Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Following the induction of DNA damage, a prominent route of cell inactivation is apoptosis. During the last ten years, specific DNA lesions that trigger apoptosis have been identified. These include O6-methylguanine, base N-alkylations, bulky DNA adducts, DNA cross-links and DNA double-strand breaks (DSBs). Repair of these lesions are important in preventing apoptosis. An exception is O6-methylguanine-thymine lesions, which require mismatch repair for triggering apoptosis. Apoptosis induced by many chemical genotoxins is the consequence of blockage of DNA replication, which leads to collapse of replication forks and DSB formation. These DSBs are thought to be crucial downstream apoptosis-triggering lesions. DSBs are detected by ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3 related) proteins, which signal downstream to CHK1, CHK2 (checkpoint kinases) and p53. p53 induces transcriptional activation of pro-apoptotic factors such as FAS, PUMA and BAX. Many tumors harbor mutations in p53. There are p53 backup systems that involve CHK1 and/or CHK2-driven E2F1 activation and p73 upregulation, which in turn transcribes BAX, PUMA and NOXA. Another trigger of apoptosis upon DNA damage is the inhibition of RNA synthesis, which leads to a decline in the level of critical gene products such as MKP1 (mitogen-activated protein kinase phosphatase). This causes sustained activation of JNK (Jun kinase) and, finally, AP-1, which stimulates death-receptor activation. DNA damage-triggered signaling and execution of apoptosis is cell-type- and genotoxin-specific depending on the p53 (p63 and p73) status, death-receptor responsiveness, MAP-kinase activation and, most importantly, DNA repair capacity. Because most clinical anti-cancer drugs target DNA, increasing knowledge on DNA damage-triggered signaling leading to cell death is expected to provide new strategies for therapeutic interventions.
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PMID:DNA damage-induced cell death by apoptosis. 1689 8

The aim of this study was to examine the cytotoxicity and mechanism of apoptosis induction of verotoxin-1 (VT-1) in human glioma cell lines. VT-1 is a member of the shiga-toxin family expressed by some serotypes of Escherichia coli and Shigella dysenteriae. Shiga-toxins have been shown to induce apoptosis by binding to its membrane receptor Gb3. The human glioma cell lines SF-767, U-343 MG, and U-251 MG were studied together with BT4C, a rat glioma cell line. Cells were first screened for Gb3 expression by flow cytometry. Fluorescein diacetate was used to determine cell viability after VT-1 and irradiation exposure and apoptosis was studied by TUNEL staining, a mitochondrial membrane potential assay, and caspase activity assays. SF-767 and U-343 MG cells were found to express Gb3 and were also sensitive to VT-1-induced cytotoxicity, whereas nonGb3-expressing U-251 MG and BT4C glioma cells were not. VT-1 depolarized the mitochondrial membrane and activated caspase-9 and -3 of SF-767 and U-343 MG cells. VT-1 exposure for 72 h resulted in approx. 60 and 90% TUNEL-stained cells, respectively. D, L-Threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) an inhibitor of glucosylceramide synthesis was used to block Gb3 synthesis. Two mumol/L PPMP for 72 h abolished SF-767 and U-343 MG expression of Gb3 and made the cells completely resistant to VT-1 induced apoptosis. Key components of MAP kinase signalling pathways that control BAX and mitochondrial function were investigated. VT-1 induced JNK phosphorylation in both cell lines, suggesting that survival signal pathways were overruled by VT-1-induced JNK activation leading to mitochondrial depolarization, caspase-9 activation and apoptosis. Immunohistochemistry of cryostat section from glioma biopsies demonstrated expression of Gb3 was in the vascular endothelial cells as well as tumor cells, but not in astrocytes. The high specificity and apoptosis inducing properties of verotoxin-1 indicates that the toxin may be a potential anti-neoplastic agent for Gb3-expressing gliomas.
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PMID:Verotoxin-1 induction of apoptosis in Gb3-expressing human glioma cell lines. 1720 57

Interactions between MEK1/2 inhibitors and the dual Abl/Src kinase inhibitor dasatinib (BMS-354825) were examined in chronic myeloid leukemia (CML) cell lines and primary specimens. Cotreatment of K562 or LAMA cells with subtoxic or marginally toxic concentrations of PD184352 (or U0126) and dasatinib synergistically potentiated mitochondrial damage, caspase activation, and apoptosis. Similar interactions were observed in CD34(+) cells from one CML patient-derived but not in a normal human CD34(+) bone marrow cell specimen. These interactions were associated with multiple perturbations in survival signaling pathways, including inactivation of Bcr/Abl, STAT5, and ERK1/2; down-regulation of Bcl-x(L) and Mcl-1; and dephosphorylation/activation of Bim. They were also associated with BAX/BAK conformational change, mitochondrial dysfunction, and caspase activation. Bim knockdown by shRNA suppressed BAX and BAK conformational change and protected cells from dasatinib/PD184352 lethality. Conversely, K562 cells ectopically expressing Mcl-1 or Bcl-x(L) were significantly less susceptible to dasatinib/PD184352 toxicity. Notably, the dasatinib/PD184352 regimen was active against leukemic cells exhibiting various forms of imatinib mesylate resistance, including Bcr/Abl overexpression, Lyn activation, and several Bcr/Abl kinase domain mutations (eg, E255K, M351T), but not T315I. Together, these findings suggest that strategies combining dasatanib with MEK1/2 inhibitors warrant further investigation in Bcr/Abl(+) malignancies, particularly in the setting of imatinib mesylate-resistant disease.
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PMID:MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825. 1721 85

Ansamycin antibiotics that target heat shock protein 90 function are being developed as anticancer agents but are also known to be dose limiting in patients due to hepatotoxicity. Herein, to better understand how the normal tissue toxicity of geldanamycins could be ameliorated to improve the therapeutic index of these agents, we examined the interactions of 17-allylamino-17-demethoxygeldanamycin (17AAG) and the secondary bile acid deoxycholic acid (DCA) in hepatocytes and fibroblasts. DCA and 17AAG interacted in a greater than additive fashion to cause hepatocyte cell death within 2 to 6 h of coadministration. As single agents DCA, but not 17AAG, enhanced the activity of extracellular signal-regulated kinase 1/2, AKT, c-Jun NH(2)-terminal kinase 1/2 (JNK1/2), and p38 mitogen-activated protein kinase (MAPK). Combined exposure of cells to DCA and 17AAG further enhanced JNK1/2 and p38 MAPK activity. Inhibition of JNK1/2 or p38 MAPK, but not activator protein-1, suppressed the lethality of 17AAG and of 17AAG and DCA. Constitutive activation of AKT, but not MAPK/extracellular signal-regulated kinase kinase 1/2, suppressed 17AAG- and DCA-induced cell killing and reduced activation of JNK1/2. DCA and 17AAG exposure promoted association of BAX with mitochondria, and functional inhibition of BAX or caspase-9, but not of BID and caspase-8, suppressed 17AAG and DCA lethality. DCA and 17AAG interacted in a greater than additive fashion to promote and prolong the generation of reactive oxygen species (ROS). ROS-quenching agents, inhibition of mitochondrial function, expression of dominant-negative thioredoxin reductase, or expression of dominant-negative apoptosis signaling kinase 1 suppressed JNK1/2 and p38 MAPK activation and reduced cell killing after 17AAG and DCA exposure. The potentiation of DCA-induced ROS production by 17AAG was abolished by Ca(2+) chelation and ROS generation, and cell killing following 17AAG and DCA treatment was abolished in cells lacking expression of PKR-like endoplasmic reticulum kinase. Thus, DCA and 17AAG interact to stimulate Ca(2+)-dependent and PKR-like endoplasmic reticulum kinase-dependent ROS production; high levels of ROS promote intense activation of the p38 MAPK and JNK1/2 pathways that signal to activate the intrinsic apoptosis pathway.
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PMID:17-Allylamino-17-demethoxygeldanamycin enhances the lethality of deoxycholic acid in primary rodent hepatocytes and established cell lines. 1730 59

Selenium is an essential trace element in conventional tissue culture media to guarantee adequate biosynthesis of selenoprotein in cellular antioxidant system to protect the cells from oxidative damage and apoptosis. This study investigated the effect of selenium, in the form of sodium selenite (SS), on developmental ability and quality of in vitro produced porcine parthenotes. For this, parthenogenetic presumptive diploid zygotes were produced by electroactivation and cultured in the absence or presence of SS at different concentrations (0, 2.5, 25, 250 ng/ml) in a serum-free defined culture medium supplemented with polyvinyl alcohol (PVA) or bovine serum albumin (BSA). Results showed that, development rate of 2-4 cell stage parthenotes to blastocyst and their cell number was increased while TUNEL index was decreased, in a dose-dependent manner, when SS was supplemented to NCSU23 + PVA. Interestingly, the blastocyst rate and their quality approached to those cultured in NCSU23 + BSA (P < 0.05), thereby suggesting PVA + 25 ng/ml SS to be a partial replacement of BSA. In the presence of PVA, supplementation of SS at a concentration of 25 ng/ml did not improve the cleavage rate of in vitro matured oocytes but there was significant improvement in the blastocyst rate (45.4 +/- 8.8% vs. 12.7 +/- 4.8%), total nuclei number (42.1 +/- 3.5 vs. 31.3 +/- 2.9) and inner cell mass (ICM) rate (29.4 +/- 1.5% vs. 21.3 +/- 1.2%) and decrease in TUNEL index (5.6 +/- 0.5 vs. 12.9 +/- 1.3) compared to nonsupplemented controls. The SS supplementation also decreased the BAX:BCL-xL transcript ratio, increased the expression of ERK1/2 and glutathione peroxidase (GPX) and reduced the level of Caspase 3 proteins (P < 0.05). These data thus suggest that SS improves the development rate and quality of porcine parthenotes by preventing oxidative damage and apoptosis.
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PMID:Selenium improves the developmental ability and reduces the apoptosis in porcine parthenotes. 1734 38

Male contraception has focused, to a great extent, on approaches that induce azoospermia or severe oligospermia through accelerated germ cell apoptosis. Understanding the specific steps in the germ cell apoptotic pathways that are affected by male contraceptives will allow more specific targeting in future contraceptive development. In this study, we have used a nonhuman primate model to characterize the key apoptotic pathway(s) in germ cell death after mild testicular hyperthermia, hormonal deprivation, or combined interventions. Groups of 8 adult (7- to 10-year-old) cynomolgus monkeys (Macaca fascicularis) received one of the following treatments: 1) two empty silastic implants; 2) two 5.5-cm testosterone (T) implants; 3) daily exposure of testes to heat (43 degrees C for 30 min) for 2 consecutive days; and 4) two T implants plus testicular heat exposure for two consecutive days. Testicular biopsies were performed before and at Days 3, 8, and 28 of treatment. Treatment with T, heat, or both led to sustained activation of both mitogen-activated protein kinase (MAPK) 1/3 and MAPK14. Activation of MAPK1/3 and MAPK14 were accompanied by an increase in B-cell leukemia/lymphoma (BCL) 2 levels in both cytosolic and mitochondrial fractions of testicular lysates (BAX levels remained unaffected) and cytochrome c and DIABLO release from mitochondria. These treatments also resulted in inactivation of BCL2 through phosphorylation at serine 70, thereby favoring the death pathway. We conclude that the serine phosphorylation of BCL2 and activation of the MAPK14-mediated mitochondria-dependent pathway are critical for male germ cell death in monkeys.
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PMID:Signaling pathways for germ cell death in adult cynomolgus monkeys (Macaca fascicularis) induced by mild testicular hyperthermia and exogenous testosterone treatment. 1737 39

Intersectins (ITSNs) are multidomain adaptor proteins implicated in endocytosis, regulation of actin polymerization, and Ras/MAPK signaling. We have previously shown that ITSN-1s is required for caveolae fission and internalization in endothelial cells (ECs). In the present study, using small interfering RNA to knock down ITSN-1s protein expression, we demonstrate a novel role of ITSN-1s as a key antiapoptotic protein. Knockdown of ITSN-1s in ECs activated the mitochondrial pathway of apoptosis as determined by genomic DNA fragmentation, extensive mitochondrial fission, activation of the proapoptotic proteins BAK and BAX, and cytochrome c efflux from mitochondria. ITSN-1 knockdown acts as a proapoptotic signal that causes mitochondrial outer membrane permeabilization, dissipation of the mitochondrial membrane potential, and generation of reactive oxygen species. These effects were secondary to decreased activation of Erk1/2 and its direct activator MEK. Bcl-X(L) overexpression prevented BAX activation and the apoptotic ECs death induced by suppression of ITSN-1s. Our findings demonstrate a novel role of ITSN-1s as a negative regulator of the mitochondrial pathway-dependent apoptosis secondary to activation of the Erk1/2 survival signaling pathway.
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PMID:Intersectin-1s regulates the mitochondrial apoptotic pathway in endothelial cells. 1740 81

The present studies have determined whether interactions between the cyclin-dependent kinase inhibitor flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA; vorinostat; Zolinza) occur in breast cancer cells. MDA-MB-231 and MCF7 cells were treated with flavopiridol (25-100 nmol/L) and vorinostat (125-500 nmol/L) in vitro, and mechanisms of cell killing were determined. Concurrent treatment of cells with flavopiridol and vorinostat or treatment of cells with flavopiridol followed by vorinostat promoted cell killing in a greater than additive fashion. Similar data were obtained with the CDK inhibitor roscovitine. Flavopiridol suppressed c-FLIP-l/s and BCL-xL expression, whereas vorinostat reduced expression of BCL-xL, and combined exposure to flavopiridol and vorinostat reduced MCL-1 and X-chromosome-linked inhibitor of apoptosis protein (XIAP) levels. Pharmacologic or genetic inhibition of caspase-8 reduced flavopiridol toxicity, but abolished killing by vorinostat and cell death caused by the vorinostat/flavopiridol regimen. Loss of BAX/BAK function or loss of BID function modestly reduced flavopiridol toxicity, but abolished vorinostat-mediated potentiation of flavopiridol toxicity, as did inhibition of caspase-9. Inhibition and/or deletion of cathepsin B function significantly attenuated vorinostat/flavopiridol lethality. Flavopiridol suppressed extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT activity and expression of activated forms of AKT and mitogen-activated protein/ERK kinase 1 maintained c-FLIP-l/s, BCL-xL, and XIAP expression and protected cells against flavopiridol/vorinostat lethality. Overexpression of c-FLIP-s and BCL-xL abolished the lethality of flavopiridol/vorinostat. Collectively, these data argue that flavopiridol enhances the lethality of vorinostat in breast cancer cells in part through the inhibition of AKT and ERK1/2 function, leading to reduced expression of multiple inhibitors of the extrinsic and intrinsic apoptosis pathways, as well as activation of cathepsin protease-dependent pathways.
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PMID:Extrinsic pathway- and cathepsin-dependent induction of mitochondrial dysfunction are essential for synergistic flavopiridol and vorinostat lethality in breast cancer cells. 1806 90

Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a novel cytokine displaying selective apoptosis-inducing activity in transformed cells without harming normal cells. The present studies focused on defining the mechanism(s) by which a GST-MDA-7 fusion protein inhibits cell survival of primary human glioma cells in vitro. GST-MDA-7 killed glioma cells with diverse genetic characteristics that correlated with inactivation of ERK1/2 and activation of JNK1-3. Activation of JNK1-3 was dependent on protein kinase R-like endoplasmic reticulum kinase (PERK), and GST-MDA-7 lethality was suppressed in PERK-/- cells. JNK1-3 signaling activated BAX, whereas inhibition of JNK1-3, deletion of BAX, or expression of dominant-negative caspase-9 suppressed lethality. GST-MDA-7 also promoted a PERK-, JNK-, and cathepsin B-dependent cleavage of BID; loss of BID function promoted survival. GST-MDA-7 suppressed BAD and BIM phosphorylation and heat shock protein 70 (HSP70) expression. GST-MDA-7 caused PERK-dependent vacuolization of LC3-expressing endosomes whose formation was suppressed by incubation with 3-methyladenine, expression of HSP70 or BiP/GRP78, or knockdown of ATG5 or Beclin-1 expression but not by inhibition of the JNK1-3 pathway. Knockdown of ATG5 or Beclin-1 expression or overexpression of HSP70 reduced GST-MDA-7 lethality. Our data show that GST-MDA-7 induces an endoplasmic reticulum stress response that is causal in the activation of multiple proapoptotic pathways, which converge on the mitochondrion and highlight the complexity of signaling pathways altered by mda-7/IL-24 in glioma cells that ultimately culminate in decreased tumor cell survival.
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PMID:Caspase-, cathepsin-, and PERK-dependent regulation of MDA-7/IL-24-induced cell killing in primary human glioma cells. 1828 15

The present studies defined the biological effects of a GST fusion protein of melanoma differentiation-associated gene-7 (mda-7), GST-MDA-7 (1 and 30 nmol/L), on cell survival and cell signaling in primary human glioma cells in vitro. GST-MDA-7, in a dose- and time-dependent fashion killed glioma cells with diverse genetic characteristics; 1 nmol/L caused arrest without death, whereas 30 nmol/L caused arrest and killing after exposure. Combined inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT function was required to enhance 1 nmol/L GST-MDA-7 lethality in all cell types, whereas combined activation of MEK1 and AKT was required to suppress 30 nmol/L GST-MDA-7 lethality; both effects are mediated in part by modulating c-Jun NH(2)-terminal kinase (JNK) 1-3 activity. The geldanamycin 17AAG inhibited AKT and ERK1/2 in GBM cells and enhanced GST-MDA-7 lethality. JNK1-3 signaling promoted BAX activation and mitochondrial dysfunction. In GBM6 cells, GST-MDA-7 (30 nmol/L) transiently activated p38 mitogen-activated protein kinase, which was modestly protective against JNK1-3-induced toxicity, whereas GST-MDA-7 (300 nmol/L) caused prolonged intense p38 mitogen-activated protein kinase activation, which promoted cell death. In GBM12 cells that express full-length mutant activated ERBB1, inhibition of ERBB1 did not modify GST-MDA-7 lethality; however, in U118 established glioma cells, stable overexpression of wild-type ERBB1 and/or truncated active ERBB1vIII suppressed GST-MDA-7 lethality. Our data argue that combined inhibition of ERK1/2 and AKT function, regardless of genetic background, promotes MDA-7 lethality in human primary human glioma cells via JNK1-3 signaling and is likely to represent a more ubiquitous approach to enhancing MDA-7 toxicity in this cell type than inhibition of ERBB1 function.
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PMID:Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling. 1828 16


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