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)

Interactions between the novel histone deacetylase inhibitor LAQ824 and the cyclin-dependent kinase inhibitor roscovitine were examined in human leukemia cells. Pretreatment (24 hours) with a subtoxic concentration of LAQ824 (30 nmol/L) followed by a minimally toxic concentration of roscovitine (10 micromol/L; 24 hours) resulted in greater than additive effects on apoptosis in U937, Jurkat, and HL-60 human leukemia cells and blasts from three patients with acute myelogenous leukemia. These events were associated with enhanced conformational changes in Bax; mitochondrial release of cytochrome c, Smac/DIABLO, and apoptosis-inducing factor; and a marked increase in caspase activation. LAQ824/roscovitine-treated cells displayed caspase-dependent down-regulation of p21(CIP1) and Mcl-1 and a pronounced caspase-independent reduction in X-linked inhibitor of apoptosis (XIAP) expression. The lethality of this regimen was significantly attenuated by ectopic expression of XIAP, a nuclear localization signal-defective p21(CIP1) mutant, Mcl-1, and Bcl-2. Combined exposure to LAQ824 and roscovitine resulted in a significant reduction in XIAP mRNA levels and diminished phosphorylation of the carboxyl-terminal domain of RNA polymerase II. Notably, roscovitine blocked LAQ824-mediated differentiation. Finally, LAQ824 and roscovitine individually and in combination triggered an increase in generation of reactive oxygen species; moreover, coadministration of the free radical scavenger N-acetylcysteine prevented LAQ824/roscovitine-mediated mitochondrial injury and apoptosis. Collectively, these findings suggest that combined treatment of human leukemia cells with LAQ824 and roscovitine disrupts maturation and synergistically induces apoptosis, lending further support for an antileukemic strategy combining novel histone deacetylase and cyclin-dependent kinase inhibitors.
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PMID:Potentiation of the lethality of the histone deacetylase inhibitor LAQ824 by the cyclin-dependent kinase inhibitor roscovitine in human leukemia cells. 1627 99

Recently, we discovered that beta-thujaplicin (BT) induces metallothionein (MT) expression in mouse keratinocytes, both in vivo and in vitro. However, the molecular mechanisms by which BT exerts its biological effects have not been elucidated. The purpose of this study is to explore the signal transduction pathway involved in the MT mRNA induction by BT. Using a HaCaT keratinocyte cell line, Northern blotting was performed for analyzing the human MT-IIA mRNA expression levels in combination with BT and a number of protein kinase (PK) inhibitors including H7, HA1004 and a PKC-specific inhibitor chelerythrin. CAT assays with the MT-IIA gene promorter-CAT construct were conducted for examining the transcriptional regulation by BT of MT. A free radical scavenger N-acetylcysteine (NAC) was used for analyzing a role of oxidative stress for the MT gene induction by BT. BT increased MT-IIA gene transcript levels and CAT activity in a dose-dependent fashion in HaCaT cells. The increase in MT-IIA mRNA levels and CAT activity were completely suppressed by H7 but not by HA1004. In addition, chelerythrin prevented BT-inducible MT-IIA promoter activation. Furthermore, NAC suppressed BT-inducible MT-IIA promoter activation. These results demonstrate that BT is a potent activator of the MT-IIA gene promoter and that PKC activation and reactive oxygen species are implicated in BT-inducible MT-IIA gene expression. BT may be a useful tool for dissecting the signal transduction pathway mediating MT-IIA promoter activation.
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PMID:Human metallothionein gene expression is upregulated by beta-thujaplicin: possible involvement of protein kinase C and reactive oxygen species. 1639 9

Prothrombin is a plasma glycoprotein involved in blood coagulation and, as we have previously reported, prothrombin kringles inhibit BCE (bovine capillary endothelial) cell proliferation. To reveal the mechanism, we investigated the influence of rk-2 (recombinant human prothrombin kringle-2) on the BCE cell cycle progression and ROS (reactive oxygen species) generation using FACS (fluorescence-activated cell sorter) analysis. Cell cycle analysis showed a decrease of G(1) phase cells in cells treated with bFGF (basic fibroblast growth factor) and an increase in cells treated with rk-2, as compared with the control cells. But, the portion of the S phase was reversed. In Western blot analysis, bFGF induced cytoplasmic translocation of p21(Waf1/Cip1) and p27(Kip1) and phosphorylation of p27(Kip1) but rk-2 treatment inhibited translocation of p21(Waf1/Cip1) and p27(Kip1) from nucleus to cytoplasm and phosphorylation of p27(Kip1). Also, rk-2 induced up-regulation of p53 and nuclear p21(Waf1/Cip1) and inhibited the cyclin D1/CDK4 (cyclin-dependent kinase 4) complex. The ROS level of rk-2-treated BCE cells was increased 2-fold when compared with the control, but treatment with NAC (N-Acetyl-L: -cysteine), an anti-oxidant, decreased ROS generation about 55% as compared with the rk-2 treatment. NAC treatment also restored cell cycle progression inhibited by rk-2 and down-regulated p53 and nuclear p21(Waf1/Cip1) expression induced by rk-2.These data suggest that rk-2 induces the BCE cell cycle arrest at G(0)-G(1) phase through inhibition of the cyclin D1/CDK4 complex caused by increase of ROS generation and nuclear cyclin-dependent kinase inhibitors.
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PMID:Recombinant human prothrombin kringle-2 induces bovine capillary endothelial cell cycle arrest at G0-G1 phase through inhibition of cyclin D1/CDK4 complex: modulation of reactive oxygen species generation and up-regulation of cyclin-dependent kinase inhibitors. 1640 May 24

Effects of the tyrphostin adaphostin and bortezomib were examined in Bcr/Abl+ leukemia cell resistant to imatinib mesylate secondary to Bcr/Abl point mutations. Adaphostin was equally effective in inducing mitochondrial damage, caspase activation, JNK activation, and Raf-1, phospho-Stat3 and -Stat5 inactivation in mutant and wild-type cells, but differentially down-regulated phospho-Bcr/Abl. Adaphostin and bortezomib synergistically induced apoptosis in wild-type and mutant cells, including T315I mutants. Notably, adaphostin+/-bortezomib potently induced ROS and lethality in mutant cells, effects attenuated by the antioxidant NAC. These findings indicate that adaphostin+/-bortezomib circumvent imatinib resistance due to Bcr/Abl point mutations most likely through ROS generation.
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PMID:Adaphostin and bortezomib induce oxidative injury and apoptosis in imatinib mesylate-resistant hematopoietic cells expressing mutant forms of Bcr/Abl. 3107 70

Abnormally high glucose levels may play an important role in early embryo development and function. In the present study, we investigated the effect of high glucose on 2-deoxyglucose (2-DG) uptake and its related signalling pathway in mouse embryonic stem (ES) cells. 2. 2-Deoxyglucose uptake was maximally inhibited by 25 mmol/L glucose after 24 h treatment. However, 25 mmol/L mannitol and dextran did not affect 2-DG uptake. Indeed, 25 mmol/L glucose decreased GLUT-1 mRNA and protein levels. The glucose (25 mmol/L)-induced inhibition of 2-DG uptake was blocked by pertussis toxin (a G(i)-protein inhibitor; 2 ng/mL), SQ 22,536 (an adenylate cyclase inhibitor; 10(-6) mol/L) and the protein kinase (PK) A inhibitor myristoylated PKI amide-(14-22) (10(-6) mol/L). Indeed, 25 mmol/L glucose increased intracellular cAMP content. 3. Furthermore, 25 mmol/L glucose-induced inhibition of 2-DG uptake was prevented by 10(-4) mol/L neomycin or 10(-6) mol/L U 73,122 (phospholipase C (PLC) inhibitors) and staurosporine or bisindolylmaleimide I (protein kinase (PK) C inhibitors). At 25 mmol/L, glucose increased translocation of PKC from the cytoplasmic fraction to the membrane fraction. The 25 mmol/L glucose-induced inhibition of 2-DG uptake and GLUT-1 protein levels was blocked by SQ 22,536, bisindolylmaleimide I or combined treatment. In addition, 25 mmol/L glucose increased cellular reactive oxygen species and the glucose-induced inhibition of 2-DG uptake were blocked by the anti-oxidants N-acetylcysteine (NAC; 10(-5) mol/L) or taurine (2 yen 10(-3) mol/L). 4. Glucose (25 mmol/L) activated p38 mitogen-activated protein kinase (MAPK) and p44/42 MAPK. Staurosporine (10(-6) mol/L), NAC (10(-5) mol/L) and PD 98059 (10(-7) mol/L) attenuated the phosphorylation of p44/42 MAPK. Both SB 203580 (a p38 MAPK inhibitor; 10(-7) mol/L) and PD 98059 (a p44/42 MAPK inhibitor; 10(-7) mol/L) blocked 25 mmol/L glucose-induced inhibition of 2-DG uptake. 5. In conclusion, high glucose inhibits 2-DG uptake through cAMP, PLC/PKC, oxidative stress or MAPK in mouse ES cells.
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PMID:High glucose-induced inhibition of 2-deoxyglucose uptake is mediated by cAMP, protein kinase C, oxidative stress and mitogen-activated protein kinases in mouse embryonic stem cells. 1648 64

We reported earlier that reactive oxygen species are implicated in necrotic injury induced by a transient exposure of cultured renal tubular cells to a high concentration of cisplatin but not in apoptosis occurring after continuous exposure to a low concentration of cisplatin. We report here the protective effect of cyclic AMP against cisplatin-induced necrosis in cultured renal tubular cells as well as cisplatin-induced acute renal failure in rats. Several pharmacological agents that stimulate cyclic AMP signaling, including the nonhydrolyzable cyclic AMP analogue dibutyryl cyclic AMP, forskolin, 3-isobutyl-1-methylxanthine, and a prostacyclin analogue, beraprost, prevented cisplatin-induced cell injury in a protein kinase A-dependent manner. Cisplatin enhanced lipid peroxidation, decreased CuZn superoxide dismutase (SOD) while enhancing MnSOD activity, and increased cellular tumor necrosis factor-alpha (TNF-alpha) content. The elevation of TNF-alpha content and cell injury induced by cisplatin were attenuated by p38 mitogen-activated protein kinase (MAPK) inhibitors including SB203580 and PD169316. Indeed, cisplatin increased the number of phosphorylated p38 MAPK-like immunoreactive cells. These intracellular events were all reversed by antioxidants such as N-acetylcysteine (NAC) and glutathione or cyclic AMP analogues. The in vivo acute renal injury after cisplatin injection was associated with the elevation of renal TNF-alpha content. The cisplatin-induced renal injury and the increase in TNF-alpha content were reversed by NAC or beraprost. These findings suggest that cyclic AMP protects renal tubular cells against cisplatin-induced oxidative injury by obliterating reactive oxygen species and subsequent inhibition of TNF-alpha synthesis through blockade of p38 MAPK activation.
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PMID:Protective effect of cyclic AMP against cisplatin-induced nephrotoxicity. 1663 17

Mechanisms of lethality of the three-substituted indolinone and putatively selective cyclin-dependent kinase (CDK)2 inhibitor 3-[1-(3H-imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516) were examined in human leukemia cells. Exposure of U937 and other leukemia cells to SU9516 concentrations > or =5 microM rapidly (i.e., within 4 h) induced cytochrome c release, Bax mitochondrial translocation, and apoptosis in association with pronounced down-regulation of the antiapoptotic protein Mcl-1. These effects were associated with inhibition of phosphorylation of the carboxyl-terminal domain (CTD) of RNA polymerase (Pol) II on serine 2 but not serine 5. Reverse transcription-polymerase chain reaction analysis revealed pronounced down-regulation of Mcl-1 mRNA levels in SU9516-treated cells. Similar results were obtained in Jurkat and HL-60 leukemia cells. Furthermore, cotreatment with the proteasome inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132) blocked SU9516-mediated Mcl-1 down-regulation, implicating proteasomal degradation in diminished expression of this protein. Ectopic expression of Mcl-1 largely blocked SU9516-induced cytochrome c release, Bax translocation, and apoptosis, whereas knockdown of Mcl-1 by small interfering RNA potentiated SU9516 lethality, confirming the functional contribution of Mcl-1 down-regulation to SU9516-induced cell death. It is noteworthy that SU9516 treatment resulted in a marked increase in reactive oxygen species production, which was diminished, along with cell death, by the free radical scavenger N-acetylcysteine (NAC). We were surprised to find that NAC blocked SU9516-mediated inhibition of RNA Pol II CTD phosphorylation on serine 2, reductions in Mcl-1 mRNA levels, and Mcl-1 down-regulation. Together, these findings suggest that SU9516 kills leukemic cells through inhibition of RNA Pol II CTD phosphorylation in association with oxidative damage and down-regulation of Mcl-1 at the transcriptional level, culminating in mitochondrial injury and cell death.
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PMID:The three-substituted indolinone cyclin-dependent kinase 2 inhibitor 3-[1-(3H-imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516) kills human leukemia cells via down-regulation of Mcl-1 through a transcriptional mechanism. 1667 43

Cadmium is a toxic heavy metal that accumulates in the environment and is commonly found in cigarette smoke and industrial effluents. This study was designed to determine the role of reactive oxygen species (ROS) generation, and its antagonism by antioxidants, in cadmium-mediated cell signaling and apoptosis in murine macrophage cultures. Cadmium-generated ROS production was observed in J774A.1 cells at 6 h, reverting to control levels at 16 and 24 h. The ROS production was concentration related between 20 and 500 microM cadmium. Activation of caspase-3 was observed at 8 h and DNA fragmentation at 16 h in the presence of 20 microM cadmium, suggesting that caspase-3 activation is a prior step to DNA fragmentation in cadmium-induced apoptosis. Inhibitors of caspase-3, -8, -9, and a general caspase inhibitor suppressed cadmium-induced caspase-3 activation and apoptosis indicating the importance of caspase-3 in cadmium-induced toxicity in these cells. Protection against the oxidative stress with N-acetylcysteine (NAC) and silymarin (an antioxidant flavonoid) blocked cadmium-induced apoptosis. Pretreatment of cells with NAC and silymarin prevented cadmium-induced cell injury, including growth arrest, mitochondrial impairment, and necrosis, and reduced the cadmium-elevated intracellular calcium ([Ca2+]i), suggesting that the oxidative stress is a source of increased [Ca2+]i. NAC inhibited cadmium-induced activation of mitogen-activated protein kinases, the c-Jun NH2-terminal protein kinase (JNK) and extracellular signal-regulated kinase (ERK). However, silymarin provided only a partial protection for JNK activation, and only at the low concentration did it inhibit cadmium-induced ERK activation. Inhibition of caspase-3 protected oxidative stress produced by cadmium, suggesting that the activation of caspase-3 also contributes to generation of reactive oxygen species (ROS). Results emphasized the role of ROS, Ca2+ and mitogen-activated protein kinases in cadmium-induced cytotoxicity in murine macrophages.
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PMID:Cadmium-induced apoptosis in murine macrophages is antagonized by antioxidants and caspase inhibitors. 1672 80

Micro-RNAs (miRNAs) are one class of small non-coding RNAs that have important regulatory roles in higher plants. Much less is known about their prevalence and function in lower land plants. Previously we cloned 100 non-structural small RNAs from the moss Physcomitrella patens but could annotate only 11 as miRNAs. To identify additional moss miRNAs among cloned small RNAs we have analyzed their genomic sequences for a characteristic miRNA precursor-like structure. This analysis revealed 19 new moss miRNAs that are predicted to be encoded by 22 putative foldbacks. Northern blot analysis confirmed the expression of 14 new miRNA representatives. Half of these were gametophore specific, the rest were detected at low levels in the protonema. We predicted 12 genes as targets of nine new miRNAs. Three of these show homology to transcription factors and the others appear to play roles in diverse physiological processes including light and cytokine signaling, which have not to date been shown to be regulated by a miRNA in flowering plants. Four target genes, which show homology to ATN1-like protein kinase, NAC transcription factors and a cytokinin receptor, have been validated by miRNA-mediated mRNA cleavage. In addition, our analysis revealed that seven small RNAs represent miRNA* and three represent intermediates of pre-miRNA processing, providing evidence for specific DICER-like cleavage steps during miRNA biogenesis in moss. Our findings suggest that miRNAs are common in mosses and set the stage for the elucidation of their varied biological functions.
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PMID:Novel micro-RNAs and intermediates of micro-RNA biogenesis from moss. 1682 79

Controlled release of membrane-tethered, dormant precursors is an intriguing activation mechanism that regulates diverse cellular functions in eukaryotes. An exquisite example is the proteolytic activation of membrane-bound transcription factors. The proteolytic cleavage liberates active transcription factors from the membranes that can enter the nucleus and evokes rapid transcriptional responses to incoming stimuli. Here, we show that a membrane-bound NAC (for NAM, ATAF1/2, CUC2) transcription factor, designated NTM1 (for NAC with transmembrane motif1), is activated by proteolytic cleavage through regulated intramembrane proteolysis and mediates cytokinin signaling during cell division in Arabidopsis thaliana. Cell proliferation was greatly reduced in an Arabidopsis mutant with retarded growth and serrated leaves in which a transcriptionally active NTM1 form was constitutively expressed. Accordingly, a subset of cyclin-dependent kinase (CDK) inhibitor genes (the KIP-related proteins) was induced in this mutant with a significant reduction in histone H4 gene expression and in CDK activity. Consistent with a role for NTM1 in cell cycling, a Ds element insertional mutant was morphologically normal but displayed enhanced hypocotyl growth with accelerated cell division. Interestingly, cytokinins were found to regulate NTM1 activity by controlling its stability. These results indicate that the membrane-mediated activation of NTM1 defines a molecular mechanism by which cytokinin signaling is tightly regulated during cell cycling.
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PMID:A membrane-bound NAC transcription factor regulates cell division in Arabidopsis. 1709 12


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