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)

It is clear that multiple signalling pathways regulate the critical balance between cell death and survival in myocardial ischaemia-reperfusion. Recent attention has focused on the activation of survival or salvage kinases, particularly during reperfusion, as a common mechanism of many cardioprotective interventions. The phosphatidyl inositol 3'-hydroxy kinase/Akt complex (PI3K/Akt) and p42/p44 mitogen-activated protein kinase cascades have been widely promoted in this respect but the cyclic guanosine 3',5'-monophosphate/cGMP-dependent protein kinase (cGMP/PKG) signal transduction cassette has been less systematically investigated as a survival cascade. We propose that activation of the cGMP/PKG signalling pathway, following activation of soluble or particulate guanylate cyclases, may play a pivotal role in survival signalling in ischaemia-reperfusion, especially in the classical preconditioning, delayed preconditioning and postconditioning paradigms. The resurgence of interest in reperfusion injury, largely as a result of postconditioning-related research, has confirmed that the cGMP/PKG pathway is a pivotal salvage mechanism in reperfusion. Numerous studies suggest that the infarct-limiting effects of preconditioning and postconditioning, exogenously donated nitric oxide (NO), natriuretic peptides, phosphodiesterase inhibitors, and other diverse drugs and mediators such as HMG co-A reductase inhibitors (statins), Rho-kinase inhibitors and adrenomedullin, whether given before and during ischaemia, or specifically at the onset of reperfusion, may be mediated by activation or enhancement of the cGMP pathway, either directly or indirectly via endogenous NO generation downstream of PI3K/Akt. Putative mechanisms of protection include PKG regulation of Ca(2+) homeostasis through the modification of sarcoplasmic reticulum Ca(2+) uptake mechanisms, and PKG-induced opening of ATP-sensitive K(+) channels during ischaemia and/or reperfusion. At present, significant technical obstacles in defining the precise roles played by cGMP/PKG signalling include the heavy reliance on pharmacological PKG inhibitors of uncertain selectivity, difficulties in determining PKG activity in intact tissue, and the growing recognition that intracellular compartmentalisation of the cGMP pool may contribute markedly to the nucleotide's biological actions and biochemical determination. Overall, the body of experimental evidence suggests that cGMP/PKG survival signalling ameliorates irreversible injury associated with ischaemia-reperfusion and may be a tractable therapeutic target.
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PMID:Cyclic GMP and protein kinase-G in myocardial ischaemia-reperfusion: opportunities and obstacles for survival signaling. 1787 5

Cardiovascular disease is the leading cause of morbidity and mortality in industrial societies, with myocardial infarction as the primary assassin. Pharmacologic agents, including the myocardial cell membrane receptor agonists adenosine, bradykinin/angiotensin-converting enzyme inhibitors, opioids and erythropoietin or the mixed cell membrane and intracellular agonists, glucose insulin potassium, and volatile anesthetics, either clinically or experimentally reduce the extent of myocardial injury when administered just prior to reperfusion. Agents that specifically target proteins, transcription factors or ion channels, including PKC agonists/antagonists, PPAR, Phosphodiesterase-5 inhibitors, 3-Hydroxy-3-methyl glutaryl coenzyme A reductase and the ATP-dependent potassium channel are also promising. However, no agent has been specifically approved to reduce reperfusion injury clinically. In this review, we will discuss the advantages and limitations of agents to combat reperfusion injury, their market development status and findings reported in both clinical and preclinical studies. The molecular pathways activated by these agents that preserve myocardium from reperfusion injury, which appear to commonly involve glycogen synthase kinase 3beta and mitochondrial permeability transition pore inhibition, are also described.
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PMID:Pharmacologic therapeutics for cardiac reperfusion injury. 1787 67

Cold-induced genes of highland barley (Hordeum vulgare L. var. nudum Hk. f.) were studied using suppression subtractive hybridization (SSH) technique. The cDNA from the materials treated with 4 degrees C was used as "tester", and that from the materials growing in green house (20+/-2 degrees C) as "driver". A subtractive library of highland barley including 640 cDNA clones was constructed in this study. Enzyme digestion of 32 clones chosen randomly from the library indicated that 87.5% of them contained inserts. The cDNA inserts of 16 clones were sequenced. Blast search analyses showed that these cDNAs were homologies to genes encoding the following proteins: metallothionein, protein kinase, ethylene signal transcription factor, bZIP transcription factor, zing finger transcription factor, ribulose-1,5-bisphosphate carboxylase, ribosomal protein, sodium: hydrogen antiporter, catalase, NADPH-cytochrome reductase, ascorbate peroxidase, DNA binding protein, and sugar transporter-like protein. These results indicated that the cDNA clones in the library were related to cold-induced genes, and suggested that the cold-tolerant mechanism of highland barley might be a complicated, interactive system involving multiple approaches and genes. Construction of subtractive cDNA library provided an advantage for further studies to isolate and clone cold-induced genes in highland barley.
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PMID:[Cold induced cDNA library construction of highland barley (Hordeum vulgare L. var. nudum Hk. f.) using suppression subtractive hybridization technology]. 1913 23

Statins are 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are prescribed extensively for cholesterol lowering in the primary and secondary prevention of cardiovascular disease. Recent compelling evidence suggests that the beneficial effects of statins may not only be due to their cholesterol lowering effects, but also, to their cholesterol-independent or pleiotropic effects. Through these so-called pleiotropic effects, statins are directly involved in restoring or improving endothelial function, attenuating vascular remodeling, inhibiting vascular inflammatory response, and perhaps, stabilizing atherosclerotic plaques. These cholesterol-independent effects of statins are predominantly due to their ability to inhibit isoprenoid synthesis, the products of which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. In particular, inhibition of Rho and its downstream target, Rho-associated coiled-coil containing protein kinase (ROCK), has emerged as the principle mechanisms underlying the pleiotropic effects of statins. This review provides an update of statin-mediated vascular effects beyond cholesterol lowering and highlights recent findings from bench to bedside to support the concept of statin pleiotropy.
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PMID:Statins and cardiovascular diseases: from cholesterol lowering to pleiotropy. 1919 75

Simvastatin inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyses conversion of HMG-CoA to mevalonate, a rate-limiting step in cholesterol synthesis. We demonstrated that simvastatin at 1 microM markedly inhibited adipocyte differentiation measured by Oil Red O staining in preadipocyte cells (3T3-L1), while expression of leptin, a marker of adipocyte differentiation, was suppressed by 1 muM simvastatin for up to 12 days of culture. Next, to elucidate mechanisms underlying the reduction of leptin expression induced by simvastatin, differentiated 3T3-L1 adipocytes were treated with various inhibitors with mevalonate or its metabolite in the presence or absence of simvastatin. Simvastatin time- and dose-dependently suppressed leptin mRNA expression. Heterogeneous nuclear RNA related to leptin mRNA was inhibited by 10 muM simvastatin, while stability of the mRNA was not changed by treatment with simvastatin in transcription-arrested 3T3-L1 cells. Simvastatin inhibition of leptin gene transcription was not abrogated by pre-treatment with cycloheximide, an inhibitor of protein synthesis. Addition of mevalonate or geranylgeranyl pyrophosphate (GGPP), a mevalonate metabolite, abolished simvastatin-induced inhibition of leptin expression in 3T3-L1 cells. Suppression of expression was observed upon addition of GGTI-298, a geranylgeranyl transferase I inhibitor, but not FTI-277, a farnesyl transferase inhibitor. Expression was suppressed by treatment with hydroxyfasudil, a protein prenylation inhibitor. Treatment with phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002 and wortmannin, reduced leptin expression in 3T3-L1 cells. Simvastatin dose-dependently increased intra-cellular cyclic AMP (cAMP) concentrations in 3T3-L1 cells, with maximal stimulation obtained at 10 muM. Addition of GGPP abolished simvastatin-induced stimulation of cAMP accumulation and protein kinase A (PKA) activity. H89, an inhibitor of PKA, completely abolished simvastatin-induced suppression of leptin expression. These results suggested that simvastatin reduced geranylgeranylprotein prenylation followed by deactivation of PI3K, leading to cAMP accumulation and subsequent activation of PKA in differentiated 3T3-L1 adipocytes. Finally, PKA inhibited leptin gene transcription without new protein synthesis.
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PMID:Simvastatin suppresses leptin expression in 3T3-L1 adipocytes via activation of the cyclic AMP-PKA pathway induced by inhibition of protein prenylation. 1925 25

Epidemiological and clinical data suggest that selenium may prevent prostate cancer; however, the cellular effects of selenium in malignant prostate cells are not well understood. We previously reported that the activity of the tumor suppressor PTEN is modulated by thioredoxin (Trx) in a RedOx-dependent manner. In this study, we demonstrated that the activity of Trx reductase (TR) is increased by sevenfold in the human prostate cancer cell line, DU-145, after 5 days of sodium selenite (Se) treatment. The treatment of DU-145 cells with increasing concentrations of Se induced an increase in PTEN lipid phosphatase activity by twofold, which correlated with a decrease in phospho-ser(473)-Akt, and an increase in phospho-Ser(370)-PTEN levels. Se also increased casein kinase-2 (CK2) activity; and the use of apigenin, an inhibitor of CK2, revealed that the regulation of the tumor suppressor PTEN by Se may be achieved via both the Trx-TR system and the RedOx control of the kinase involved in the regulation of PTEN activity.
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PMID:Sodium selenite increases the activity of the tumor suppressor protein, PTEN, in DU-145 prostate cancer cells. 1937 5

The ubiquitous tripeptide glutathione (GSH) is an essential factor in many biological processes, thus its depletion has a major impact on cell function and survival. In this study, we examined regulation of GSH in cardiomyocytes under chronic oxidative stress elicited by myocardial infarction (MI). Cardiac dysfunction was induced in rats by coronary artery ligation, and experiments were conducted in myocytes isolated from non-infarcted left ventricle and septum after 6-8 weeks. Fluorescence microscopy studies using the probe monochlorobimane showed that [GSH] in myocytes from post-MI hearts was 42% less than in sham control hearts (P < 0.05). However, depleted GSH levels were normalized after 5-6 h by an insulin mimetic (bis-peroxovanadium-1,10-phenanthroline, bpV(phen); 10 micromol l(-1)) or by exogenous pyruvate (5 mmol l(-1)). The increase in [GSH] by bpV(phen) was partly inhibited by buthionine sulphoximine (BSO; 50 micromol l(-1)), a blocker of GSH synthesis, and by 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU; 100 micromol l(-1)), an inhibitor of glutathione disulphide reductase. By comparison, the effect of pyruvate was not altered by BSO but was completely blocked by BCNU. Studies using inhibitors of signalling cascades indicated that upregulation of [GSH] by bpV(phen) in myocytes from post-MI hearts was mediated by mitogen activated protein kinase/extracellular signal-regulated kinase kinase 1/2 and p38 mitogen-activated protein kinase but not by phosphatidylinositol 3-kinase. The effect of pyruvate was not altered by any kinase inhibitor tested. In cells loaded with the probe TEMPO-9-AC to monitor superoxide anion, baseline fluorescence was 2.3-fold greater in post-MI myocytes than in sham control myocytes (P < 0.05) and was markedly decreased by diphenyleneiodonium (30 micromol l(-1)), an inhibitor of NADPH oxidase, exogenous GSH (10 mmol l(-1)) or bpV(phen). In parallel studies, [GSH] in post-MI myocytes was also normalized by diphenyleneiodonium or exogenous GSH. These data show that GSH is differentially regulated by receptor tyrosine kinase-dependent and -independent agonists that maintain functional GSH levels necessary to neutralize excess generation of reactive oxygen species in the failing heart.
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PMID:Glutathione homeostasis in ventricular myocytes from rat hearts with chronic myocardial infarction. 1939 62

The mechanisms involved in sensing oxidative signalling molecules, such as H2O2, in plant and animal cells are not completely understood. In the present study, we tested the postulate that oxidation of Met (methionine) to MetSO (Met sulfoxide) can couple oxidative signals to changes in protein phosphorylation. We demonstrate that when a Met residue functions as a hydrophobic recognition element within a phosphorylation motif, its oxidation can strongly inhibit peptide phosphorylation in vitro. This is shown to occur with recombinant soybean CDPKs (calcium-dependent protein kinases) and human AMPK (AMP-dependent protein kinase). To determine whether this effect may occur in vivo, we monitored the phosphorylation status of Arabidopsis leaf NR (nitrate reductase) on Ser534 using modification-specific antibodies. NR was a candidate protein for this mechanism because Met538, located at the P+4 position, serves as a hydrophobic recognition element for phosphorylation of Ser534 and its oxidation substantially inhibits phosphorylation of Ser534 in vitro. Two lines of evidence suggest that Met oxidation may inhibit phosphorylation of NR-Ser534 in vivo. First, phosphorylation of NR at the Ser534 site was sensitive to exogenous H2O2 and secondly, phosphorylation in normal darkened leaves was increased by overexpression of the cytosolic MetSO-repair enzyme PMSRA3 (peptide MetSO reductase A3). These results are consistent with the notion that oxidation of surface-exposed Met residues in kinase substrate proteins, such as NR, can inhibit the phosphorylation of nearby sites and thereby couple oxidative signals to changes in protein phosphorylation.
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PMID:Coupling oxidative signals to protein phosphorylation via methionine oxidation in Arabidopsis. 1966 8

gamma-Tocotrienol, a member of the vitamin E family of compounds, induces apoptosis in a variety of cancer cell types. However, previous studies have clearly demonstrated that gamma-tocotrienol-induced apoptosis in neoplastic mouse +SA mammary epithelial cells is not mediated through mitochondrial stress or death receptor apoptotic signaling. Therefore, studies were conducted to determine the role of endoplasmic reticulum (ER) stress in mediating gamma-tocotrienol-induced apoptosis in +SA mammary tumor cells. Treatment with 15-40 microM gamma-tocotrienol induced +SA cell death in a dose-responsive manner, and these effects were associated with a corresponding increase in poly (ADP-ribose) polymerase (PARP)-cleavage and activation of protein kinase-like endoplasmic reticulum kinase/eukaryotic translational initiation factor/activating transcription factor 4 (PERK/eIF2alpha/ATF-4) pathway, a marker of ER stress response. These treatments also caused a large increase in C/EBP homologous protein (CHOP) levels, a key component of ER stress mediated apoptosis that increases expression of tribbles 3 (TRB3). Knockdown of CHOP by specific siRNAs attenuated gamma-tocotrienol-induced PARP-cleavage, CHOP and TRB3 expression. gamma-Tocotrienol treatment also reduced full-length caspase-12 levels, an indication of caspase-12 cleavage and activation. Intracellular levels of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase, an ER-transmembrane enzyme catalyzing the synthesis of mevalonate, decreased following gamma-tocotrienol treatment, but combined treatment with mevalonate did not reverse gamma-tocotrienol-induced apoptosis, suggesting that a decrease in HMGCoA reductase activity is not required for gamma-tocotrienol induced apoptosis. These results demonstrate that ER stress apoptotic signaling is associated with gamma-tocotrienol-induced apoptosis in +SA mammary tumor cells.
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PMID:Endoplasmic reticulum stress mediates gamma-tocotrienol-induced apoptosis in mammary tumor cells. 1977 20

Cassava (Manihot esculenta Crantz) is a root crop that accumulates large quantities of starch, and it is an important source of carbohydrate. Study on gene expressions during storage root development provides important information on storage root formation and starch accumulation as well as unlock new traits for improving of starch yield. cDNA-Amplified Fragment Length Polymorphism (AFLP) was used to compare gene expression profiles in fibrous and storage roots of cassava cultivar Kasetsart 50. Total of 155 differentially expressed transcript-derived fragments with undetectable or low expression in leaves were characterized and classified into 11 groups regarding to their functions. The four major groups were no similarity (20%), hypothetical or unknown proteins (17%), cellular metabolism and biosynthesis (17%) and cellular communication and signaling (14%). Interestingly, sulfite reductase (MeKD82), calcium-dependent protein kinase (CDPK) (MeKD83), ent-kaurene synthase (KS) (MeKD106) and hexose transporter (HT) (MeKD154) showed root-specific expression patterns. This finding is consistent with previously reported genes involved in the initiation of potato tuber. Semi-quantitative reverse transcription polymerase chain reaction of early-developed root samples confirmed that those four genes exhibited significant expression with similar pattern in the storage root initiation and early developmental stages. We proposed that KS and HT may involve in transient induction of CDPK expression, which may play an important role in the signaling pathway of storage root initiation. Sulfite reductase, on the other hand, may involve in storage root development by facilitating sulfur-containing protein biosynthesis or detoxifying the cyanogenic glucoside content through aspartate biosynthesis.
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PMID:AFLP-based transcript profiling for cassava genome-wide expression analysis in the onset of storage root formation. 2053 86


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