genomics and biology are covered. First, the basic features of the genome, including the automated assembly, gene calls, and global gene analyses are summarized. The second section covers components of the centromere and kinetochore complexes, chromatin assembly and modification, and transcription and translation initiation factors. The third area discusses genome defense mechanisms, including repeat induced point mutation, quelling and meiotic silencing, and DNA repair and recombination. In the fourth section, topics relevant to metabolism and transport include extracellular digestion; membrane transporters; aspects of carbon, sulfur, nitrogen, and lipid metabolism; the mitochondrion and energy metabolism; the proteasome; and protein glycosylation, secretion, and endocytosis. Environmental sensing is the focus of the fifth section with a treatment of two-component systems; GTP-binding proteins; mitogen-activated protein, p21-activated, and germinal center kinases; calcium signaling; protein phosphatases; photobiology; circadian rhythms; and heat shock and stress responses. The sixth area of analysis is growth and development; it encompasses cell wall synthesis, proteins important for hyphal polarity, cytoskeletal components, the cyclin/cyclin-dependent kinase machinery, macroconidiation, meiosis, and the sexual cycle. The seventh section covers topics relevant to animal and plant pathogenesis and human disease. The results demonstrate that a large proportion of Neurospora genes do not have homologues in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe. The group of unshared genes includes potential new targets for antifungals as well as loci implicated in human and plant physiology and disease.
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PMID:Lessons from the genome sequence of Neurospora crassa: tracing the path from genomic blueprint to multicellular organism. 1500 97

Signals from several receptor tyrosine kinases are transduced by activation of the Ras family of GTP-binding proteins. Activation of Ras initiates a kinase cascade that culminates in activation of the mitogen-activated protein kinases (MAPKs). The MAPKs include the c-jun NH(2)-terminal protein kinases (JNKs) and extracellular signal-regulated kinases (ERKs), both of which phosphorylate Elk-1/TCF, a factor that activates transcription of the c-fos gene. In this report, we identify a novel 19 kDa gene product as a negative regulator of signaling through the ERK1/2 pathway. While these studies were in progress, the human homologue of this gene was characterized as diphosphoinositol polyphosphate phosphohydrolase (DIPP1) [EMBO J. 17 (1998) 6599], a phosphohydrolase that converts diphosphate groups on diphosphoinositol polyphosphates to monophosphates. Ectopic expression of murine DIPP1 (muDIPP1) blocked activation of the c-fos promoter by the ERK1/2 pathway. Inhibition of signal transduction through the ERK1/2 pathway by muDIPP1 occurs at or downstream from activation of MEK. In vitro kinase studies suggest that muDIPP1 is not a direct inhibitor of MEK or ERK activity, although, ectopic expression at near physiological levels results in attenuation of ERK phosphorylation in vivo. Interestingly, a site mutant of muDIPP1 lacking phosphohydrolase activity blocked signaling through the ERK1/2 pathway with greater efficiency than wild-type muDIPP1. This result suggests that inhibition of signaling through the ERK1/2 pathway is a distinct function of muDIPP1 that is not dependent on, but may be regulated by, its activity as a phosphohydrolase.
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PMID:Ectopic expression of murine diphosphoinositol polyphosphate phosphohydrolase 1 attenuates signaling through the ERK1/2 pathway. 1521 65

Cytotoxic necrotizing factor type 1 (CNF1) from Escherichia coli activates the small GTP-binding proteins of the Rho family (Rho, Rac, and Cdc42) by catalyzing their deamidation at a specific glutamine residue. Since RhoA, Rac, and Cdc42 play a pivotal role in cell migration during the early phase of wound repair, we investigated whether CNF1 was able to interfere with wound healing in intestinal epithelial monolayers (T84 cells). After mechanical injury, we found that CNF1 blocks epithelial wound repair within 48 h. This effect was characterized by cell elongation and filopodium formation on the leading edge, in association with permanent phosphorylation of the focal adhesion kinase (FAK) via Rho activation. Moreover, inhibition of Rho kinase with Y-27632 decreased CNF1-mediated permanent FAK phosphorylation, leading to complete restitution of wound repair within 24 h. In addition, we found that CNF1 induced upregulation of mitogen-activated protein kinases (MAPK) activation. Moreover, activation of Rac and MAPK by CNF1 increased matrix metalloproteinase 9 expression in wounded T84 monolayers. Taken together, these results provide evidence that CNF1 strongly impairs intestinal epithelial wound healing.
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PMID:Escherichia coli cytotoxic necrotizing factor 1 inhibits intestinal epithelial wound healing in vitro after mechanical injury. 1538 72

Protein kinases, particularly mitogen-activated protein kinases and receptor-tyrosine kinases play crucial roles in mammalian cellular metabolism by regulating intracellular signaling pathways that control proliferation, differentiation, cytokine gene induction and cytokine responsiveness, matrix metalloproteinase gene expression, mechanical transduction, as well as programmed cell death (apoptosis). Many of these pathways are also important components of cartilage homeostasis because alterations in intracellular signaling pathways appear to play a prominent role in chondrocyte dysfunction that is part of osteoarthritis pathogenesis and disease progression. Several mitogen-activated protein kinases and receptor-tyrosine kinases have been characterized as participating in chondrocyte signaling pathways. They are c-Jun-amino-terminal protein kinase, p38 kinase, extracellular signal-regulated protein kinase, and Ror2. Janus kinases and signal transducers and activators of transcription factors (Janus kinase/signal transducers and activators of transcription pathway) are also implicated in modulating the chondrogenic phenotype. Mitogen-activated protein kinase activation is required for their role as phosphorylating enzymes. Activation results from mitogen-activated protein kinase phosphorylation carried out by at least seven upstream kinases known as mitogen-activated protein kinase kinases. Additional upstream kinases (for example, MKKKKs and MKKKs) often require low molecular weight GTP-binding proteins to mediate the mitogen-activated protein-kinase kinases cascade. Identifying the functions of mitogen-activated protein kinases in normal and aging cartilage and the extent to which mitogen-activated protein kinases may be altered in osteoarthritis cartilage and synovium will be critical for developing novel therapies for osteoarthritis management.
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PMID:Protein kinases in chondrocyte signaling and osteoarthritis. 1548 58

The YadA protein of Yersinia pseudotuberculosis promotes tight adhesion and invasion into mammalian cells through beta(1)-integrins. In this work, we demonstrate that YadA also triggers the production of interleukin-8 (IL-8) in host cells and we identify intracellular signal transduction mechanisms involved in YadA-initiated cell invasion and/or IL-8 synthesis. Tyrosine protein kinases, including the focal adhesion kinase (FAK) and c-Src, as well as the small GTPase Ras, were shown to play a significant role in both YadA-promoted cell processes. YadA-mediated cell contact led to autophosphorylation of FAK at position Tyr397 and induced GTP-loading of Ras. Furthermore, IL-8 production and invasion induced by YadA were strongly reduced in FAK- and c-Src-deficient cells and in cells overexpressing dominant interfering forms of FAK, c-Src or Ras. We also demonstrate that YadA activates the Ras-dependent Raf-MEK1/2-ERK1/2 pathway and mitogen-activated protein kinases (MAPKs) p38 and JNK. Moreover, inhibition of ERK1/2 by pharmacological agents or overexpression of dominant negative FAK, c-Src or Ras abrogated IL-8 release, whereas invasion remained unaffected. In contrast, actin polymerization and phosphatidylinositol 3-kinase (PI3K) activity is essential for YadA-promoted cell entry, but not for cytokine secretion. We conclude that YadA triggers FAK-Src complex formation and subsequent Ras activation, which leads to the stimulation of MAPKs-dependent IL-8 production or to PI3K-dependent invasion.
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PMID:Cell invasion and IL-8 production pathways initiated by YadA of Yersinia pseudotuberculosis require common signalling molecules (FAK, c-Src, Ras) and distinct cell factors. 1561 24

We have previously demonstrated that both isoprenylcysteine carboxylmethyltransferase (ICMT) and one of its substrates, the RhoGTPase Rac1, are critical for the tumor necrosis factor alpha (TNF alpha) stimulation of vascular cell adhesion molecule-1 expression in endothelial cells (EC). Here, we have shown that ICMT regulates TNF alpha stimulation of Rac1 activity. TNF alpha stimulation of EC increased the membrane association of Rac1, an event that is essential for Rac1 activity. ICMT inhibitor N-acetyl-S-farnesyl-L-cysteine (AFC) blocked the accumulation of Rac1 into the membrane both in resting and TNF alpha-stimulated conditions. Similarly, the membrane-associated Rac1 was lower in Icmt-deficient versus wild-type mouse embryonic fibroblasts (MEFs). TNF alpha also increased the level of GTP-Rac1, the active form of Rac1, in EC. AFC completely suppressed the TNF alpha stimulation of increase in GTP-Rac1 levels. Confocal microscopy revealed resting EC Rac1 was present in the plasma membrane and also in the perinuclear region. AFC mislocalized Rac1, both from the plasma membrane and the perinuclear region. Mislocalization of Rac1 was also observed in Icmt-deficient versus wild-type MEFs. To determine the consequences of ICMT inhibition, we investigated the effect of AFC on p38 mitogen-activated protein (MAP) kinase phosphorylation, which is downstream of Rac1. AFC inhibited the TNF alpha stimulation of p38 MAP kinase phosphorylation in EC. TNF alpha stimulation of p38 MAP kinase phosphorylation was also significantly attenuated in Icmt-deficient versus wild-type MEFs. To understand the mechanism of inhibition of Rac1 activity, we examined the effect of ICMT inhibition on the interaction of Rac1 with its inhibitor, Rho guanine nucleotide dissociation inhibitor (RhoGDI). The association of Rac1 with its inhibitor RhoGDI was dramatically increased in the Icmt-deficient versus wild-type MEFs both in resting as well as in TNF alpha-stimulated conditions, suggesting that RhoGDI was involved in inhibiting Rac1 activity under the conditions of ICMT inhibition. These results suggest that ICMT regulates Rac1 activity by controlling the interaction of Rac1 with RhoGDI. We hypothesize that ICMT regulates the release of Rac1 from RhoGDI.
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PMID:Tumor necrosis factor alpha stimulation of Rac1 activity. Role of isoprenylcysteine carboxylmethyltransferase. 1564 76

Epigallocatechin-3-gallate (EGCG), a major constituent of the polyphenoids in green tea, has been reported to possess a wide range of biologic activities, including antifibrogenesis. Activated hepatic stellate cells (HSCs) are central to hepatic fibrosis, and Rho (a small GTPase)-signaling pathways have been implicated in the activation and proliferation of HSCs. In this study, we investigated the effect of EGCG on Rho-signaling pathways in activated human HSC-derived TWNT-4 cells. EGCG inhibited stress-fiber formation, an indicator of Rho activation, and changed the distribution of alpha-smooth-muscle actin. These inhibitory effects of EGCG were restored by overexpression of constitutively active Rho. A pull-down assay revealed that activated Rho (GTP-bound state) was strongly inhibited by ECGC and accompanied by suppressed phosphorylation of focal adhesion kinase, which is a regulator of Rho-signaling pathways. 5-Bromo-2'-deoxy-uridine incorporation demonstrated that ECGC (100 micromol/L suppressed cell growth by 80%, and terminal deoxynucleotidyl transferase viotin-deoxyruidine triphosphate nick end-labeling revealed that EGCG (100 micromol/L) caused apoptosis in half of the total cells. EGCG also strongly inhibited lysophoaphatidic acid (an activator of Rho) and induced phosphorylation of mitogen-activated protein kinases (Erk1/2, c-jun kinase, and p38). These findings demonstrate that EGCG regulates the structure and growth of HSCs by way of Rho-signaling pathways and suggest that EGCG has therapeutic potential in the setting of liver fibrosis.
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PMID:Epigallocatechin-3-gallate, a green-tea polyphenol, suppresses Rho signaling in TWNT-4 human hepatic stellate cells. 1597 60

The retinoid-inducible gene 1 (RIG1) protein is a retinoid-inducible growth regulator. Previous studies have shown that the RIG1 protein inhibits the signaling pathways of Ras/mitogen-activated protein kinases. However, neither the mode of action nor the site of inhibition of RIG1 is known. This study investigated the effects of RIG1, and the mechanisms responsible for these effects, on the activation of Ras proteins in HtTA cervical cancer cells. RIG1 reduced the levels of activated Ras (Ras-GTP) and total Ras protein in cells transfected with mutated H-, N-, or K-Ras(G12V), or in cells transfected with the wild type H- or N-Ras followed by stimulation with epidermal growth factor. The half-life of Ras protein decreased from more than 36 h in control cells to 18 h in RIG1-transfected cells. RIG1 immunoprecipitated with the Ras protein in co-transfected cellular lysates. In contrast to the predominant plasma membrane localization in control cells, the H-Ras fusion protein EGFP-H-Ras was localized within a discrete cytoplasmic compartment where it co-localized with RIG1. RIG1 inhibited more than 93% of the Elk- and CHOP-mediated transactivation induced by H- or K-Ras(G12V). However, RIG1 did not inhibit the transactivation induced by MEK1 or MEK3, and failed to suppress the phosphorylation of extracellular signal-regulated kinases 1 and 2 induced by the constitutively activated B-Raf(V599E). The RIG1 with carboxyl terminal truncation (RIG1DeltaC) did not immunoprecipitate with Ras and had no effect on Ras activation or transactivation of the downstream signal pathways. These data indicate that RIG1 exerts its inhibitory effect at the level of Ras activation, which is independent of Ras subtype but dependent on the membrane localization of the RIG1 protein. This inhibition of Ras activation may be mediated through downregulation of Ras levels and alteration of Ras subcellular distribution.
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PMID:RIG1 inhibits the Ras/mitogen-activated protein kinase pathway by suppressing the activation of Ras. 1600 86

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