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)

We show that the mitogen-activated protein (MAP) kinase pathway that responds to osmotic stress in Aspergillus fumigatus is also involved in nutritional sensing. This MAP kinase regulates conidial germination in response to the nitrogen source and is activated upon starvation for either carbon or nitrogen during vegetative growth.
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PMID:A mitogen-activated protein kinase that senses nitrogen regulates conidial germination and growth in Aspergillus fumigatus. 1507 85

The extracellular signal regulated protein kinases (ERK1/2) are essential for normal development and functional plasticity of the central nervous system. However, a growing number of recent studies in models of cerebral ischemia, brain trauma and neurodegenerative diseases implicate a detrimental role for ERK1/2 signaling during oxidative neuronal injury. Neurons undergoing oxidative stress-related injuries typically display a biphasic or sustained pattern of ERK1/2 activation. A variety of potential targets of reactive oxygen species and reactive nitrogen species could contribute to ERK1/2 activation. These include cell surface receptors, G proteins, upstream kinases, protein phosphatases and proteasome components, each of which could be direct or indirect targets of reactive oxygen or nitrogen species, thereby modulating the duration and magnitude of ERK1/2 activation. Neuronal oxidative stress also appears to influence the subcellular trafficking and/or localization of activated ERK1/2. Differences in compartmentalization of phosphorylated ERK1/2 have been observed in diseased or injured human neurons and in their respective animal and cell culture model systems. We propose that differential accessibility of ERK1/2 to downstream targets, which is dictated by the persistent activation of ERK1/2 within distinct subcellular compartments, underlies the neurotoxic responses that are driven by this kinase.
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PMID:Oxidative neuronal injury. The dark side of ERK1/2. 1515 95

Schizosaccharomyces pombe utilizes two opposing signaling pathways to sense and respond to its nutritional environment. Glucose detection triggers a cyclic AMP signal to activate protein kinase A (PKA), while glucose or nitrogen starvation activates the Spc1/Sty1 stress-activated protein kinase (SAPK). One process controlled by these pathways is fbp1+ transcription, which is glucose repressed. In this study, we isolated strains carrying mutations that reduce high-level fbp1+ transcription conferred by the loss of adenylate cyclase (git2delta), including both wis1- (SAPK kinase) and spc1- (SAPK) mutants. While characterizing the git2delta suppressor strains, we found that the git2delta parental strains are KCl sensitive, though not osmotically sensitive. Of 102 git2delta suppressor strains, 17 strains display KCl-resistant growth and comprise a single linkage group, carrying mutations in the cgs1+ PKA regulatory subunit gene. Surprisingly, some of these mutants are mostly wild type for mating and stationary-phase viability, unlike the previously characterized cgs1-1 mutant, while showing a significant defect in fbp1-lacZ expression. Thus, certain cgs1- mutant alleles dramatically affect some PKA-regulated processes while having little effect on others. We demonstrate that the PKA and SAPK pathways regulate both cgs1+ and pka1+ transcription, providing a mechanism for cross talk between these two antagonistically acting pathways and feedback regulation of the PKA pathway. Finally, strains defective in both the PKA and SAPK pathways display transcriptional regulation of cgs1+ and pka1+, suggesting the presence of a third glucose-responsive signaling pathway.
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PMID:Suppressors of an adenylate cyclase deletion in the fission yeast Schizosaccharomyces pombe. 1518 83

In Schizosaccharomyces pombe, glucose concentrations below a certain threshold trigger the stress-activated protein kinase (SAPK) signal transduction pathway and promote increased transcription of Atf1-dependent genes coding for the general stress response. Removal of glucose specifically induces the nuclear accumulation of green fluorescent protein-labeled Pap1 (GFP-Pap1) and the expression of genes dependent on this transcription factor. In contrast, depletion of the nitrogen source triggers the SAPK pathway but does not activate Pap1-dependent gene transcription, indicating that carbon stress rather than growth arrest leads to an endogenous oxidative condition that favors nuclear accumulation of Pap1. The reductant agents glutathione or N-acetylcysteine suppress the nuclear accumulation of GFP-Pap1 induced by glucose deprivation without inhibiting the activation of the MAPK Sty1. In addition, cells expressing a mutant GFP-Pap1 unable to accumulate into the nucleus upon hydrogen peroxide-mediated oxidative stress failed to show this protein into the nucleus in the absence of glucose. These results support the concept of a concerted action between the SAPK pathway and the Pap1 transcription factor during glucose exhaustion by which glucose limitation induces activation of the SAPK pathway prior to the oxidative stress caused by glucose deprivation. The ensuing induction of Atf1-dependent genes (catalase) decreases the level of hydroperoxides allowing Pap1 nuclear accumulation and function. Congruent with this interpretation, glucose-depleted cells show higher adaptive response to exogenous oxidative stress than those maintained in the presence of glucose.
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PMID:A cooperative role for Atf1 and Pap1 in the detoxification of the oxidative stress induced by glucose deprivation in Schizosaccharomyces pombe. 1524 18

Nitrogen dioxide is a highly toxic reactive nitrogen species (RNS) recently discovered as an inflammatory oxidant with great potential to damage tissues. We demonstrate here that cell death by RNS was caused by c-Jun N-terminal kinase (JNK). Activation of JNK by RNS was density dependent and caused mitochondrial depolarization and nuclear condensation. JNK activation by RNS was abolished in cells lacking functional Fas or following expression of a truncated version of Fas lacking the intracellular death domain. In contrast, RNS induced JNK potently in cells expressing a truncated version of tumor necrosis factor receptor 1 or cells lacking tumor necrosis factor receptor 1 (TNF-R1), illustrating a dependence of Fas but not TNF-R1 in RNS-induced signaling to JNK. Furthermore, Fas was oxidized, redistributed, and colocalized with Fas-associated death domain (FADD) in RNS-exposed cells, illustrating that RNS directly targeted Fas. JNK activation and cell death by RNS occurred in a Fas ligand- and caspase-independent manner. While the activation of JNK by RNS or FasL required FADD, the cysteine-rich domain 1 containing preligand assembly domain required for FasL signaling was not involved in JNK activation by RNS. These findings illustrate that RNS cause cell death in a Fas- and JNK-dependent manner and that this occurs through a pathway distinct from FasL. Thus, avenues aimed at preventing the interaction of RNS with Fas may attenuate tissue damage characteristic of chronic inflammatory diseases that are accompanied by high levels of RNS.
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PMID:Reactive nitrogen species-induced cell death requires Fas-dependent activation of c-Jun N-terminal kinase. 1525 43

Apart from their genotoxic effects, both fibrous and non-fibrous particles are known to induce signalling pathways involved in the development of malignant lung diseases. Different direct effects of particles as well as indirect cellular effects are believed to induce changes in apoptosis or proliferation in target cells. Signalling events, e.g. the induction of mitogen-activated protein kinase (MAPK) cascades resulting in the activation of the transcription factor AP-1, as well as the induction of the transcription factor NFkappaB which mainly mediates the expression of pro-inflammatory genes are discussed. There is some insight into the molecular mechanisms eliciting these pathways. Therefore, this review aims to give an overview on signalling pathways as well as initial events including effects of reactive oxygen and nitrogen species, membrane receptors and particle uptake.
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PMID:Signal transduction pathways relevant for neoplastic effects of fibrous and non-fibrous particles. 1528 30

During inflammation, microglial cells go through phenotypic and functional changes that include the production and release of large amounts of oxygen and nitrogen radicals. As such, activated microglia are subject to heightened oxidative stress. The multicatalytic proteasome clears oxidized and damaged proteins from cells, and has been shown to be an important aspect of the microglial compensatory response to activation. The female sex steroid estrogen is both cytoprotective and anti-inflammatory, and has been shown to affect microglial signaling in particular. To determine if estrogen might affect the proteasome in microglial cells, we examined the effects of 17 beta-estradiol treatment on proteasome activity in N9 microglial cells. Specifically, we measured ATP-dependent and ATP-independent chymotrypsin-like, trypsin-like, and peptidyl glutamyl peptide hydrolase (PGPH)-like activities in response to both 17 beta-estradiol and interferon gamma. Data indicate that estrogen, but not interferon gamma, significantly increases ATP-dependent chymotrypsin-like and PGPH-like activity. Furthermore, this effect was blocked by the p44/42 MAPK inhibitor PD98059. Hence, these data demonstrate that through the MAPK pathway, estrogen can upregulate proteasome activity, suggesting a possible mechanism for estrogen's cytoprotective effects.
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PMID:Estrogen increases proteasome activity in murine microglial cells. 1530 98

Although co-ordinate interaction between different signal transduction pathways is essential for developmental decisions, interpathway connections are often obscured and difficult to identify due to cross-talk. Here signals from the fission yeast stress-activated MAPK Spc1 are shown to regulate Cgs2, a negative regulator of the cAMP-dependent protein kinase (protein kinase A) pathway. Pathway integration is achieved via Spc1-dependent binding of Atf1-Pcr1 heterodimer to an M26 DNA site in the cgs2+ promoter, which remodels chromatin to regulate expression of cgs2+ and targets downstream of protein kinase A. This direct interpathway connection co-ordinates signals of nitrogen and carbon source depletion to affect a G0 cell-cycle checkpoint and sexual differentiation. The Atf1-Pcr1-M26 complex-dependent chromatin remodeling provides a molecular mechanism whereby Atf1-Pcr1 heterodimer can function differentially as either a transcriptional activator, or as a transcriptional repressor, or as an inducer of meiotic recombination. We also show that the Atf1-Pcr1-M26 complex functions as both an inducer and repressor of chromatin remodeling, which provides a way for various chromatin remodeling-dependent effector functions to be regulated.
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PMID:Atf1-Pcr1-M26 complex links stress-activated MAPK and cAMP-dependent protein kinase pathways via chromatin remodeling of cgs2+. 1544 37

Alzheimer's disease can be considered a protein misfolding disease. In particular, inappropriate processing of a proteolytic fragment of amyloid precursor protein, amyloid beta-protein (Abeta), in early stages of Alzheimer's disease may lead to stabilization of small oligomers that are highly mobile and have a potential to be extremely toxic assemblies. Recently, the importance of such soluble species of Abeta in triggering synaptic dysfunction, long before neuronal loss occurs, has become apparent. Animal models have revealed that plasticity of hippocampal excitatory synaptic transmission is relatively selectively vulnerable to Abeta both in vitro and in vivo. This review focuses on the mechanisms of Abeta inhibition of long-term potentiation at synapses in the rodent hippocampus from two complimentary perspectives. Firstly, we examine evidence that the synaptic activity of this peptide resides primarily in oligomeric rather than monomeric or fibrillar Abeta species. Secondly, the importance of different oxidative/nitrosative stress-linked cascades including JNK, p38 MAPK and NADPH oxidase/iNOS-generated reactive oxygen/nitrogen free radicals in mediating the inhibition of LTP by Abeta is emphasised. These mechanistic studies provide a plausible explanation for the sensitivity of hippocampus-dependent memory to impairment in the early preclinical stages of Alzheimer's disease.
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PMID:Mechanisms of the inhibitory effects of amyloid beta-protein on synaptic plasticity. 1558 82

In addition to powering energy needs of the cell, mitochondria function as pivotal integrators of cell survival/death signals. In recent years, numerous studies indicate that each of the major kinase signaling pathways can be stimulated to target the mitochondrion. These include protein kinase A, protein kinase B/Akt, protein kinase C, extracellular signal-regulated protein kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. Although most studies focus on phosphorylation of pro- and antiapoptotic proteins (BAD, Bax, Bcl-2, Bcl-xL), kinase-mediated regulation of complex I activity, anion and cation channels, metabolic enzymes, and Mn-SOD mRNA has also been reported. Recent identification of a number of scaffold proteins (AKAP, PICK, Sab) that bring specific kinases to the cytoplasmic surface of mitochondria further emphasizes the importance of mitochondrial kinase signaling. Immunogold electron microscopy, subcellular fractionation and immunofluorescence studies demonstrate the presence of kinases within subcompartments of the mitochondrion, following diverse stimuli and in neurodegenerative diseases. Given the sensitivity of these signaling pathways to reactive oxygen and nitrogen species, in situ activation of mitochondrial kinases may represent a potent reverse-signaling mechanism for communication of mitochondrial status to the rest of the cell.
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PMID:Kinase signaling cascades in the mitochondrion: a matter of life or death. 1558 66


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