Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Through the inhibition of monoamine oxidase type B (MAO-B), (-)-deprenyl (selegiline) prevents the conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the toxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+) and also prevents the neurotoxicity in the dopaminergic neurons in animal models. Cumulative observations suggest that selegiline may also protect against MPP+-induced neurotoxicity, possibly through the induction of pro-survival genes. We have observed that thioredoxin (Trx) mediates the induction of mitochondrial manganese superoxide dismutase (MnSOD) and Bcl-2 during preconditioning-induced hormesis. We therefore investigated whether the redox protein Trx plays any role in the neuroprotective mechanism of selegiline against MPP+-induced cytotoxicity in human SH-SY5Y neuroblastoma cells and also in primary neuronal cultures of mouse midbrain dopaminergic neurons. After confirming that selegiline protects against MPP+-induced cytotoxicity, we observed further that selegiline, at 1 microM or less, induced Trx for protection against oxidative injury caused by MPP+. The induction of Trx was blocked by protein kinase A (PKA) inhibitor and mediated by a PKA-sensitive phospho-activation of mitogen-activated protein (MAP) kinase Erk1/2 and the transcription factor c-Myc. Selegiline-induced Trx and associated neuroprotection were concomitantly blocked by the antisense against Trx mRNA, but not the sense or antisense mutant phosphothionate oligonucleotides, not only in human SH-SY5Y cells but also in mouse primary neuronal culture of midbrain dopaminergic neurons. Furthermore, the redox cycling of Trx may mediate the protective action of selegiline because the inhibition of Trx reductase by 1-chloro-2,4-dinitrobenzene ameliorated the effect of selegiline. Trx (1 microM) consistently increased the expression of mitochondrial proteins MnSOD and Bcl-2, supporting cell survival (Andoh et al., 2002). In conclusion, without modifying MAO-B activity, selegiline augments the gene induction of Trx, leading to elevated expression of antioxidative MnSOD and antiapoptotic Bcl-2 proteins for protecting against MPP+-induced neurotoxicity.
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PMID:Role of the redox protein thioredoxin in cytoprotective mechanism evoked by (-)-deprenyl. 1609 47

It is generally accepted that exhausting endurance exercise exhibits strong effects on the immune system. Such effects have been attributed to changes in the cellular composition of peripheral blood as well as to changes in the expression of plausible candidate genes. The list of candidate genes is far from being complete, since this issue has not yet been investigated in a systematic way. In this study, we used a custom-made cDNA microarray focused on inflammation as a screening approach to study gene expression in eight one-half marathon runners before, immediately after, and 24 h after exercise. Significant differential gene expression was verified by quantitative real-time PCR. Linear regression analysis showed that microarray expression analysis of cell type-specific surface molecules reflects the observed individual cellular shifts in peripheral blood cells with high statistical significance. In line with the results of former studies, we observed an upregulation of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAP-K2), L-selectin, and IL-1 receptor antagonist (IL-1ra) after exhaustive exercise. The main results of this study report, for the first time, the downregulation of CD81; the upregulation of thioredoxin, which may play an important part in anti-oxidative defense; and, surprisingly, the downregulation of the anti-carcinogenic gene glutathione-S-transferase-3 (GSTM3) in peripheral blood. The study shows cDNA microarray expression analysis as a reliable systematic instrument to complete the list of candidate genes that may play a role in exhaustive exercise-induced modulation of the immune response.
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PMID:cDNA microarray analysis reveals novel candidate genes expressed in human peripheral blood following exhaustive exercise. 1611 70

The chemopreventive agent sulforaphane (SFN) exerts anti-inflammatory activity by thiol-dependent inhibition of nuclear factor kappaB (NF-kappaB) DNA binding. To further analyze the underlying mechanisms, we focused on the thioredoxin/thioredoxin reductase (TrxR) system as a key redox mechanism regulating NF-kappaB DNA binding. Using cultured Raw 264.7 mouse macrophages as a model, 1-chloro-2,4-dinitrobenzene (CDNB), a known inhibitor of TrxR, was identified as an inhibitor of lipopolysaccharide (LPS)-mediated nitric oxide (NO) production and of NF-kappaB DNA binding. CDNB and SFN acted synergistically with respect to inhibition of LPS-induced NO release, and we consequently identified SFN as a novel inhibitor of TrxR enzymatic activity in vitro. Short-term treatment of Raw macrophages with SFN or CDNB resulted in the inhibition of TrxR activity in vivo with half-maximal inhibitory concentration of 25.0 +/- 3.5 microM and 9.4 +/- 3.7 microM, respectively, whereas after a 24-h treatment with 25 microM SFN, TrxR activity was >1.5-fold elevated. In additional experiments, we could exclude that inhibition of trans-activating activity of NF-kappaB contributed to the reduced expression of pro-inflammatory proteins by SFN, based on transient transfection experiments with a (kappaB)(2)- chloramphenicol acetyltransferase construct and a lack of inhibition of protein kinase A activity. These findings further emphasize the importance of redox modulation or thiol reactivity for the regulation of NF-kappaB-dependent transcription by SFN. Antioxid. Redox Signal. 7, 1601-1611.
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PMID:Time-dependent modulation of thioredoxin reductase activity might contribute to sulforaphane-mediated inhibition of NF-kappaB binding to DNA. 1635 23

In 1996, cDNA sequences referred to as plant peroxiredoxins (Prx), i.e. a 1-Cys Prx and a 2-Cys Prx, were reported from barley. Ten years of research have advanced our understanding of plant Prx as thiol-based peroxide reductases with a broad substrate specificity, ranging from hydrogen peroxide to alkyl hydroperoxides and peroxinitrite. Prx have several features in common. (i) They are abundant proteins that are routinely detected in proteomics approaches. (ii) They interact with proteins such as glutaredoxins, thioredoxins, and cyclophilins as reductants, but also non-dithiol-disulphide exchange proteins. By work with transgenic plants, their activity was shown to (iii) affect metabolic integrity, (iv) protect DNA from damage in vitro and as shown here in vivo, and (v) modulate intracellular signalling related to reactive oxygen species and reactive nitrogen species. (vi) In all organisms Prx are encoded by small gene families that are of particular complexity in higher plants. A comparison of the Prx gene families in rice and Arabidopsis thaliana supports previous suggestions on Prx function in specific subcellular and metabolic context. (vii) Prx gene expression and activity are subjected to complex regulation realized by an integration of various signalling pathways. 2-Cys Prx expression depends on redox signals, abscisic acid, and protein kinase cascades. Besides these general properties, the chloroplast Prx have acquired specific roles in the context of photosynthesis. The thioredoxin-dependent peroxidase activity can be measured in crude plant extracts and contributes significantly to the overall H(2)O(2) detoxification capacity. Thus organellar Prx proteins enable an alternative water-water cycle for detoxification of photochemically produced H(2)O(2), which acts independently from the ascorbate-dependent Asada-Halliwell-Foyer cycle. 2-Cys Prx and Prx Q associate with thylakoid membrane components. The mitochondrial PrxII F is essential for root growth under stress. Following a more general introduction, the paper summarizes present knowledge on plant organellar Prx, addressing Prx in signalling, and also suggests some lines for future research.
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PMID:The function of peroxiredoxins in plant organelle redox metabolism. 1660 33

Apoptosis signal-regulating kinase 1 (ASK1), a serine/threonine protein kinase, is a reactive oxygen species-sensitive mitogen-activated protein kinase kinase kinase and activates both p38 and c-Jun N-terminal kinase pathways. Two isoforms of thioredoxin (Trx), cytosolic and mitochondrial Trx (Trx1 and Trx2, respectively), have been identified in mammalian cells. Trx1 was initially identified as an ASK1-binding protein. Trx1 and Trx2 bind directly to the N-terminal regulatory domain of ASK1 and inhibit ASK1-dependent apoptosis. Numerous other proteins interact with ASK1 and regulate its activity. In cardiomyocytes, ASK1 is involved not only in cardiac apoptosis, leading to cardiac remodeling, but also in cardiac hypertrophy as well as nonapoptotic cardiomyocyte death.
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PMID:The role of apoptosis signal-regulating kinase 1 in cardiomyocyte apoptosis. 1698 25

The aim of this study was to investigate the inhibitory effect of non-aglycone cyanidin on TNF-alpha-induced endothelial cell apoptosis and its mechanism through enhancing expression of thioredoxin in endothelial cells. We found that exposure of the serum-starved BAECs to TNF-alpha increased significantly the number of dead cells, the cleaved caspase-3 and cleaved poly(ADP-ribose)polymerase (RARP)assayed by Western blot, whereas supplementation with cyanidin considerably suppressed these events. Inhibitors of the Akt, ERK1/2, Src kinase and transfection with a dominant-negative Akt cDNA blocked the inhibitory effect of cyanidin on cleaved caspase-3. Cyanidin significantly elevated expression of endothelial nitric oxide synthase (eNOS) and thioredoxin (Trx). The increased Trx expression was blocked by siRNA transfection of cGMP-dependent protein kinase (PKG) and by using a PKG inhibitor, KT5823. Cyanidin also ameliorated TNF-alpha-induced decrease of Trx S-nitrosylation and intracellular glutathione and elevation of 4-hydroxynonenal (4-HNE), a major aldehydic product of lipid peroxidation. Furthermore, cyanidin also restored S-nitrosylation of caspase-3 and reduced the rise in expression and acetylation of tumor suppression gene p53. However, KT5823 or L-NAME, an inhibitor of eNOS, removed the preventive effects of cyanidin. Our data show that inhibitory effect of cyanidin on TNF-alpha-induced apoptosis involves multiple pathways, such as Akt activation, eNOS and thioredoxin expression in endothelial cells.
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PMID:Inhibitory effect of polyphenol cyanidin on TNF-alpha-induced apoptosis through multiple signaling pathways in endothelial cells. 1704 69

In a recent study, we described that UV-C irradiation resulted in redox-dependent activation and relocalization of A-SMase (acid sphingomyelinase) to the external surface of raft membrane microdomains, hydrolysis of SM (sphingomyelin) associated with the plasma membrane outer leaflet, ceramide generation and apoptosis. In the present study, we have investigated the influence of PKCzeta (protein kinase Czeta), an atypical form of PKC on this pathway. This study shows that PKCzeta overexpression resulted in the abrogation of UV-C-induced A-SMase translocation and activation into the raft microdomains, lack of ceramide generation and apoptosis inhibition. Moreover, PKCzeta overexpression resulted in a decrease in UV-C-induced ROS (reactive oxygen species) production, which correlated with increased gene expression level of various antioxidant enzymes, including TRx (thioredoxin), TR (thioredoxin reductase) 1, TR2 and peroxiredoxin 1/TPx2 (thioredoxin peroxidase 2). Importantly, enforced TPx2 gene expression inhibited UV-C-induced A-SMase translocation. Finally, PKCzeta inhibition led to a significant reduction in TPx2 protein expression. Altogether, these results suggest that PKCzeta interferes with the UV-activated sphingolipid signalling pathway by regulating the TRx system. These findings may have important consequences for UV-induced carcinogenesis and resistance to phototherapy.
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PMID:PKCzeta protects against UV-C-induced apoptosis by inhibiting acid sphingomyelinase-dependent ceramide production. 1734 42

Catecholamines in adipose tissue promote lipolysis via cAMP, whereas insulin stimulates lipogenesis. Here we show that H(2)O(2) generated by insulin in rat adipocytes impaired cAMP-mediated amplification cascade of lipolysis. These micromolar concentrations of H(2)O(2) added before cAMP suppressed cAMP activation of type IIbeta cyclic AMP-dependent protein kinase (PKA) holoenzyme, prevented hormone-sensitive lipase translocation from cytosol to storage droplets, and inhibited lipolysis. Similarly, H(2)O(2) impaired activation of type IIalpha PKA holoenzyme from bovine heart and from that reconstituted with regulatory IIalpha and catalytic alpha subunits. H(2)O(2) was ineffective (a) if these PKA holoenzymes were preincubated with cAMP, (b) if added to the catalytic alpha subunit, which is active independently of cAMP activation, and (c) if the catalytic alpha subunit was substituted by its C199A mutant in the reconstituted holoenzyme. H(2)O(2) inhibition of PKA activation remained after H(2)O(2) elimination by gel filtration but was reverted with dithiothreitol or with thioredoxin reductase plus thioredoxin. Electrophoresis of holoenzyme in SDS gels showed separation of catalytic and regulatory subunits after cAMP incubation but a single band after H(2)O(2) incubation. These data strongly suggest that H(2)O(2) promotes the formation of an intersubunit disulfide bond, impairing cAMP-dependent PKA activation. Phylogenetic analysis showed that Cys-97 is conserved only in type II regulatory subunits and not in type I regulatory subunits; hence, the redox regulation mechanism described is restricted to type II PKA-expressing tissues. In conclusion, phylogenetic analysis results, selective chemical behavior, and the privileged position in holoenzyme lead us to suggest that Cys-97 in regulatory IIalpha or IIbeta subunits is the residue forming the disulfide bond with Cys-199 in the PKA catalytic alpha subunit. A new molecular point for cross-talk among heterologous signal transduction pathways is demonstrated.
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PMID:Signaling the signal, cyclic AMP-dependent protein kinase inhibition by insulin-formed H2O2 and reactivation by thioredoxin. 1832 45

A wide array of dietary phytochemicals have been reported to induce the expression of enzymes involved in both cellular antioxidant defenses and elimination/inactivation of electrophilic carcinogens. Induction of such cytoprotective enzymes by edible phytochemicals largely accounts for their cancer chemopreventive and chemoprotective activities. Nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a crucial role in the coordinated induction of those genes encoding many stress-responsive and cytoptotective enzymes and related proteins. These include NAD(P)H:quinone oxidoreductase-1, heme oxygenase-1, glutamate cysteine ligase, glutathione S-transferase, glutathione peroxidase, thioredoxin, etc. In resting cells, Nrf2 is sequestered in the cytoplasm as an inactive complex with the repressor Kelch-like ECH-associated protein 1 (Keap1). The release of Nrf2 from its repressor is most likely to be achieved by alterations in the structure of Keap1. Keap1 contains several reactive cysteine residues that function as sensors of cellular redox changes. Oxidation or covalent modification of some of these critical cysteine thiols would stabilize Nrf2, thereby facilitating nuclear accumulation of Nrf2. After translocation into nucleus, Nrf2 forms a heterodimer with other transcription factors, such as small Maf, which in turn binds to the 5'-upstream CIS-acting regulatory sequence, termed antioxidant response elements (ARE) or electrophile response elements (EpRE), located in the promoter region of genes encoding various antioxidant and phase 2 detoxifying enzymes. Certain dietary chemopreventive agents target Keap1 by oxidizing or chemically modifying one or more of its specific cysteine thiols, thereby stabilizing Nrf2. In addition, phosphorylation of specific serine or threonine residues present in Nrf2 by upstream kinases may also facilitate the nuclear localization of Nrf2. Multiple mechanisms of Nrf2 activation by signals mediated by one or more of the upstream kinases, such as mitogen-activated protein kinases, phosphatidylionositol-3-kinase/Akt, protein kinase C, and casein kinase-2 have recently been proposed. This review highlights the cytoprotective gene expression induced by some representative dietary chemopreventive phytochemicals with the Nrf2-Keap1 system as a prime molecular target.
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PMID:Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. 1893 64

State transitions allow for the balancing of the light excitation energy between photosystem I and photosystem II and for optimal photosynthetic activity when photosynthetic organisms are subjected to changing light conditions. This process is regulated by the redox state of the plastoquinone pool through the Stt7/STN7 protein kinase required for phosphorylation of the light-harvesting complex LHCII and for the reversible displacement of the mobile LHCII between the photosystems. We show that Stt7 is associated with photosynthetic complexes including LHCII, photosystem I, and the cytochrome b6f complex. Our data reveal that Stt7 acts in catalytic amounts. We also provide evidence that Stt7 contains a transmembrane region that separates its catalytic kinase domain on the stromal side from its N-terminal end in the thylakoid lumen with two conserved Cys that are critical for its activity and state transitions. On the basis of these data, we propose that the activity of Stt7 is regulated through its transmembrane domain and that a disulfide bond between the two lumen Cys is essential for its activity. The high-light-induced reduction of this bond may occur through a transthylakoid thiol-reducing pathway driven by the ferredoxin-thioredoxin system which is also required for cytochrome b6f assembly and heme biogenesis.
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PMID:Analysis of the chloroplast protein kinase Stt7 during state transitions. 1926 Jul 61


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