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 Fas ligand (Fas-L) expressed on mature erythroblasts may induce apoptosis of more immature erythroid cells that express Fas, whereas stem cell factor (SCF) may prevent Fas-mediated cell death in hematopoietic progenitor cells. The manner in which SCF prevents Fas-mediated cell death still is unclear. Given the essential role of SCF and the potentially important involvement of the Fas/Fas-L system in the development of erythrocytes, we studied mechanisms related to SCF prevention of Fas-mediated apoptosis. We used primary cultured human erythroid colony-forming cells (ECFC) derived from CD34+ cells and enriched glycophorin A positive (GPA+) c-kit+ cells in ECFC. Apoptosis of ECFC was induced by an Fas-L mimetic monoclonal antibody CH11. DNA fragmentation and the activation of caspase-3 and caspase-8 were measured using commercially available kits. Characterization of expanded cells was performed using multiparameter flow cytometry. Lyn kinase activity was measured by enolase kinase assays. SCF inhibited the CH11-induced DNA fragmentation of ECFC as well as enriched GPA+ c-kit+ cells in ECFC, but not those of GPA+ c-kit- cells. SCF also inhibited the activation of caspase-3 and caspase-8, without downregulation of the surface expression of Fas, suggesting that SCF prevents apoptosis through uncoupling of Fas ligation from subsequent caspase activation. PP2, a specific inhibitor of Src-family kinases, antagonized the effects of SCF in preventing Fas-mediated apoptosis. We propose that SCF prevents Fas-mediated apoptosis of erythroid progenitor cells in a manner dependent on the activity of Src-family tyrosine kinases. We also identified active Lyn in erythroid cells. These data suggest the presence of a novel Src-family-dependent function of SCF in the development of erythrocytes.
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PMID:Stem cell factor prevents Fas-mediated apoptosis of human erythroid precursor cells with Src-family kinase dependency. 1116 2

Here, we describe a new function for plasmin and matrix metalloproteinases (MMPs), which is to regulate the regression of capillary tubes in three-dimensional extracellular matrix environments. Using a well-described capillary morphogenesis system in three-dimensional collagen matrices, a new model of capillary regression has been established by adding plasminogen to the culture medium. Plasminogen is converted to plasmin by endothelial cell plasminogen activators which then induces matrix metalloproteinase-dependent collagen gel contraction and capillary regression. Plasminogen addition results in activation of MMP-1 and MMP-9, which then results in collagen proteolysis followed by capillary regression. The endothelial cells undergo apoptosis following gel contraction as detected by flow cytometric analysis as well as by detectable caspase-3 cleavage and caspase-dependent cleavage of the actin cytoskeletal regulatory protein, gelsolin. In addition, directly correlating with the contraction response, tyrosine phosphorylation of p130cas, an adapter protein in the focal adhesion complex, is observed followed by disappearance of the protein. Proteinase inhibitors that block MMPs (TIMP-1 or TIMP-2), plasminogen activators (PAI-1) or plasmin (aprotinin) completely block the gel contraction and regression process. In addition, chemical inhibitors of MMPs that block capillary regression also block MMP-1 and MMP-9 activation suggesting that a key element in this regression response is the molecular control of MMP activation by endothelial cells. Blocking antibodies directed to MMP-1 or MMP-9 interfere with capillary regression while blocking antibodies directed to PAI-1 accelerate capillary regression suggesting that endogenous synthesis of PAI-1 negatively regulates this process. These data present a novel system to study a new mechanism that may regulate regression of capillary tubes, namely, plasmin and MMP-mediated degradation of extracellular matrix.
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PMID:Matrix metalloproteinase-1 and -9 activation by plasmin regulates a novel endothelial cell-mediated mechanism of collagen gel contraction and capillary tube regression in three-dimensional collagen matrices. 1118 Nov 75

SU5416 and SU6668 are potent antiangiogenic small-molecule inhibitors of receptor tyrosine kinases, including those of the vascular endothelial growth factor and platelet-derived growth factor receptor families. The stem cell factor (SCF) receptor, c-kit, is structurally related to these receptors and, although not expressed on mature peripheral blood cells, is expressed in leukemic blasts derived from 60% to 80% of acute myeloid leukemia (AML) patients. The c-kit kinase inhibitory activity of SU5416 and SU6668 was evaluated in MO7E cells, a human myeloid leukemia cell line. Tyrosine autophosphorylation of the receptor, induced by SCF, was inhibited in these cells by SU5416 and SU6668 in a dose-dependent manner (inhibitory concentration of 50% [IC(50)] 0.1-1 microM). Inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, a signaling event downstream of c-kit activation, was also inhibited in a dose-dependent manner. Both compounds also inhibited SCF-induced proliferation of MO7E cells (IC(50) 0.1 microM for SU5416; 0.29 microM for SU6668). Furthermore, both SU5416 and SU6668 induced apoptosis in a dose- and time-dependent manner as measured by the increase in activated caspase-3 and the enhanced cleavage of its substrate poly(ADP-ribose) polymerase. These findings with MO7E cells were extended to leukemic blasts from c-kit(+) patients. In patient blasts, both SU5416 and SU6668 inhibited SCF-induced phosphorylation of c-kit and ERK1/2 and induced apoptosis. These studies indicate that SU5416 and SU6668 inhibit biologic functions of c-kit in addition to exhibiting antiangiogenic properties and suggest that the combination of these activities may provide a novel therapeutic approach for the treatment of AML.
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PMID:The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. 1122 88

Apoptotic proteases cleave and inactivate survival signaling molecules such as Akt/PKB, phospholipase C (PLC)-gamma1, and Bcl-2. We have found that treatment of A431 cells with tumor necrosis factor-alpha in the presence of cycloheximide resulted in the cleavage of epidermal growth factor receptor (EGFR) as well as the activation of caspase-3. Among various caspases, caspase-1, caspase-3 and caspase-7 were most potent in the cleavage of EGFR in vitro. Proteolytic cleavage of EGFR was inhibited by both YVAD-cmk and DEVD-fmk in vitro. We also investigated the effect of caspase-dependent cleavage of EGFR upon the mediation of signals to downstream signaling molecules such as PLC-gamma1. Cleavage of EGFR by caspase-3 significantly impaired the tyrosine phosphorylation of PLC-gamma1 in vitro. Given these results, we suggest that apoptotic protease specifically cleaves and inactivates EGFR, which plays crucial roles in anti-apoptotic signaling, to abrogate the activation of EGFR-dependent downstream survival signaling molecules.
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PMID:Proteolytic cleavage of epidermal growth factor receptor by caspases. 1122 7

Endotoxin is one of the major factors causing myocardial depression and death during sepsis in humans. Recently, it was reported that endotoxin may induce cardiomyocyte apoptosis. Also, multiple caspase activation has been implicated in endotoxin-induced apoptosis in several organ systems. In this study, we investigated whether endotoxin would increase myocardial caspase activities and evaluated the effects of in vivo administration (3 mg/kg) of the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone(z-VAD.fmk), the caspase-3-like inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp-chloromethylketone (z-DEVD.cmk), and the caspase-1-like inhibitor acetyl-Tyr-Val-Ala-Asp-chloromethylketone (Ac-YVAD. fmk), on endotoxin-induced myocardial dysfunction and apoptosis. Endotoxin administration (10 mg/kg iv) induced myocardial contractile dysfunction that was associated with caspase activity increases and nuclear apoptosis. Broad-spectrum z-VAD.fmk and z-DEVD.cmk improved endotoxin-induced myocardial dysfunction and reduced caspase activation and nuclear apoptosis when given immediately and 2 h after endotoxin. In contrast, no effects of Ac-YVAD.fmk were observed on myocardial function and caspase-induced apoptosis. Administration of caspase inhibitors 4 h after endotoxin treatment was not able to protect the rat heart from myocardial dysfunction and nuclear apoptosis. These observations provide evidence that in our model, caspase activation plays a role in endotoxin-induced myocardial apoptosis. Caspase inhibition strategy may represent a therapeutic approach to endotoxin-induced myocardial dysfunction.
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PMID:Differential effects of caspase inhibitors on endotoxin-induced myocardial dysfunction and heart apoptosis. 1124 71

The majority of elderly men are affected by benign and malign diseases of the prostate that are governed by endocrine factors and local stromal/epithelial and luminal/epithelial interactions. Prostate epithelial cells secrete numerous factors into the seminal plasma (SMP) that are thought to be responsible for nutrition, accurate pH, and ionic environment of sperm. Our hypothesis assumes that prostatic factors responsible for optimal fertility might have retrograde influences on epithelial cell growth, differentiation, and function. SMP was analyzed for proteins and other biologically active substances by size exclusion high-performance liquid chromatography. Each fraction was investigated for its effect on cell growth and death. A low molecular mass fraction (2-4 kDa) was responsible for inducing apoptosis in proliferating prostate epithelial cells. Signal transduction was mediated by the production of cAMP; no significant changes in tyrosine phosphorylation of membrane receptors were observed. Mechanisms of apoptosis, i.e., caspase- and mitochondria-dependent pathways, were investigated in prostate epithelial cells by caspase activity assays, annexin/propidium iodide staining, changes in mitochondrial potential, p53, Par-4, Bax, and Bcl-2 protein levels. SMP induced p53- and Bcl-2-dependent apoptosis without activation of caspase-3. Obviously, SMP contains protective factors that help eliminate degenerated cells and control epithelial renewal. Age-related changes in the composition of SMP or the susceptibility of epithelial cells might, therefore, contribute to proliferative prostatic diseases
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PMID:A low-molecular-weight fraction of human seminal plasma activates adenylyl cyclase and induces caspase 3-independent apoptosis in prostatic epithelial cells by decreasing mitochondrial potential and Bcl-2/Bax ratio. 1125 85

Photodynamic therapy (PDT), a cancer treatment using a photosensitizer and visible light, has been shown to induce apoptosis or necrosis. We report here that Purpurin-18 (Pu18) in combination with light induces rapid apoptotic cell death in the human leukemia cell line (HL60) at low doses and necrosis at higher concentrations. Cells treated with Pu18 and light under apoptotic conditions exhibited DNA laddering and an increase in both cellular content of subdiploid DNA and externalization of phosphatidylserine (PS), indicating DNA fragmentation and loss of membrane phospholipid asymmetry. In the absence of light activation, Pu18 at nanomolar concentrations had no detectable cytotoxic effect. Caspase-3 activity was increased even after 1 h from treatment with low doses of Pu18 and light. The PS exposure and nuclear features of apoptosis were prevented by treatment of cells before illumination with caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (Z-DEVD-FMK). Conversely, the caspase-1 inhibitor, acetyl-Tyr-Val-Ala-Asp-aldehyde (Ac-YVAD-CHO) failed to suppress the apoptosis. No protective effect of the three caspase inhibitors was observed when the cells were exposed to necrotic concentrations of Pu18 and light. Our results show that caspase-3, but not caspase-1, is involved in the signaling of apoptotic events in PDT with Pu18-induced apoptosis of HL60 cells. Moreover, both the time course of PS exposure and the effect of caspase inhibitors on it indicate that it is regulated in the same manner as DNA fragmentation.
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PMID:Purpurin-18 in combination with light leads to apoptosis or necrosis in HL60 leukemia cells. 1128 Oct 26

Hwansodan has been used as a prescription for senile and vascular dementia in Oriental medicine. We investigated the neuroprotective effects of Hwansodan water extract on the apoptotic death of PC12 cells by serum deprivation. Hwansodan significantly rescued PC12 cells from apoptotic death by serum deprivation in a dose-dependent manner. The nuclear staining of PC12 cells clearly showed that Hwansodan attenuated nuclear condensation and fragmentation, which represents typical neuronal apoptotic characteristics. Hwansodan also prevents DNA fragmentation and caspase-3-like protease activation in serum-deprived PC12 cells and induces the tyrosine phosphorylation of proteins around 44 kDa, which was identified as ERK1 with electrophoretic gel mobility shift by Western blot. In addition, MEK inhibitor PD98059 and Ras inactivator, alpha-hydroxyfarnesylphosphonic acid and mevastatin, attenuated the neuroprotective effects of Hwansodan in serum-deprived PC12 cells. These results indicate that Ras/MEK/ERK signaling pathway plays a role in neuroprotective effects of Hwansodan in serum-deprived PC12 cells.
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PMID:Hwansodan protects PC12 cells against serum-deprivation-induced apoptosis via a mechanism involving Ras and mitogen-activated protein (MAP) kinase pathway. 1128 16

The purpose of this study was to investigate the possible molecular mechanisms of the antiproliferative effect induced by protocatechualdehyde (PA, a dihydroxybenzene derivative). The viability of cytotoxic T cells (CfLL-2) stimulated by IL2 was significantly inhibited at 0.12 mM PA. This inhibitory effect was associated with the induction of apoptosis detected by DNA fragmentation assay. DNA ladder appeared at 0.12 mM PA and the intensity of DNA ladder was visible at 0.3 mM PA. PA inhibited the Ib2-dependent tyrosine phosphorylation of 91, 80 and 55 KDa proteins, but did not affect IL2-dependent serine/threonine phosphorylation of proteins. The levels of bcl-2 protein and mRNA were suppressed by PA. An alteration in bax protein expression on the apoptosis process in CTLL-2 cells was not observed. However, caspase-3 activity was increased by PA. Our results demonstrate that PA inhibited cell proliferation and induced apoptosis in CTLL-2 cells. It is concluded that PA is a potent anti-proliferative agent and is expected to be a promising candidate for novel therapeutics.
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PMID:Induction of apoptosis in CTLL-2 cells by protocatechualdehyde. 1139 45

Decreased phosphorylation of focal adhesion kinase (FAK) is associated with loss of focal adhesions and actin stress fibers and precedes the onset of apoptosis in renal epithelial cells caused by nephrotoxicants (Van de Water, B., Nagelkerke, J. F., and Stevens, J. L. (1999) J. Biol. Chem. 274, 13328-13337). The role of FAK in the control of apoptosis caused by nephrotoxicants was further investigated in LLC-PK1 cells that were stably transfected with either green fluorescent protein (GFP)-FAK or dominant negative acting deletion mutants of FAK, GFP-FAT, and GFP-FRNK. GFP-FAT and GFP-FRNK delayed the formation of focal adhesions and prevented the localization of endogenous (phosphorylated) FAK at these sites. GFP-FAT and GFP-FRNK overexpression potentiated the onset of apoptosis caused by the nephrotoxicant dichlorovinyl-cysteine. This was associated with an increased activation of caspase-3. GFP-FAT also potentiated apoptosis caused by doxorubicin but not cisplatin. The potentiation of apoptosis by GFP-FAT was related to an almost complete dephosphorylation of FAK; this did not occur in cells overexpressing only GFP. This dephosphorylation was associated with a pronounced loss of focal adhesion organization in GFP-FAT cells, in association with loss of tyrosine phosphorylation of paxillin. In conclusion, the data indicate an important role of cell-matrix signaling in the control of chemically induced apoptosis; loss of FAK activity caused by toxic chemicals results in perturbations of focal adhesion organization with a subsequent inactivation of associated (signaling) molecules and loss of survival signaling.
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PMID:Suppression of chemically induced apoptosis but not necrosis of renal proximal tubular epithelial (LLC-PK1) cells by focal adhesion kinase (FAK). Role of FAK in maintaining focal adhesion organization after acute renal cell injury. 1144 17


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