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)

The primary pathogenic mechanism of amyotrophic lateral sclerosis (ALS) remains largely unclear. We recently observed that motoneuron cell death mediated by G93A or A4V mutant SOD1, causing familial ALS, was related with decrease of survival signals, such as phosphatidylinositol 3-kinase (PI3-K) and Akt, which play a pivotal role in neuronal survival. Using a G93A or A4V mutant SOD1 transfected VSC4.1 motoneuron cells (G93A or A4V cells, respectively), we presently investigated whether PI3-K activator could reduce mutant SOD1-mediated motoneuron cell death. To investigate the effect of PI3-K activator on viability of G93A and A4V cells, these cells were treated with 10, 50 or 100ng/ml PI3-K activator for 24h and viability and intracellular signals, including Akt, glycogen synthase kinase-3 (GSK-3), heat shock transcription factor-1 (HSTF-1), cytosolic cytochrome c, caspase-3 and poly(ADP-ribose) polymerase (PARP), were compared with those without treatment (control). Compared with non-treated control G93A or A4V cells, the PI3-K activator treatment increased their viability by enhancing the survival signals, including pAkt, pGSK-3, and by inhibiting the death signals, including caspase-3 activation and PARP cleavage. These results suggest that PI3-K activator protects G93A or A4V cells from mutant SOD1-mediated motoneuron cell death by both activating survival signals and inactivating death signals.
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PMID:Phosphatidylinositol 3-kinase activator reduces motor neuronal cell death induced by G93A or A4V mutant SOD1 gene. 1599 7

In diabetes, oxidative stress plays a key role in the pathogenesis of vascular complications, and an early step of such damage is considered to be the development of an endothelial dysfunction. Hyperglycemia directly promotes an endothelial dysfunction inducing process of overproduction of superoxide and consequently peroxynitrite, that damages DNA and activates the nuclear enzyme poly(ADP-ribose) polymerase. This process, depleting NAD+, slowing glycolsis, ATP formation and electron transport, results in acute endothelial dysfunction in diabetic blood vessels and contributes to the development of diabetic complications. These new findings may explain why classical antioxidants, like vitamin E, that work scavenging already formed toxic oxidation products, have failed to show beneficial effects on diabetic complications, and suggest new and attractive "causal" antioxidant therapy. New, low molecular mass compounds that act as SOD or catalase mimetics or L-propionyl-carnitine and lipoic acid, that work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such strategy, and preliminary studies support this hypothesis. This "causal" therapy would also be associated with other promising tools such as LY 333531, PJ34 and FP15, which block protein kinase beta isoform, poly(ADP-ribose) polymerase and peroxynitrite, respectively. It is now evident that, statins, ACE inhibitors, AT-1 blockers, calcium channel blockers and thiazolidinediones have a strong intracellular antioxidant activity, and it has been suggested that many of their beneficial ancillary effects are due to this property. This preventive activity against oxidative stress generation can justify a large utilization and association of this compounds for preventing complications in diabetic patients where antioxidant defences have been shown to be defective.
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PMID:Molecular targets of diabetic vascular complications and potential new drugs. 1602 69

The protein kinase, PAK1, is overexpressed in human breast cancer and may contribute to malignancy through induction of proliferation and invasiveness. In this study, we examined the role of PAK1 in the survival of detached MCF10A breast epithelial cells to test whether it may also regulate the early stages of neoplasia. MCF10A cells undergo anoikis, as measured by the cleavage of caspase 3 and poly(ADP-ribose) polymerase (PARP), after more than 8 hours of detachment. Endogenous Akt, PAK1, and BAD are phosphorylated in attached MCF10A cells, but these phosphorylation events are all lost during the first 8 hours of detachment. Expression of constitutively active PAK1 or Akt suppresses the cleavage of caspase 3 and PARP in detached MCF10A cells. Co-overexpression of active PAK1 with dominant-negative Akt, or of active Akt with dominant-negative PAK1, still suppresses anoikis. Thus, Akt and PAK1 enhance survival through pathways that are at least partially independent. PAK1-dependent regulation of anoikis is likely to occur early in the apoptotic cascade as expression of dominant-negative PAK1 increased the cleavage of the upstream caspase 9, while constitutively active PAK1 inhibited caspase 9 activation. These results support a role for activated PAK1 in the suppression of anoikis in MCF10A epithelial cells.
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PMID:Active p21-activated kinase 1 rescues MCF10A breast epithelial cells from undergoing anoikis. 1602 43

Point mutations such as G93A and A4V in the human Cu/Zn-superoxide dismutase gene (hSOD1) cause familial amyotrophic lateral sclerosis (fALS). In spite of several theories to explain the pathogenic mechanisms, the mechanism remains largely unclear. Increased activity of glycogen synthase kinase-3 (GSK-3) has recently been emphasized as an important pathogenic mechanism of neurodegenerative diseases, including Alzheimer's disease and ALS. To investigate the effects of G93A or A4V mutations on the phosphatidylinositol-3-kinase (PI3-K)/Akt and GSK-3 pathway as well as the caspase-3 pathway, VSC4.1 motoneuron cells were transfected with G93A- or A4V-mutant types of hSOD1 (G93A and A4V cells, respectively) and, 24 h after neuronal differentiation, their viability and intracellular signals, including PI3-K/Akt, GSK-3, heat shock transcription factor-1 (HSTF-1), cytochrome c, caspase-3 and poly(ADP-ribose) polymerase (PARP), were compared with those of wild type (wild cells). Furthermore, to elucidate the role of the GSK-3beta-mediated cell death mechanism, alterations of viability and intracellular signals in those mutant motoneurons were investigated after treating the cells with GSK-3beta inhibitor. Compared with wild cells, viability was greatly reduced in the G93A and A4V cells. However, the treatment of G93A and A4V cells with GSK-3beta inhibitor increased their viability by activating HSTF-1 and by reducing cytochrome c release, caspase-3 activation and PARP cleavage. However, the treatment did not affect the expression of PI3-K/Akt and GSK-3beta. These results suggest that the G93A or A4V mutations inhibit PI3-K/Akt and activate GSK-3beta and caspase-3, thus becoming vulnerable to oxidative stress, and that the GSK-3beta-mediated cell death mechanism is important in G93A and A4V cell death.
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PMID:Role of GSK-3beta activity in motor neuronal cell death induced by G93A or A4V mutant hSOD1 gene. 1604 83

Our recent findings demonstrated that the Epstein-Barr virus-encoding small nonpolyadenylated RNA (EBER) confers resistance to various apoptotic stimuli and contributes to the maintenance of malignant phenotypes in Burkitt's lymphoma. In this study we investigated the role of EBER in the human epithelial Intestine 407 cell line, which is known to be susceptible to Fas (Apo1/CD95)-mediated apoptosis. Fas, a member of the tumor necrosis factor receptor family, transduces extracellular signals to the apoptotic cellular machinery, leading to cell death. Transfection of the EBER gene into Intestine 407 cells significantly protected the cells from Fas-mediated apoptosis, whereas EBER-negative cell lines underwent apoptosis after Fas treatment. EBER bound double-stranded RNA-dependent protein kinase R (PKR), an interferon-inducible serine/threonine kinase, and abrogated its kinase activity. Moreover, expression of the catalytically inactive dominant-negative PKR provided resistance to Fas-induced apoptosis. Expression of EBER or dominant-negative PKR also inhibited the cleavage of poly(ADP-ribose) polymerase, a mediator of the cellular response to DNA damage, downstream of the Fas-mediated apoptotic pathway. These results in combination indicate that EBER confers resistance to Fas-mediated apoptosis by blocking PKR activity in Intestine 407 cells, consistent with the idea that EBER contributes to the maintenance of epithelioid malignancies.
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PMID:Epstein-Barr virus-encoded poly(A)- RNA confers resistance to apoptosis mediated through Fas by blocking the PKR pathway in human epithelial intestine 407 cells. 1616 Jan 54

Sulforaphane (SFN) is a major isothiocyanate compound in cruciferous vegetables such as broccoli, cauliflower, and Brussels sprouts. Preclinical animal models have recently shown that SFN and other isothiocyanates may be useful for prostrate cancer (PCa) chemoprevention. In this study we used a DU145 human PCa cell culture model to investigate the role of protein kinase signaling pathway(s) in SFN-induced cell cycle arrest and apoptosis and whether another chemopreventive agent selenium enhances the apoptosis potency of SFN. The results showed that SFN exposure for 24 h or longer significantly decreased the number of viable DU145 cells in a dose-dependent manner with an IC50 of asymptotically equal to 10 microM. The decreased cell number was associated with G2/M phase arrest and apoptotic cell death, with the latter being evidenced by caspase-mediated cleavage of poly(ADP-ribose) polymerase and increased release of histone-associated DNA fragments. A peptide inhibitor of caspase-8 completely blocked SFN-induced apoptosis and that for caspase-9 exerted a major protection; however, neither inhibitor attenuated SFN-induced G2/M arrest. Regarding potential mediators, SFN treatment induced a transient rise of reactive oxygen species (ROS) peaking within (1/2) h and the activation of JNK within 1 h but did not have any detectable effect on the phosphorylation of p38MAPK or ERK1/2 from 6 h to 24 h. Pretreatment of cells with N-acetylcysteine to enrich intracellular glutathione blocked SFN-induced ROS and apoptotic cell death. Inhibiting the JNK activity with a pharmacologic inhibitor SP600125 abolished the induction of G2/M arrest and apoptosis by SFN, whereas chemical inhibitors for p38MAPK and MEK1/2 did not have any modulating effect on SFN-induced apoptosis. Taken together, the data indicate that SFN decreased viable DU145 cell number in large part through the generation of ROS and JNK-mediated signaling to G2/M arrest and caspase-dependent apoptosis. Selenium in the form of inorganic sodium selenite salt or methylseleninic acid did not enhance SFN-induced apoptosis in this cell culture model.
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PMID:Involvement of c-Jun N-terminal kinase in G2/M arrest and caspase-mediated apoptosis induced by sulforaphane in DU145 prostate cancer cells. 1620 52

Interactions between the cyclin-dependent kinase (CDK) inhibitor flavopiridol and histone deacetylase (HDAC) inhibitors (suberoylanilide hydroxamide and sodium butyrate) were examined in human leukemia cells (U937 and HL-60) ectopically expressing Bcl-2/Bcl-x(L) and in primary AML cells. Coadministration of flavopiridol with HDAC inhibitors synergistically potentiated mitochondrial damage (cytochrome c, second mitochondria-derived activator of caspases/direct IAP binding protein with low pI, and apoptosis-inducing factor release), caspase activation, poly(ADP-ribose) polymerase degradation, and cell death in both wild type and Bcl-2- or Bcl-x(L)-overexpressing cells and induced a pronounced loss of clonogenicity. In contrast, Bcl-2 and Bcl-x(L) largely blocked these events in cells exposed to the cytotoxic agent 1-beta-d-arabinofuranosylcytosine (ara-C). Enforced expression of dominant-negative Fas-associated death domain failed to protect cells from the flavopiridol/histone deacetylase inhibitor (HDACI) regimen, arguing against the involvement of the receptor pathway in lethality. Ectopic expression of a phosphorylation loop-deleted Bcl-2 or Bcl-2 lacking the serine(70) phosphorylation site, which dramatically protected cells from ara-C lethality, delayed but did not prevent flavopiridol/HDAC inhibitor-induced mitochondrial injury, cell death, or loss of clonogenicity. Ectopic expression of Bcl-2 or Bcl-x(L) was also unable to prevent the flavopiridol/HDACI regimen from inducing a conformational change in and mitochondrial translocation of Bax, and it did not attenuate Bax dimerization. As a whole, these findings indicate that in contrast to certain conventional cytotoxic agents such as ara-C, overexpression of Bcl-2 or Bcl-x(L) are largely ineffective in preventing perturbations in Bax, mitochondrial injury, and cell death in human leukemia cells subjected to simultaneous CDK and HDAC inhibition. They also raise the possibility that a strategy combining CDK and HDAC inhibitors may be effective against drug-resistant leukemia cells overexpressing Bcl-2 or Bcl-x(L).
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PMID:Flavopiridol and histone deacetylase inhibitors promote mitochondrial injury and cell death in human leukemia cells that overexpress Bcl-2. 3082 53

It has been shown that dietary red palm oil (RPO) supplementation improves reperfusion function. However, no exact protective cellular mechanisms have been established. To determine a potential mechanism for functional improvement, we examined the regulation of both mitogen-activated protein kinases (MAPKs) and PKB/Akt in the presence and absence of dietary RPO supplementation in ischemia/reperfusion-induced injury. Wistar rats were fed a control diet or control diet plus 7 g RPO/kg diet for 6 weeks. Hearts were excised and mounted on an isolated working heart perfusion apparatus. Cardiac function was measured before and after hearts were subjected to 25 min of total global ischemia. Hearts subjected to the same conditions were freeze clamped and used to characterize the degree of phosphorylation of extracellular signal-regulated kinase, p38, c-Jun NH(2)-terminal protein kinase (JNK) and PKB/Akt. Dietary RPO supplementation significantly improved aortic output recovery (72.1 +/- 3.2% vs. 54.0 +/- 3.2%, P < .05). This improved aortic output recovery was associated with significant increases in p38 and PKB/Akt phosphorylation during reperfusion when compared with control hearts. Furthermore, a significant decrease in JNK phosphorylation and attenuation of poly(ADP-ribose) polymerase cleavage occurred in the RPO-supplemented group during reperfusion. Our results suggest that dietary RPO supplementation caused differential phosphorylation of the MAPKs and PKB/Akt during ischemia/reperfusion-induced injury. These changes in phosphorylation were associated with improved functional recovery and reduced cleavage of an apoptotic marker, arguing that dietary RPO supplementation may confer protection via the MAPK and PKB/Akt signaling pathways during ischemia/reperfusion-induced injury.
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PMID:p38-MAPK and PKB/Akt, possible role players in red palm oil-induced protection of the isolated perfused rat heart? 1622 99

Overexpression of the transcription factor E2F-1 induces apoptosis in a variety of carcinoma cells and inactivates murine double minute protein 2, a factor associated with poor prognosis in soft tissue sarcomas. We have shown previously that the double-stranded RNA-activated protein kinase PKR plays an important role in mediating this apoptotic response in carcinoma cells to E2F-1. We sought to evaluate the potential of E2F-1 gene therapy in soft tissue sarcomas and to study the involvement of PKR in the response to E2F-1 overexpression in mesenchymal cells. A replication-deficient adenovirus carrying the E2F-1 gene (Ad5E2F) was used to induce E2F-1 overexpression in the p53 mutated leiomyosarcoma cell line, SKLMS-1. Western blot analysis confirmed E2F-1 overexpression and up-regulation of the antiapoptotic factor Bcl-2 48 hours following infection with Ad5E2F. Apoptosis in Ad5E2F-treated cells was confirmed by fluorescence-activated cell sorting analysis and by poly(ADP-ribose) polymerase cleavage and DNA fragmentation assays. Vector-dependent up-regulation of PKR correlated with the amount of Ad5E2F-induced apoptosis. In vivo treatment of SKLMS-1 tumor-bearing BALB/c mice with intratumoral injections of Ad5E2F at a dose of 2 x 10(10) viral particles resulted in significant inhibition in tumor growth compared with control-treated animals (P < 0.016). Complete disappearance of all tumors was seen in two of seven mice in the Ad5E2F-treated animals. Immunohistochemical analysis of tumor specimens showed overexpression of E2F-1 and up-regulation of PKR in Ad5E2F-treated tumors. These findings show that adenovirus-mediated overexpression of E2F-1 results in up-regulation of PKR and significant growth suppression of leiomyosarcomas in vivo. Taken together, these data suggest that E2F-1 gene therapy and PKR modulation might be a promising treatment strategy for these tumors that are highly resistant to conventional therapies.
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PMID:Gene therapy with E2F-1 up-regulates the protein kinase PKR and inhibits growth of leiomyosarcoma in vivo. 1627 92

The CKII (EC 2.7.1.37) inhibitory compound was purified from the root barks of Cudrania tricuspidata and identified as (2S)-2-[2,4-dihydroxy-5-(3-methyl-but-2-enyl)-phenyl]-5,7-dihyroxy-6-(3-methyl-but-2-enyl)chroman-4-one (euchrestaflavanone B). Euchrestaflavanone B was shown to inhibit the phosphotransferase activity of CKII with IC50 of about 78 microM. Steady-state studies revealed that euchrestaflavanone B acted as a competitive inhibitor with respect to the substrate ATP. A value of 16.4 microM was obtained for the apparent Ki. Concentration of 0.8 microM euchrestaflavanone B caused 50% growth inhibition of human cancer cells U937 and HeLa. Euchrestaflavanone B-induced cell death was characterized with the cleavage of poly(ADP-ribose) polymerase and procaspase-3, indicating that the inhibitor triggered apoptosis. Because protein kinase CKII is involved in cell proliferation and oncogenesis, these results suggest that euchrestaflavanone B may function by inhibiting oncogenic disease, at least in part, through the inhibition of CKII activity.
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PMID:Inhibition of protein kinase CKII activity by euchrestaflavanone B purified from Cudrania tricuspidata. 1640 97


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