Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using a set of genomic TY1A-lacZ fusions, we show that Ste12 and Tec1, two transcription factors of the Kss1 mitogen-activated protein kinase (MAPK) cascade activate Ty1 transcription in Saccharomyces cerevisiae. This result strongly suggests that the invasive-filamentous pathway regulates Ty1 transcription. Since this pathway is active in diploid cells, we suspected that Ty1 transposition might occur in this cell type, despite the fact that this event has been never reported before (unless activated by heterologous promoters such as that of GAL1). We demonstrate here that constitutive activation of the invasive-filamentous pathway by the STE11-4 allele or by growth in low-nitrogen medium induces Ty1 transcription and retrotransposition in diploid cells. We show that Ty1 retrotransposition can be activated by STE11-4 in haploid cells as well. Our findings provide the first evidence that Ty1 retrotransposition can be activated by environmental signals that affect differentiation. Activation of the Kss1 MAPK cascade by stress is known to cause filament formation that permits the search for nutrients away from the colonization site. We propose that activation of Ty1 retrotransposition by this cascade could play a role in adaptive mutagenesis in response to stress.
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PMID:Activation of the Kss1 invasive-filamentous growth pathway induces Ty1 transcription and retrotransposition in Saccharomyces cerevisiae. 1089 12

Cellular differentiation, mating, and filamentous growth are regulated in many fungi by environmental and nutritional signals. For example, in response to nitrogen limitation, diploid cells of the yeast Saccharomyces cerevisiae undergo a dimorphic transition to filamentous growth referred to as pseudohyphal differentiation. Yeast filamentous growth is regulated, in part, by two conserved signal transduction cascades: a mitogen-activated protein kinase cascade and a G-protein regulated cyclic AMP signaling pathway. Related signaling cascades play an analogous role in regulating mating and virulence in the plant fungal pathogen Ustilago maydis and the human fungal pathogens Cryptococcus neoformans and Candida albicans. We review here studies on the signaling cascades that regulate development of these and other fungi. This analysis illustrates both how the model yeast S. cerevisiae can serve as a paradigm for signaling in other organisms and also how studies in other fungi provide insights into conserved signaling pathways that operate in many divergent organisms.
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PMID:Signal transduction cascades regulating fungal development and virulence. 1110 18

In response to nitrogen limitation, diploid cells of the yeast Saccharomyces cerevisiae undergo a dimorphic transition to filamentous pseudohyphal growth. At least two signaling pathways regulate filamentation. One involves components of the MAP kinase cascade that also regulates mating of haploid cells. The second involves a nutrient-sensing G-protein-coupled receptor that signals via an unusual G(alpha) protein, cAMP and protein kinase A. Recent studies reveal crosstalk between these pathways during pseudohyphal growth. Related MAP kinase and cAMP pathways regulate filamentation and virulence of human and plant fungal pathogens, and represent novel targets for antifungal drug design.
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PMID:Signal transduction cascades regulating pseudohyphal differentiation of Saccharomyces cerevisiae. 1112 75

Pseudohyphal growth in both haploid and diploid strains of Saccharomyces cerevisiae reflects concerted changes in different cellular processes: budding pattern, cell elongation and cell adhesion. These changes are triggered by environmental signals and are controlled by several pathways which act in parallel. Nitrogen deprivation, and possibly other stresses, activate a MAP kinase cascade which has the transcription factor Ste12 as its final target. A cAMP-dependent pathway, in which the protein kinase Tpk2 plays a specific role, is also required for the morphogenetic switch. Both pathways contribute to modulate the expression of the MUC1/FLO11 gene which encodes a cell-surface flocculin required for pseudohyphal and invasive growth. The MAP kinase cascade could also control the activity of the cyclin/Cdc28 complexes which affect both the budding pattern of yeast and cell elongation. A further protein which stimulates filamentous growth in S. cerevisiae is Phd1; although its mode of action is unknown, it may be regulated by a cAMP-dependent protein kinase, as occurs with the homologous protein Efg1 from Candida albicans, which is required for the formation of true hyphae. Morphogenesis in different yeast genera share common elements, but there are also important differences. Although a complete picture cannot yet be drawn, partial models may be proposed for the interaction of the regulatory pathways, both in the case of S. cerevisiae and in that of C. albicans.
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PMID:Control of pseudohyphae formation in Saccharomyces cerevisiae. 1115 42

In Saccharomyces cerevisiae pseudohyphae formation may be triggered by nitrogen deprivation and is stimulated by cAMP. It was observed that even in a medium with an adequate nitrogen supply, cAMP can induce pseudohyphal growth when S. cerevisiae uses ethanol as carbon source. This led us to investigate the effects of the carbon source and of a variety of stresses on yeast morphology. Pseudohyphae formation and invasive growth were observed in a rich medium (YP) with poor carbon sources such as lactate or ethanol. External cAMP was required for the morphogenetic transition in one genetic background, but was dispensable in strain sigma 1278b which has been shown to have an overactive Ras2/cAMP pathway. Pseudohyphal growth and invasiveness also took place in YPD plates when the yeast was subjected to different stresses: a mild heat-stress (37 degrees C), an osmotic stress (1 m NACl), or addition of compounds which affect the lipid bilayer organization of the cell membrane (aliphatic alcohols at 2%) or alter the glucan structure of the cell wall (Congo red). We conclude that pseudohyphal growth is a physiological response not only to starvation but also to a stressful environment; it appears to require the coordinate action of a MAP kinase cascade and a cAMP-dependent pathway.
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PMID:Pseudohyphal growth is induced in Saccharomyces cerevisiae by a combination of stress and cAMP signalling. 1120 70

Transient generation of reactive oxygen or nitrogen (ROS/RNS), detected with dihydrodichlorofluoroscein by fluorescence microscopy, occurs within minutes of exposing cells to ionizing radiation. In the 1-10 Gy dose range, the amount of ROS/RNS produced/cell is constant, but the percentage of producing cells increases with dose (20 to 80%). Reversible depolarization of the mitochondrial membrane potential () and decrease in fluorescence of a mitochondria-entrapped dye, calcein, are observed coincidentally. Radiation-induced ROS/RNS, depolarization, and calcein fluorescence decrease are inhibited by the mitochondrial permeability transition inhibitor, cyclosporin A, but not the structural analogue, cyclosporin H. Radiation-stimulated ROS/RNS is also inhibited by overexpressing the Ca(2+)-binding protein, calbindin 28K, or treating cells with an intracellular Ca(2+) chelator. Radiation-induced ROS/RNS is observed in several cell types with the exception of rho(o) cells deficient in mitochondrial electron transport. rho(o) cells show neither radiation-induced ROS/RNS production nor depolarization. We propose that radiation damage in a few mitochondria is transmitted via a reversible, Ca(2+)-dependent mitochondrial permeability transition to adjacent mitochondria with resulting enhanced ROS/RNS generation. Measurements of radiation-induced mitogen-activated protein kinase activity indicate that this sensing/amplification mechanism is necessary for activation of some cytoplasmic signaling pathways by low doses of radiation.
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PMID:Ionizing radiation-induced, mitochondria-dependent generation of reactive oxygen/nitrogen. 1135 2

Synthetic lipopeptides based on bacterial lipoprotein are efficient activators for monocytes/macrophages inducing the release of interleukin (IL)-1, IL-6, tumour necrosis factor-alpha (TNF-alpha), reactive oxygen/nitrogen intermediates, and the translocation of nuclear factor kappaB (NFkappaB). In this report we investigate the signal transduction pathways involved in leucocyte activation by the synthetic lipopeptide N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-(R)-cysteinyl-seryl-(lysyl)3-lysine (P3CSK4). We show that P3CSK4 activates mitogen-activated protein (MAP)-kinases ERK1/2 and MAP kinase (MAPK)-kinases MEK1/2 in bone-marrow-derived macrophages (BMDM) and in the macrophage cell line RAW 264.7. Additionally, we could detect differences between the P3CSK4 and lipopolysaccharide (LPS)-induced phosphorylation of MAP kinases: Different levels in phosphorylation were found both in kinetics and dose-response using RAW 264.7 cells or BMDM from BALB/c and LPS responder mice (C57BL/10ScSn) or LPS non-responder mice (C57BL/10ScCr). The lipopeptide activated the MAPK-signalling cascade in both LPS responder and non-responder macrophages, whereas LPS induced the MAPK signalling pathway only in macrophages derived from LPS responder mice. An approximately 70% decrease of lipopeptide induced NFkappaB translocation and an about 50% reduction of nitric oxide (NO) release was observed in the presence of anti-CD14. These data correspond to the reduction of phosphorylation of ERK1/2 after stimulation with P3CSK4 in the presence of anti-CD14 antibodies. Inhibition of MEK1/2 by PD98059 completely reduced the lipopeptide-induced phosphorylation of ERK1/2 indicating that MEK1/2 are solely responsible for the phosphorylation of the downstream-located MAP kinases ERK1/2.
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PMID:Immunostimulation by the synthetic lipopeptide P3CSK4: TLR4-independent activation of the ERK1/2 signal transduction pathway in macrophages. 1138 Jun 92

Cytokine oncostatin M (OM) has profound effects on proliferation and differentiation of breast cancer cells. OM treated cells show reduced growth rate and differentiated phenotypes. The mechanisms underlying the OM growth-inhibitory activity in breast cancer cells have not been fully elucidated. In this study, we investigated the OM-elicited signaling pathways in breast cancer cell lines MDA-MB231 and MCF-7. We show that OM rapidly activates the extracellular signal-regulated kinase (ERK) and the signal transducer and activator of transcription (STAT) 1 and 3 in both cell lines. Intriguingly, OM-induced growth inhibition and morphological changes in MDA-MB231 cells are completely abolished by inhibitors to ERK upstream kinase MEK (nitrogen/extracellular-regulated protein kinase kinase), but the MEK inhibitors have little effects on OM growth-inhibitory activity in MCF-7 cells. In addition, expressions of the cyclin kinase inhibitors p21 and p27 are strongly induced by OM in MCF-7 cells, but their expression is only slightly increased by OM in MDA-MB231 cells. These data together demonstrate that the growth-inhibitory activity of OM can be mediated by different signaling pathways in a cell line-specific manner. While the MEK/ERK pathway is the predominant signaling pathway that leads to the growth inhibition of MDA-MB231 cells, activation of additional signaling pathways are necessary for OM to exert its growth-inhibitory activity in MCF-7 cells.
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PMID:Oncostatin M-induced growth inhibition and morphological changes of MDA-MB231 breast cancer cells are abolished by blocking the MEK/ERK signaling pathway. 1143 97

Oxidized low-density lipoprotein (oxLDL) is known to activate a number of signal transduction pathways in endothelial cells. Among these are the c-Jun NH(2)-terminal kinase (JNK), also known as stress-activated protein kinase, and extracellular signal-regulated kinase (ERK). These mitogen-activated protein kinases (MAP kinase) determine cell survival in response to environmental stress. Interestingly, JNK signaling involves redox-sensitive mechanisms and is activated by reactive oxygen and nitrogen species derived from both NADPH oxidases, nitric oxide synthases (NOS), peroxides, and oxidized low-density lipoprotein (oxLDL). The role of endothelial NOS (eNOS) in the activation of JNK in response to oxLDL has not been examined. Herein, we show that on exposure of endothelial cells to oxLDL, both ERK and JNK are activated through independent signal transduction pathways. A key role of eNOS activation through a phosphatidylinositol-3-kinase-dependent mechanism leading to phosphorylation of eNOS is demonstrated for oxLDL-dependent activation of JNK. Moreover, we show that activation of ERK by oxLDL is critical in protection against the cytotoxicity of oxLDL.
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PMID:Endothelial NOS-dependent activation of c-Jun NH(2)- terminal kinase by oxidized low-density lipoprotein. 1170 40

Rapamycin binds and inhibits the Tor protein kinases, which function in a nutrient-sensing signal transduction pathway that has been conserved from the yeast Saccharomyces cerevisiae to humans. In yeast cells, the Tor pathway has been implicated in regulating cellular responses to nutrients, including proliferation, translation, transcription, autophagy, and ribosome biogenesis. We report here that rapamycin inhibits pseudohyphal filamentous differentiation of S. cerevisiae in response to nitrogen limitation. Overexpression of Tap42, a protein phosphatase regulatory subunit, restored pseudohyphal growth in cells exposed to rapamycin. The tap42-11 mutation compromised pseudohyphal differentiation and rendered it resistant to rapamycin. Cells lacking the Tap42-regulated protein phosphatase Sit4 exhibited a pseudohyphal growth defect and were markedly hypersensitive to rapamycin. Mutations in other Tap42-regulated phosphatases had no effect on pseudohyphal differentiation. Our findings support a model in which pseudohyphal differentiation is controlled by a nutrient-sensing pathway involving the Tor protein kinases and the Tap42-Sit4 protein phosphatase. Activation of the MAP kinase or cAMP pathways, or mutation of the Sok2 repressor, restored filamentation in rapamycin treated cells, supporting models in which the Tor pathway acts in parallel with these known pathways. Filamentous differentiation of diverse fungi was also blocked by rapamycin, demonstrating that the Tor signaling cascade plays a conserved role in regulating filamentous differentiation in response to nutrients.
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PMID:The TOR signal transduction cascade controls cellular differentiation in response to nutrients. 1173 4


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