Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The maturation of epiphyseal chondrocytes is accompanied by dramatic changes in energy metabolism and shifts in proteins concerned with the induction of apoptosis. We evaluated the role of mitochondria in this process by evaluating the membrane potential (Delta psi m) of chondrocytes of embryonic tibia and the epiphyseal growth plate. We observed that there was a maturation-dependent change in fluorescence, indicating a fall in the Delta psi m. The level of mitochondrial Bcl-2 was decreased during maturation, while in the same time period there was an obvious increase in Bax levels in the mitochondrial fraction of the terminally differentiated chondrocytes. Bcl(xL), another anti-apoptotic protein, was also robustly expressed in the mitochondrial fraction, but its expression was not dependent on the maturation status of the chondrocytes. We found that caspase-3 was present throughout the growth plate and in hypertrophic cells in culture. We blocked caspase-3 activity and found that alkaline phosphatase staining and mineral formation was decreased, and the cells had lost their characteristic shape. Moreover, we noted that the undifferentiated cells were insensitive to elevated concentrations of inorganic phosphate (Pi). It is concluded that during hypertrophy, the change in membrane potential, the increased binding of a pro-apoptotic protein to mitochondria, and the activation of caspase-3 serve to prime cells for apoptosis. Only when the terminally differentiated chondrocytes are challenged with low levels of apoptogens there is activation of apoptosis.
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PMID:Development of the terminally differentiated state sensitizes epiphyseal chondrocytes to apoptosis through caspase-3 activation. 1713 57

The effects of the gypenosides (Gyp), a component of Gynostemma pentaphyllum Makino, on the cell viability, cell cycle and induction of apoptosis were investigated in human colon cancer colo 205 cells. Gyp was cytotoxic to colo 205 cells with an IC50 of 113.5 microg/ml. The decreasing number of viable cells appeared to be due to the induction of cell cycle arrest and apoptotic cell death, since Gyp induced morphological changes and internucleosomal DNA fragmentation and increased the sub-G1 group. The production of reactive oxygen species and Ca2+ and the depolarization of mitochondrial membrane potential were observed, dose- and time-dependently, after treatment with various concentrations of Gyp. Gyp treatment also gradually decreased the expression of the anti-apoptotic proteins Bcl-2 and Bcl-xl, but increased the expression of the pro-apoptotic protein Bax. Gyp increased the levels of p53 and promoted the release of cytochrome c and the activation of caspase-3 before leading to apoptosis. These results provide information towards an understanding of the mechanisms by which Gyp induces cell cycle arrest and apoptosis in human colon cancer cells.
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PMID:Gypenosides induced apoptosis in human colon cancer cells through the mitochondria-dependent pathways and activation of caspase-3. 1720 Nov 50

The role of alpha1,3fucosyltransferase-VII (alpha1,3 FucT-VII) in cell apoptosis was studied in human hepatocellular carcinoma H7,721 cells. After the cells were transfected with alpha1,3 FucT-VII cDNA, the expression of apoptotic protease, procaspase-3, was decreased, while the anti-apoptotic proteins, phospho-PKB and phospho-Bad were increased as compared with mock (vector) transfected cells, indicating that alpha1,3FucT-VII is a potential anti-apoptotic factor in H7,721 cells. After "alpha1,3FucT-VII" cells were irradiated by UV to induce apoptosis, the anti-apoptotic potential of alpha1,3FucT-VII became more apparent, as evidenced by the less apoptotic cell % and active cleaved caspase-3, more phospho-p38 MAPK and JNK (two anti-apoptotic signaling molecules in H7,721 cells responsible to UV stress) when compared with the "Mock" cells. In contrast, "alpha1,3FucT-VII" cells facilitated the apoptosis induced by all-trans retinoic acid (ATRA), which was verified by the greater sub-G1 (apoptotic cells) peak in flow cytometry analysis, more expressions of active caspase-3 and pro-apoptotic protein Bax, as well as less expressions of anti-apoptotic proteins, Bcl-2 and Bcl-X(L). The up regulation of alpha1,3FucT-VII mRNA and cell surface SLe(x) (alpha1,3FucT-VII product) by UV and down regulation of them by ATRA was speculated to be one of the mechanisms that alpha1,3FucT-VII decreased and increased the susceptibility of apoptosis induced by UV and ATRA respectively.
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PMID:Alpha1,3 Fucosyltransferase-VII modifies the susceptibility of apoptosis induced by ultraviolet and retinoic acid in human hepatocarcinoma cells. 1743 81

Since the signal transduction mechanisms responsible for liver regeneration mediated by the plasminogen/plasmin system remain largely undetermined, we have investigated whether plasmin regulates the pro-apoptotic protein Bim(EL) in primary hepatocytes. Plasmin bound to hepatocytes in part via its lysine binding sites (LBS). Plasmin also triggered phosphorylation of ERK1/2 without cell detachment. The plasmin-induced phosphorylation of ERK1/2 was inhibited by the LBS inhibitor epsilon-aminocaproic acid (EACA), the serine protease inhibitor aprotinin, and the MEK inhibitor PD98059. DFP-inactivated plasmin failed to phosphorylate ERK1/2. Plasmin temporally decreased the starvation-induced expression of Bim(EL) and activation of caspase-3 via the ERK1/2 signaling pathway, resulting in an enhancement of cell survival. The amount of mRNA for Bim increased 1 day after the injection of CCl(4) in livers of plasminogen knockout (Plg-KO) and the wild-type (WT) mice. The increase in Bim(EL) protein persisted for at least 7 days post-injection in livers of Plg-KO mice, whereas WT mice showed an increase in Bim(EL) protein 1 day after the injection. Plg-KO and WT mice showed notable phosphorylation of ERK1/2 7 and 3 days after the injection of CCl(4), respectively. Our data suggest that the plasminogen/plasmin system could decrease Bim(EL) expression via the ERK1/2 signaling pathway during liver regeneration.
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PMID:Plasmin decreases the BH3-only protein BimEL via the ERK1/2 signaling pathway in hepatocytes. 1748 86

Coagulation Factor (F)Xa is a serine protease that plays a crucial role during blood coagulation by converting prothrombin into active thrombin. Recently, however, it emerged that besides this role in coagulation, FXa induces intracellular signaling leading to different cellular effects. Here, we show that coagulation factor (F)Xa drives tumor cells of epithelial origin, but not endothelial cells or monocytes, into apoptosis, whereas it even enhances fibroblast survival. FXa signals through the protease activated receptor (PAR)-1 to activate extracellular-signal regulated kinase (ERK) 1/2 and p38. This activation is associated with phosphorylation of the transcription factor CREB, and in tumor cells with up-regulation of the BH3-only pro-apoptotic protein Bim, leading to caspase-3 cleavage, the main hallmark of apoptosis. Transfection of tumor cells with dominant negative forms of CREB or siRNA for either PAR-1, Bim, ERK1 and/or p38 inhibited the pro-apoptotic effect of FXa. In fibroblasts, FXa-induced PAR-1 activation leads to down-regulation of Bim and pre-treatment with PAR-1 or Bim siRNA abolishes proliferation. We thus provide evidence that beyond its role in blood coagulation, FXa plays a key role in cellular processes in which Bim is the central player in determining cell survival.
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PMID:Coagulation factor Xa drives tumor cells into apoptosis through BH3-only protein Bim up-regulation. 1753 Dec 20

Heat shock induced gene expression and other cellular responses help limit the damage caused by stress and thus facilitate cellular recovery. Cellular damage also triggers apoptotic cell death through several pathways. This paper briefly reviews interactions of the major heat shock proteins with components of the apoptotic pathways. Hsp90, which acts as a chaperone for unstable signal transducers to keep them poised for activation, interacts with RIP and Akt and promotes NF-kappa B mediated inhibition of apoptosis; in addition it also blocks some steps in the apoptotic pathways. Hsp70 is mostly anti-apoptotic and acts at several levels like inhibition of translocation of Bax into mitochondria, release of cytochrome c from mitochondria,formation of apoptosome and inhibition of activation of initiator caspases. Hsp70 also modulates JNK,NF-kappa B and Akt signaling pathways in the apoptotic cascade. In contrast, Hsp60 has both anti-and pro-apoptotic roles. Cytosolic Hsp60 prevents translocation of the pro-apoptotic protein Bax into mitochondria and thus promotes cell survival but it also promotes maturation of procaspase-3,essential for caspase mediated cell death. Our recent in vivo studies show that RNAi for the Hsp60D in Drosophila melanogaster prevents induced apoptosis. Hsp27 exerts its anti-apoptotic influence by inhibiting cytochrome c and TNF-mediated cell death. alpha beta crystallin suppresses caspase-8 and cytochrome c mediated activation of caspase-3. Studies in our laboratory also reveal that absence or reduced levels of the developmentally active as well as stress induced non-coding hsr omega transcripts, which are known to sequester diverse hnRNPs and related nuclear RNA-binding proteins,block induced apoptosis in Drosophila. Modulation of the apoptotic pathways by Hsps reflects their roles as "weak links" between various "hubs" in cellular networks. On the other hand, non-coding RNAs, by virtue of their potential to bind with multiple proteins,can act as "hubs" in these networks. In view of the integrative nature of living systems, it is not surprising that stress-induced genes,generally believed to primarily function in cell survival pathways, inhibit or even promote cell death pathways at multiple levels to ensure homeostasis at cell and/or organism level. The heat shock genes obviously do much more than merely help cells survive stress.
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PMID:Heat shock genes - integrating cell survival and death. 1753 79

Altered or deficient activation of apoptosis signalling pathways may contribute to drug resistance. Here, we assess the role of apoptotic mediators in eliciting an anti-proliferative response to paclitaxel (PTX) in a T cell acute lymphoblastic leukemia (ALL) cell line CEM and its epothilone-paclitaxel resistant sub-line CEM/dEpoB300. Furthermore, the cellular response to PTX was compared to those elicited by cells in response to treatment with albendazole (ABZ; a microtubule depolymerizing agent). In cell proliferation studies, CEM cells were sensitive to both PTX and ABZ, while the CEM/dEpoB300 cells were highly resistant to PTX (IC(50) 2.86 nM versus 30.26 nM, respectively). In contrast, the resistant cells showed a 2-fold increase in sensitivity to ABZ (0.32 microM in CEM compared to 0.16 microM in CEM/dEpoB300). Analysis of caspase-3 activity and cytochrome c release in response to PTX or ABZ treatment (24, 48 and 72 h) revealed that, compared to the parent cells, the resistant cells have diminished response to PTX and enhanced response to ABZ. A similar pattern was observed for the pro-apoptotic protein Bax. Levels of the anti-apoptotic protein Bcl-2 was highly elevated in CEM/dEpoB300 cells and in these cells, ABZ was more effective in lowering the Bcl-2 levels than PTX. Similarly, ABZ treatment led to profound down regulation of the Mcl-1 protein. These results reveal for the first time, the changes in apoptotic mediators following development of resistance to PTX in an ALL cell and the significantly increased sensitivity of these PTX resistant cells to ABZ.
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PMID:Epothilone-paclitaxel resistant leukemic cells CEM/dEpoB300 are sensitive to albendazole: Involvement of apoptotic pathways. 1756 Sep 63

We studied the role of Bim, a pro-apoptotic BCL-2 family member in Airborne particulate matter (PM 2.5 microm)-induced apoptosis in alveolar epithelial cells (AEC). PM induced AEC apoptosis by causing significant reduction of mitochondrial membrane potential and increase in caspase-9, caspase-3 and PARP-1 activation. PM upregulated pro-apoptotic protein Bim and enhanced translocation of Bim to the mitochondria. ShRNABim blocked PM-induced apoptosis by preventing activation of the mitochondrial death pathway suggesting a role of Bim in the regulation of mitochondrial pathway in AEC. Accordingly, we provide the evidence that Bim mediates PM-induced apoptosis via mitochondrial pathway.
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PMID:Bim mediates mitochondria-regulated particulate matter-induced apoptosis in alveolar epithelial cells. 1771 72

The herpes simplex virus type 2 (HSV-2) protein ICP10PK has anti-apoptotic activity in virus-infected hippocampal cultures through activation of the Ras/Raf-1/MEK/ERK pathway. To exclude the possible contribution of other viral proteins to cell fate determination, we examined the survival of primary hippocampal cultures and neuronally differentiated PC12 cells transfected with ICP10PK from apoptosis caused by nerve growth factor (NGF) withdrawal. NGF deprivation caused apoptosis in cultures mock-transfected or transfected with the kinase-negative ICP10 mutant p139(TM), but not in ICP10PK-transfected cultures. In one clone (PC47), ICP10PK inhibited caspase-3 activation through up-regulation/stabilization of adenylate cyclase (AC), activation of PKA and MEK, and the convergence of the two pathways on extracellular signal-regulated kinase activation. The anti-apoptotic proteins Bag-1 and Bcl-2 were stabilized and the pro-apoptotic protein Bad was phosphorylated (inactivated). In another clone (PC70), ICP10PK inhibited apoptosis through MEK-dependent up-regulation of the anti-apoptotic protein XIAP (that inhibits the activity of processed caspase-3) and down-regulation of the apoptogenic protein Smac/DIABLO. This may be cell-type specific, but the baculovirus p35 protein did not potentiate the neuroprotective activity of ICP10PK in PC12 cells, suggesting that ICP10PK inhibits both caspase activation and activity. The data indicate that ICP10PK inhibits apoptosis independent of other viral proteins and is a promising neuronal gene therapy platform.
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PMID:The herpes simplex virus type 2 gene ICP10PK protects from apoptosis caused by nerve growth factor deprivation through inhibition of caspase-3 activation and XIAP up-regulation. 1787 40

Green tea, owing to its beneficial effect on health, is becoming more and more popular worldwide. (-)-Epigallocatechin-3-gallate (EGCG), the main ingredient of green tea polyphenols, is a known protective effect on injured neurons in neurodegenerative disease, such as Alzheimer's disease and Parkinson's disease. Paraquat (PQ) is a widely used herbicide that possesses a similar structure to MPP(+) and is toxic to mesencephalic dopaminergic neurons. In the present study, PQ-injured PC12 cells were chosen as an in vitro cell model of Parkinson's disease and the neuroprotective effects of EGCG were investigated. The results showed that EGCG attenuated apoptosis of PC12 cells induced by PQ. The possible mechanism may be associated with maintaining mitochondrial membrane potential, inhibiting caspase-3 activity and downregulating the expression of pro-apoptotic protein Smac in cytosol. The present study supports the notion that EGCG could be used as a neuroprotective agent for treatment of neurodegenerative diseases.
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PMID:Neuroprotective effects of (-)-epigallocatechin-3-gallate (EGCG) on paraquat-induced apoptosis in PC12 cells. 1793 47


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