Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dysregulation of apoptosis is one of the likely underlying mechanisms of neointimal thickening, a disorder in which proinflammatory cytokines may influence the function of vascular smooth muscle cells (VSMCs) and contribute to atherogenesis. One of these cytokines, tumor necrosis factor-alpha (TNF-alpha), induces 2 possibly conflicting pathways, 1 leading to the activation of nuclear factor-kappaB (NF-kappaB) and the other leading to caspase-mediated apoptosis. We investigated whether specific inhibition of NF-kappaB affects TNF-alpha-dependent apoptosis in human VSMCs. To inhibit NF-kappaB activation specifically, we constructed a recombinant adenovirus vector expressing a truncated form of the inhibitor protein IkappaBalpha (AdexIkappaBDeltaN) that lacks the phosphorylation sites essential for activation of NF-kappaB. The IkappaBDeltaN was overexpressed by adenoviral infection and was resistant to stimulus-dependent degradation. Electromobility gel shift and luciferase assays demonstrated that overexpression of IkappaBDeltaN inhibited NF-kappaB activation induced by TNF-alpha or interleukin-1beta (IL-1beta). In cells overexpressing IkappaBDeltaN, TNF-alpha dramatically induced apoptosis, whereas IL-1beta had no effect. The induction was suppressed by treatment with a selective inhibitor of the caspase-3 family, Z-DEVD-fmk, and the overexpression of IkappaBDeltaN induced TNF-alpha-mediated caspase-3 and caspase-2 activity. These results indicate that overexpression of IkappaBDeltaN induces TNF-alpha-dependent apoptosis by efficient and specific suppression of NF-kappaB and upregulation of caspase-3 and caspase-2 activity in human VSMCs. Our findings suggest that adenovirus-mediated IkappaBDeltaN gene transfer may be useful in the treatment of disorders associated with inflammatory conditions, such as the response to vascular injury and atherosclerosis.
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PMID:Overexpression of truncated IkappaBalpha induces TNF-alpha-dependent apoptosis in human vascular smooth muscle cells. 1103 Dec 4

TRAIL induces apoptosis in various tumor cells. We report here that caspase-8 is required in TRAIL-induced cell death. Western blot analyses and enzyme assays showed that exposing Jurkat cells to TRAIL resulted in activation of caspases-8 followed by caspase-3 and -9. Acetyl-IETD-fluoromethylketone, a caspase-8 inhibitor, potently suppressed TRAIL-induced cell death compared to acetyl-DEVD-fluoromethylketone and acetyl-LEHD-fluoromethylketone, inhibitors of caspase-3 and caspase-9, respectively. JB6 cells, a caspase-8-deficient Jurkat variant, were completely resistant to TRAIL. However, reconstitution with a caspase-8, but not with caspase-2 or -3, sensitized JB6 cells to subsequent exposure to TRAIL. These results are indicative of the crucial function of caspase-8 in TRAIL-induced apoptosis in Jurkat cells.
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PMID:Reconstitution of caspase-8 sensitizes JB6 cells to TRAIL. 1103 23

When PC12 cells are deprived of trophic support they undergo apoptosis. We have previously shown that survival of trophic factor-deprived PC12M1 cells can be promoted by activation of the G protein-coupled muscarinic receptors. The mechanism whereby muscarinic receptors inhibit apoptosis is poorly understood. In the present study we investigated this mechanism by examining the effect of muscarinic receptor activation on the serum deprivation-induced activity of key players in apoptosis, the caspases, in PC12M1 cells. The results showed that m1 muscarinic activation inhibits caspase activity induced by serum deprivation. This effect appeared to be caused by the prevention of activation of caspases such as caspase-2 and caspase-3, and not by the inhibition of existing activity. Muscarinic receptor activation also stimulated the mitogen-activated protein kinase/extracellular signaling-regulated kinase (MAPK/ERK) and phosphoinositide (PI) 3-kinase signaling pathways. The PI 3-kinase pathway inhibitors wortmannin and LY294002, as well as the MAPK/ERK pathway PD98059 inhibitor, did not however suppress the inhibitory effect of the muscarinic receptors on caspase activity. The results therefore suggested that the muscarinic survival effect is mediated by a pathway that leads to caspase inhibition by MAPK/ERK- and PI 3-kinase-independent signaling cascades.
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PMID:M1 muscarinic receptors block caspase activation by phosphoinositide 3-kinase- and MAPK/ERK-independent pathways. 1104 77

Resveratrol (3,5,4'-trihydroxy-trans-stilbene), in the concentration range of 20 microM and above, induced arrest in the S-phase and apoptosis in the T cell-derived T-ALL lymphocytic leukemia cell line CEM-C7H2 which is deficient in functional p53 and p16. Expression of transgenic p16/INK4A, which causes arrest in G0/G1, markedly reduced the percentage of apoptotic cells. Antagonist antibodies to Fas or FasL, or constitutive expression of crmA did not diminish the extent of resveratrol-induced apoptosis. Furthermore, a caspase-8-negative, Fas-resistant Jurkat cell line was sensitive to resveratrol-induced apoptosis which could be strongly inhibited in the Jurkat as well as in the CEM cell line by z-VAD-fmk and z-IETD-fmk. The almost complete inhibition by z-IETD-fmk and the lack of inhibition by crmA suggested caspase-6 to be the essential initiator caspase. Western blots revealed the massive conversion of procaspase-6 to its active form, while caspase-3 and caspase-2 were proteolytically activated to a much lesser extent.
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PMID:Resveratrol causes arrest in the S-phase prior to Fas-independent apoptosis in CEM-C7H2 acute leukemia cells. 1104 78

We have attempted to elucidate the precise mechanism of nitric oxide (NO)-induced apoptotic neuronal cell death. Enzymatic cleavages of DEVD-AFC, VDVAD-AFC, and LEHD-AFC (specific substrates for caspase-3-like protease (caspase-3 and -7), caspase-2, and caspase-9, respectively) were observed by treatment with NO. Western blot analysis showed that pro-forms of caspase-2, -3, -6, and -7 are decreased during apoptosis. Interestingly, Ac-DEVD-CHO, a caspase-3-like protease inhibitor, blocked not only the decreases in caspase-2 and -7, but also the formation of p17 from p20 in caspase-3 induced by NO, suggesting that caspase-3 exists upstream of caspase-2 and -7. Bongkrekic acid, a potent inhibitor of mitochondrial permeability transition, specifically blocked both the loss of mitochondrial membrane potential and subsequent DNA fragmentation in response to NO. Thus, NO results in neuronal apoptosis through the sequential loss of mitochondrial membrane potential, caspase activation, and degradation of inhibitor of caspase-activated DNase (CAD) (CAD activation).
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PMID:Mechanism of nitric oxide-induced apoptosis in human neuroblastoma SH-SY5Y cells. 1107 88

Integrin receptors mediate several functions including prevention of matrix detachment-induced apoptosis (anoikis) of several adherent cell types. We report here that antagonists of beta1 integrins trigger an apoptotic signaling pathway in adherent differentiated LAN-5 human neuroblastoma cells, a cell line which represents a model system for the study of human neurons. The pathway is characterized by cytochrome c release into the cytoplasm, and activation of caspase-9 and caspase-3, 4-6h after treatment; cleavage products of caspase-8 and caspase-2 were not detectable in the cells. Coordinate inactivation of cell survival pathways, including cleavage of focal adhesion kinase, decreased expression of protein kinase B, and reduced phosphorylation of the pro-apoptotic protein, Bad, also characterized the signaling pathway. These events occurred in adherent cells; DNA fragmentation and detachment followed as late events 18-24h after addition of beta1 integrin antagonists. zDEVD-fmk, an irreversible inhibitor of caspase-3-like enzymes, and cytochalasin D, an actin depolymerizing agent, blocked caspase-3 cleavage and delayed cell death. In contrast to these results, undifferentiated, adherent and dividing LAN-5 cells did not die in response to beta1 integrin antagonists. These studies identify a distinct apoptotic pathway which is triggered by antagonists of beta1 integrins on differentiated adherent neuronal cells.
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PMID:beta1 integrin antagonism on adherent, differentiated human neuroblastoma cells triggers an apoptotic signaling pathway. 1111 63

The recognized role of caspases as executioners of apoptosis, led us to investigate their involvement in death responses induced by okadaic acid (OA) in HeLa S(3) and MCF-7 cells. A one-day treatment with OA induced accumulation of the 85kDa poly(ADP-ribose) polymerase (PARP) fragment in cell lysates but the response was prevented if cells were treated with OA in the presence of the caspase inhibitors Z-VAD-FMK and Z-DEVD-FMK. The HeLa S(3) and MCF-7 cells were found to contain measurable levels of the intact caspase-2, -7, -8 and -9 zymogens, whereas caspase-3 was found only in HeLa cells. After one day of OA treatment, pro-caspase-2, -3, -7 and -9 isoforms were found processed in HeLa cells, whereas only pro-caspase-2 was processed in MCF-7 cells. Pro-caspase-8, in turn, was mostly unprocessed in both cell lines. The possible interference of caspase inhibitors on cell death was also evaluated, and we found that both Z-VAD-FMK and Z-DEVD-FMK could contribute different extents of protection of MCF-7 and HeLa cells from toxic effects caused by OA. We concluded that OA triggers multiple pathways of caspase processing, contributing to death responses triggered by OA in HeLa S(3) and MCF-7 cells.
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PMID:The toxic responses induced by okadaic acid involve processing of multiple caspase isoforms. 1113 34

Apoptotic cell death is induced in SH-SY5Y neuroblastoma cells following exposure to the protein kinase inhibitors staurosporine (100 nM) and 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine: H-7 (100 microM). This is associated with reduced levels of PARP 117 kDa and with the concomitant formation of PARP-cleaved products of 89 kDa that result from caspase-3 activation. The process is inhibited with DEVD-fmk, a potent caspase-3 (and caspase-8) inhibitor, thus indicating that staurosporine- and H-7-induced cell death in SH-SY5Y is mediated by caspase activation. Increased caspase-2- and caspase-3-like activities, but not caspase-9-like activity, were demonstrated by monitoring proteolysis of the corresponding colorimetric substrates. Caspase-2 activity peaked at 6 h, whereas caspase-3 peaked at 12 h in parallel with the maximal loss of cell viability. No modifications in the expression levels of Fas and Fas-L were observed by Western blotting. Furthermore, no activation of caspase-8 was elicited by colorimetric assays through the process of apoptosis of neuroblastoma cells. These findings indicate that the Fas/Fas-L-caspase-8 pathway of cell death signaling is not involved in staurosporine- and H-7-induced apoptosis in SH-SY5Y neuroblastoma cells.
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PMID:Staurosporine- and H-7-induced cell death in SH-SY5Y neuroblastoma cells is associated with caspase-2 and caspase-3 activation, but not with activation of the FAS/FAS-L-caspase-8 signaling pathway. 1114 7

RGD motif-containing peptides have been used in various studies of cell adhesion and growth. We report that RGD triggered apoptosis at a concentration of 1 mmol/L, whereas RAD-containing peptides failed to induce apoptosis in HL-60 cells. RGD-treated cells revealed internucleosomal DNA fragmentation. Western blot reveals caspase-3 activation in RGD peptide-treated cells. A caspase-3 inhibitor z-VAD-FMK completely blocked the apoptosis, but a caspase-1 inhibitor (Ac-YVAD-CMK) and caspase-2 inhibitor (z-VDVAD-FMK) did not block the apoptosis, suggesting that caspase-3 might have a critical role in the execution process of apoptosis induced by RGD. RGD peptides have been used extensively to inhibit tumor metastasis. Our results should help in further understanding the RGD peptide-induced apoptosis, which is important since RGD peptides have a potential role in therapies of the future.
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PMID:RGD peptide-induced apoptosis in human leukemia HL-60 cells requires caspase-3 activation. 1120 Oct 51

Even though cerebral vasospasm after subarachnoid hemorrhage (SAH) causes cerebral ischemia or infarction, the metabolic alterations in cerebrospinal fluids (CSF) after SAH have not been studied. This study was undertaken to measure the levels of glucose, lactate, pyruvate and glutamate in CSF from double hemorrhage dog models. Thirty-two mongrel dogs of either sex, weighing 18-24 kg, underwent double hemorrhage by percutaneous needle puncture of the cistema magna and injection of autologous blood on day 0 and day 2. The dogs were then sacrificed on day 3, 5 and 7, after collecting CSF. In another study, the dogs were treated with mitogen-activated protein kinase (MAPK) inhibitors PD98059 and U0126, and caspase-2 and caspase-3 inhibitors from day 3 to day 6 after initial blood injection. CSF was collected on day 7 before dogs were sacrificed. The concentration of glucose, lactate, pyruvate and glutamate in CSF was measured by photometrical method. Compared with CSF collected on day 0, glucose was decreased on days 5-7, lactate was increased on days 2-7, pyruvate was increased on days 2-7, and glutamate was increased on days 3-7 (p < 0.05). In the groups treated with MAPK or caspase inhibitors, most of the metabolic alterations remained unchanged as compared with CSF from untreated dogs. Clinically, caspase inhibitors-2 and -3, and MAPK inhibitor U0126 all failed to prevent vasospasm. MAPK inhibitor PD98059 partially prevented vasospasm. Our data demonstrated a metabolic alteration of glucose, glutamate, lactate and pyruvate in CSF during cerebral vasospasm. This metabolic change in consistent with the time course of cerebral vasospasm. This study suggests that brain energy metabolites and excitative amino acids are altered during cerebral vasospasm.
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PMID:Metabolic alterations in cerebrospinal fluid from double hemorrhage model of dogs. 1121 Apr 38


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