UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study we report that a replication-defective adenovirus construct of GMF cDNA (GMF-V) induced overexpression of GMF protein in neuroblastoma (N18) cells caused cytotoxicity and loss of cell viability. A significant increase in activation of GSK-3beta occurred after infection with GMF-V when compared with mock and lacZ controls. Overexpression of GMF also increased caspase-3 activity, an early marker of apoptosis. Depletion of GMF gene by introducing GMF-specific siRNA (GsiRNA) completely blocked both activation of GSK-3beta and caspase-3 activation whereas a control scrambled siRNA (CsiRNA) had no effect. A cell-permeable peptide inhibitor of GSK-3beta, and lithium completely prevented GMF-dependent activation of caspase-3. These results demonstrate that GSK-3 mediates activation of the death domain caspase by GMF overexpression. We also show that the phosphorylation of GSK-3-dependent site of Tau was a consequence of GMF-overexpression in N18 cells. Taken together our results imply that GMF is involved in the signaling leading to the activation of GSK-3beta and caspase-3 in N18 cells and strongly suggest its involvement in neurodegeneration since GSK-3beta is known to hyperphosphorylate tau which is associated with the neurotoxicity of neurofibrillary tangles in Alzheimer's disease.
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PMID:Glia maturation factor overexpression in neuroblastoma cells activates glycogen synthase kinase-3beta and caspase-3. 1805 98

The role of presenilin-1 (PS1) in neuronal phosphatidylinositol 3-kinase (PI3K)/Akt signaling was investigated in primary neuronal cultures from wild-type (WT) and PS1 null (PS1-/-) embryonic mouse brains. Here we show that in PS1-/- cultures, the onset of neuronal maturation coincides with a decrease in the PI3K-dependent phosphorylation-activation of Akt and phosphorylation-inactivation of glycogen synthase kinase-3 (GSK-3). Mature PS1-/- neurons show increased activation of apoptotic caspase-3 and progressive degeneration preceded by dendritic retraction. Expression of exogenous WT PS1 or constitutively active Akt in PS1-/- neurons stimulates PI3K signaling and suppresses both caspase-3 activity and dendrite retraction. The survival effects of PS1 are sensitive to inhibitors of PI3K kinase but insensitive to gamma-secretase inhibitors. Familial Alzheimer disease (FAD) mutations suppress the ability of PS1 to promote PI3K/AKT signaling, prevent phosphorylation/inactivation of GSK-3 and promote activation of caspase-3. These mutation effects are reversed upon coexpression of constitutively active Akt. Together, our data indicate that the neuroprotective role of PS1 depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients.
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PMID:Wild-type but not FAD mutant presenilin-1 prevents neuronal degeneration by promoting phosphatidylinositol 3-kinase neuroprotective signaling. 1818 91

Lithium has been shown to be neuroprotective against various insults including ethanol exposure. We previously reported that ethanol-induced apoptotic neurodegeneration in the postnatal day 7 (P7) mice is associated with decreases in phosphorylation levels of Akt, glycogen synthase kinase-3beta (GSK-3beta), and AMP-activated protein kinase (AMPK), and alteration in lipid profiles in the brain. Here, P7 mice were injected with ethanol and lithium, and the effects of lithium on ethanol-induced alterations in phosphorylation levels of protein kinases and lipid profiles in the brain were examined. Immunoblot and immunohistochemical analyses showed that lithium significantly blocked ethanol-induced caspase-3 activation and reduction in phosphorylation levels of Akt, GSK-3beta, and AMPK. Further, lithium inhibited accumulation of cholesterol ester (ChE) and N-acylphosphatidylethanolamine (NAPE) triggered by ethanol in the brain. These results suggest that Akt, GSK-3beta, and AMPK are involved in ethanol-induced neurodegeneration and the neuroprotective effects of lithium by modulating both apoptotic and survival pathways.
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PMID:Lithium blocks ethanol-induced modulation of protein kinases in the developing brain. 1819 Jul 91

Cholangiocarcinoma is a highly malignant neoplasm of the biliary tree. It has a high rate of mortality, and currently, there is no effective chemoprevention and treatment. This study was designed to investigate the potential effect of omega 3 polyunsaturated fatty acids (omega 3-PUFA) on human cholangiocarcinoma cell growth and to determine their mechanisms of actions. Treatment of three human cholangiocarcinoma cells (CCLP1, HuCCT1, SG231) with two omega 3-PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), for 12 to 72 h resulted in a dose- and time-dependent inhibition of cell growth; in contrast, arachidonic acid, a omega 6-PUFA, had no significant effect. The omega 3-PUFA effect is due to the induction of apoptosis, given that DHA induced the cleaved form of PARP, caspase-3, and caspase-9. DHA and EPA treatment caused dephosphorylation (and hence, the activation) of glycogen synthase kinase-3beta (GSK-3beta) with a decline of beta-catenin protein. Accordingly, DHA treatment also decreased the beta-catenin-mediated T cell factor/lymphoid enhancer factor (TCF/LEF) reporter activity, and inhibited the expression of c-Met, a beta-catenin-controlled downstream gene implicated in cholangiocarcinogenesis. The GSK-3beta inhibitor, SB216763, partially prevented DHA-induced reduction of beta-catenin protein and TCF/LEF reporter activity, and restored cell growth, suggesting the involvement of GSK-3beta dephosphorylation in omega 3-PUFA-induced beta-catenin degradation. In parallel, DHA treatment also induced the formation of the beta-catenin/Axin/GSK-3beta binding complex, further leading to beta-catenin degradation. Moreover, DHA inhibited the expression of cyclooxygenase-2 (COX-2) and enhanced the expression of 15-hydroxyprostaglandin dehydrogenase, a physiologic COX-2 antagonist, in human cholangiocarcinoma cells. These findings suggest that omega 3-PUFAs block cholangiocarcinoma cell growth at least in part through inhibition of Wnt/beta-catenin and COX-2 signaling pathways. Thus, utilization of omega 3-PUFAs may represent an effective and safe therapeutic approach for the chemoprevention and treatment of human cholangiocarcinoma.
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PMID:Cyclooxygenase-2-derived prostaglandin E2 activates beta-catenin in human cholangiocarcinoma cells: evidence for inhibition of these signaling pathways by omega 3 polyunsaturated fatty acids. 1819 52

DNA damage by ionizing radiation (IR) can induce activations of both NF-kappaB and p53 through the upstream kinase ataxia telangiectasia mutated (ATM). NF-kappaB activation could also be signaled through two distinct or overlapped pathways; IkappaB kinases (IKKs)-IkappaBalpha and Akt-glycogen synthase kinase-3 (GSK-3). In the present study, however, we show that activation of Akt1 and the subsequent phosphorylation and inactivation of GSK-3beta by IR could also occur in ATM-deficient AT5BIVA cells as well as in normal MRC5CV1 fibroblasts. Similarly, lithium chloride (LiCl) was found to increase the phosphorylation of GSK-3beta independently of ATM. Transfection with either wild-type or kinase dead mutant GSK-3beta to the cells further indicated that phosphorylations of Akt1 and GSK-3beta were closely associated with the transcriptional transactivation of NF-kappaB in response to ionizing radiation. On the other hand, LiCl, having no effect on caspase-3 activation, significantly increased p53 phosphorylation and apoptotic death of the normal MRC5CV1 cells while IR, activating both caspase-3 and p53, profoundly affected AT5BIVA cell death. Hence, our data suggest that although ATM-mediated IKK-IkappaBalpha pathway might be a typical pathway for IR-induced NF-kappaB activation, GSK-3beta phosphorylation could also partially contribute to the transcriptional transactivation of NF-kappaB in an ATM-independent manner and that GSK-3beta phosphorylation could induce ATM-mediated cell apoptosis through the activation of p53.
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PMID:Ionizing radiation can induce GSK-3beta phosphorylation and NF-kappaB transcriptional transactivation in ATM-deficient fibroblasts. 1824 62

Intense mesangial cell apoptosis contributes to the pathogenesis of diabetic nephropathy. Although reactive oxygen radicals and Wnt signaling components are potent regulators that modulate renal tissue remodeling and morphogenesis, cross-talk between oxidative stress and Wnt/beta-catenin signaling in controlling high-glucose-impaired mesangial cell survival and renal function have not been tested. In this study, high glucose induced Ras and Rac1 activation, superoxide burst, and Wnt5a/beta-catenin destabilization and subsequently promoted caspase-3 and poly (ADP-ribose) polymerase cleavage and apoptosis in mesangial cell cultures. The pharmacological and genetic suppression of superoxide synthesis by superoxide dismutase and diphenyloniodium, dominant-negative Ras (S17N), and dominant-negative Rac1 (T17N) abrogated high-glucose-induced glycogen synthase kinase (GSK-3beta) activation and caspase-3 and poly (ADP-ribose) polymerase degradation. Inactivation of Ras and Racl also reversed Wnt/beta-catenin expression and survival of mesangial cells. Stabilization of beta-catenin by the transfection of stable beta-catenin (Delta45) and kinase-inactive GSK-3beta attenuated high-glucose-mediated mesangial cell apoptosis. Exogenous superoxide dismutase administration attenuated urinary protein secretion in diabetic rats and abrogated diabetes-mediated reactive oxygen radical synthesis in renal glomeruli. Immunohistological observation revealed that superoxide dismutase treatment abrogated diabetes-induced caspase-3 cleavage and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) and increased Wnt5a/beta-catenin expression in renal glomeruli. Taken together, high glucose induced oxidative stress and apoptosis in mesangial cells. The Ras and Rac1 regulation of superoxide appeared to raise apoptotic activity by activating GSK-3beta and inhibiting Wnt5a/beta-catenin signaling. Controlling oxidative stress and Wnt/beta-catenin signaling has potential for protecting renal tissue against the deleterious effect of high glucose.
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PMID:Superoxide destabilization of beta-catenin augments apoptosis of high-glucose-stressed mesangial cells. 1833 14

Previously we demonstrated that insulin protects against neuronal oxidative stress by restoring antioxidants and energy metabolism. In this study, we analysed how insulin influences insulin-(IR) and insulin growth factor-1 receptor (IGF-1R) intracellular signaling pathways after oxidative stress caused by ascorbate/Fe2+ in rat cortical neurons. Insulin prevented oxidative stress-induced decrease in tyrosine phosphorylation of IR and IGF-1R and Akt inactivation. Insulin also decreased the active form of glycogen synthase kinase-3beta (GSK-3beta) upon oxidation. Since phosphatidylinositol 3-kinase (PI-3K)/Akt-mediated inhibition of GSK-3beta may stimulate protein synthesis and decrease apoptosis, we analysed mRNA and protein expression of "candidate" proteins involved in antioxidant defense, glucose metabolism and apoptosis. Insulin prevented oxidative stress-induced increase in glutathione peroxidase-1 and decrease in hexokinase-II expression, supporting previous findings of changes in glutathione redox cycle and glycolysis. Moreover, insulin precluded Bcl-2 decrease and caspase-3 increased expression. Concordantly, insulin abolished caspase-3 activity and DNA fragmentation caused by oxidative stress. Thus, insulin-mediated activation of IR/IGF-1R stimulates PI-3K/Akt and inhibits GSK-3beta signaling pathways, modifying neuronal antioxidant defense-, glucose metabolism- and anti-apoptotic-associated protein synthesis. These and previous data implicate insulin as a promising neuroprotective agent against oxidative stress associated with neurodegenerative diseases.
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PMID:Insulin neuroprotection against oxidative stress is mediated by Akt and GSK-3beta signaling pathways and changes in protein expression. 1834 71

Lithium modulates glycogen synthase kinase 3beta (GSK-3beta), a kinase involved in Alzheimer disease-related tau pathology. To investigate mechanisms of aging and the potential therapy of lithium in neurodegenerative disease, we treated senescence-accelerated mouse (SAM)P8 mice, a murine model of senescence, and mice of the control SAMR1 strain with lithium. The treatment reduced hippocampal caspase 3 and calpain activation, indicating that it provides neuroprotection. Lithium also reduced both the levels and activity of GSK-3beta and the activity of cyclin-dependent kinase 5 and reduced hyperphosphorylation of 3 different phosphoepitopes of tau: Ser199, Ser212, and Ser396. In lithium-treated primary cultures of SAMP8 and SAMR1 cerebellar neurons, there was a marked reduction in protease activity mediated by calpain and caspase 3. Both lithium and SB415286, a specific inhibitor of GSK-3beta, reduced apoptosis in vitro. Taken together, these in vivo and in vitro findings of lithium-mediated reductions in GSK-3beta and cyclin-dependent kinase 5 activities, tau phosphorylation, apoptotic activity, and cell death provide a strong rationale for the use of lithium as a potential treatment in neurodegenerative diseases.
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PMID:Lithium treatment decreases activities of tau kinases in a murine model of senescence. 1852 Jul 79

Neurofibrillary tangles (NFTs), comprising human intracellular microtubule-associated protein tau, are one of the hallmarks of tauopathies, including Alzheimer's disease. Recently, a report that caspase-cleaved tau is present in NFTs has led to the hypothesis that the mechanisms underlying NFT formation may involve the apoptosis cascade. Here, we show that adenoviral infection of tau into COS-7 cells induces activation of c-jun N-terminal kinase (JNK), followed by excessive phosphorylation of tau and its cleavage by caspase. However, JNK activation alone was insufficient to induce sodium dodecyl sulfate (SDS)-insoluble tau aggregation and additional phosphorylation by GSK-3beta was required. In SH-SY5Y neuroblastoma cells, overexpression of active JNK and GSK-3beta increased caspase-3 activation and cytotoxicity more than overexpression of tau alone. Taken together, these results indicate that, although JNK activation may be a primary inducing factor, further phosphorylation of tau is required for neuronal death and NFT formation in neurodegenerative diseases, including those characterized by tauopathy.
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PMID:Active c-jun N-terminal kinase induces caspase cleavage of tau and additional phosphorylation by GSK-3beta is required for tau aggregation. 1854 Aug 81

Only acylated ghrelin (AG) binds GH secretagog receptor 1a (GHS-R1a) and has central endocrine activities. An anti-apoptotic effect of AG in neuronal cells has recently been reported. However, whether there is a neuroprotective effect of unacylated ghrelin (UAG), the most abundant form of ghrelin in plasma, is still unknown. Therefore, we investigated whether UAG was neuroprotective against ischemic neuronal injury using primary cultured rat cortical neurons exposed to oxygen and glucose deprivation (OGD). Both AG and UAG inhibited OGD-induced apoptosis. Exposure of cells to the receptor-specific antagonist D-Lys-3-GHRH-6 abolished the protective effects of AG against OGD, whereas those of UAG were preserved, suggesting the involvement of a receptor that is distinct from GHS-R1a. Chemical inhibition of MAPK and phosphatidylinositol-3-kinase (PI3K) blocked the anti-apoptotic effects of AG and UAG. Ghrelin siRNA enhanced apoptosis either during OGD or even in normoxic conditions. The protective effects of AG and UAG were accompanied by an increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2, Akt, and glycogen synthase kinase-3beta (GSK-3beta). Furthermore, treatment of cells with AG or UAG resulted in nuclear translocation of beta-catenin. In addition, both AG and UAG increased the Bcl-2/Bax ratio, prevented cytochrome c release, and inhibited caspase-3 activation. The data indicate that, independent of acylation, ghrelin can function as a neuroprotective agent that inhibits apoptotic pathways. These effects may be mediated via activation of the MAPK and PI3K/Akt pathways. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3beta and stabilization of beta-catenin contribute to the anti-apoptotic effects of ghrelin.
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PMID:Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3 beta and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen-glucose deprivation-induced apoptosis in primary rat cortical neuronal cells. 1854 46

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