Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor (TNF)-alpha is released in acute inflammatory lung syndromes linked to the extensive vascular dysfunction associated with increased permeability and endothelial cell apoptosis. TNF-alpha induced significant decreases in transcellular electrical resistance across pulmonary endothelial cell monolayers, reflecting vascular barrier dysfunction (beginning at 4 h and persisting for 48 h). TNF-alpha also triggered endothelial cell apoptosis beginning at 4 h, which was attenuated by the caspase inhibitor Z-Val-Ala-Asp-fluoromethylketone. Exploring the involvement of the actomyosin cytoskeleton in these important endothelial cell responses, we determined that TNF-alpha significantly increased myosin light chain (MLC) phosphorylation, with prominent stress fiber and paracellular gap formation, which paralleled the onset of decreases in transcellular electrical resistance and enhanced apoptosis. Reductions in MLC phosphorylation by the inhibition of either MLC kinase (ML-7, cholera toxin) or Rho kinase (Y-27632) dramatically attenuated TNF-alpha-induced stress fiber formation, indexes of apoptosis, and caspase-8 activity but not TNF-alpha-induced barrier dysfunction. These studies indicate a central role for the endothelial cell cytoskeleton in TNF-alpha-mediated apoptosis, whereas TNF-alpha-induced vascular permeability appears to evolve independently of contractile tension generation.
 ...
PMID:Differential effect of MLC kinase in TNF-alpha-induced endothelial cell apoptosis and barrier dysfunction. 1135 Jul 95

Treatment of cells with phorbol ester, phorbol-12-myristate-13-acetate (PMA), triggers differentiation or apoptosis, depending on the cell type. In this study, we used an erythroblastic cell line, TF-1, to investigate the molecular mechanism that determines the cell fate in response to PMA exposure. Upon PMA treatment in the presence of serum or lysophosphatidic acid (LPA), TF-1 cells exhibited contraction followed by apoptosis. By contrast, under serum-free conditions, cells became adherent and survived after PMA treatment. Here, we show that the pathway of Rho kinase (ROCK)/myosin light chain (MLC) phosphorylation/myosin-mediated contraction was activated in PMA-induced apoptotic cells in serum-containing medium, but not in the adherent and survived cells. Pretreatment of cells with a specific ROCK inhibitor, Y27632, not only abrogated MLC phosphorylation and membrane contraction, but also prevented PMA-induced activation of caspase-3 and subsequent cell death, indicating that ROCK-dependent myosin-mediated contraction elicits an upstream signal required for caspase-3 activation in PMA-induced apoptosis. Interestingly, we further found that caspases-8 and -10 are the initiator caspases in PMA-induced apoptosis and a ROCK-dependent enhancement of specific complex formation between the Fas-associated death domain (FADD) and pro-caspase-10 in pro-apoptotic cells. In summary, these results revealed that, following PMA treatment, the upregulation of the RhoA/ROCK pathway contributes to a cellular context that switches-on myosin-mediated contraction, which provides a mechanism for triggering apoptotic induction mediated by caspase-8 and -10.
 ...
PMID:Caspase activation during phorbol ester-induced apoptosis requires ROCK-dependent myosin-mediated contraction. 1286 35

Upon engagement, the CD95 receptor is rapidly clustered into cellular 'caps'. This receptor capping is one of the first events to take place following activation and it has been proposed to be important for the initiation of apoptotic signaling. As the biological roles of CD95 capping are still elusive, we explored in detail the role of capping in induction of apoptosis in lymphocytes. CD95 capping was shown to be uncoupled from apoptosis, as apoptosis could occur in the absence of CD95 capping and, vice versa, capping could occur without inducing apoptosis. CD95 capping occurred concomitantly with reorganization of the actin cytoskeleton and aggregation of lipid rafts. While inhibition of actin polymerization and caspase-8 activity had cell type-specific effects on capping in type I and type II cells, the rapid CD95-mediated cellular polarization, as visualized by the orchestrated reorganization of CD95, F-actin and lipid rafts, was shown to be dependent on signaling by Rho kinase (ROCK) in both cell types, however, by distinct activation mechanisms in the respective cell type. CD95 activated RhoA exclusively in the type II cell, whereas ROCK activation was caspase-dependent in the type I cell. Taken together, our results imply that CD95 capping and the subsequent cellular polarization is a ROCK signaling-regulated process that does not correlate with the induction of apoptosis, but is more likely to be involved in the emerging non-apoptotic functions of CD95.
 ...
PMID:CD95 capping is ROCK-dependent and dispensable for apoptosis. 1585 33

The small G-protein RhoA regulates the actin cytoskeleton, and its involvement in cell proliferation has also been established. In contrast, little is known about whether RhoA participates in cell survival or apoptosis. In cardiomyocytes in vitro, RhoA induces hypertrophic cell growth and gene expression. In vivo, however, RhoA expression leads to development of heart failure (Sah, V. P., Minamisawa, S., Tam, S. P., Wu, T. H., Dorn, G. W., Ross, J. Jr., Chien, K. R., and Brown, J. H. (1999) J. Clin. Investig. 103, 1627-1634), a condition widely associated with cardiomyocyte apoptosis. We demonstrate here that adenoviral overexpression of activated RhoA in cardiomyocytes induces hypertrophy, which transitions over time to apoptosis, as evidenced by caspase activation and nucleosomal DNA fragmentation. The Rho kinase inhibitors Y-27632 and HA-1077 and expression of a dominant negative Rho kinase block these responses. Caspase-9, but not caspase-8, is activated, and its inhibition prevents DNA fragmentation, consistent with involvement of a mitochondrial death pathway. Interestingly, RhoA expression induces a 3-4-fold up-regulation of the proapoptotic Bcl-2 family protein Bax. RhoA also increases levels of activated Bax and the amount of Bax protein localized at mitochondria. Bax mRNA is increased by RhoA, indicating transcriptional regulation, and the ability of a dominant negative p53 mutant to block Bax up-regulation implicates p53 in this response. The involvement of Bax in RhoA-induced apoptosis was examined by treatment with a Bax-inhibitory peptide, which was found to significantly attenuate DNA fragmentation and caspase-9 and -3 activation. The dominant negative p53 also prevents RhoA-induced apoptosis. We conclude that RhoA/Rho kinase activation up-regulates Bax through p53 to induce a mitochondrial death pathway and cardiomyocyte apoptosis.
 ...
PMID:RhoA/Rho kinase up-regulate Bax to activate a mitochondrial death pathway and induce cardiomyocyte apoptosis. 1723 27

Deleted in colon cancer (DCC) and UNC5 function as netrin dependence receptors by inducing apoptosis in the absence of their ligand and accordingly were recently designated as putative conditional tumor suppressors. Herein, we determined whether netrin-1 and its receptors are implicated in cancer cell invasion and tumor progression. Expression of DCC, UNC5 and adenosine A2B-receptors (A2B-Rs) was investigated by reverse transcription polymerase chain reaction in human colon cancer cells. The impact of DCC restitution and netrin-1 was evaluated on collagen type I invasion, tumor growth and metastasis in nude mice, cancer cell survival and gene expression profiling. Flow cytometry, poly(ADP-ribose)polymerase-1 and caspase-8 activation were used to evaluate the impact of DCC on cell death. Both netrin-1 and A2B-R activation induced the invasive phenotype through the Rho-Rho kinase axis in DCC-deficient human colorectal cancer cells. Restitution of wild-type DCC blocked invasion induced by netrin-1, A2B-R agonist and other agents. Ectopic expression of netrin-1 led to increased growth of human colon tumor xenografts in athymic mice. Conversely, introduction of wt-DCC in kidney MDCKts.src-ggl cells strongly inhibited metastasis in lymph nodes and lungs and increased sensitivity to apoptosis in hypoxia. DNA microarrays revealed that netrin and DCC had common and divergent impacts on gene expression linked to cell cycle, survival, surface signaling and adhesion. Our findings underscore that netrin is a potent invasion and tumor growth-promoting agent and that DCC is a metastasis suppressor gene targeting both proinvasive and survival pathways in a cumulative manner.
 ...
PMID:Opposing roles of netrin-1 and the dependence receptor DCC in cancer cell invasion, tumor growth and metastasis. 1733 89

During times of war or natural disasters, rhabdomyolysis leading to acute kidney injury (AKI) can assume epidemic proportions. Fasudil attenuates ischemia/reperfusion-induced AKI. We investigated the therapeutic effect of an early application of fasudil on AKI induced by rhabdomyolysis and explored the potential mechanisms. Male Wistar rats were randomly divided into a control group (saline, 7 mL/kg, i.m.), a Gly group (50% glycerol, 7 mL/kg, i.m.), and a fasudil group (50% glycerol, 7 mL/kg, i.m.; fasudil, 20 mg/kg bodyweight, i.p., three times every 24 h beginning 72 h before glycerol administration). Serum creatinine, blood urea nitrogen (BUN), and histopathological changes were used to demonstrate kidney function 24 h after the glycerol injection. Cell apoptosis and the expression of rho-associated protein kinase member (ROCK1), phosphatase and tensin homolog (PTEN), P-Akt, and caspase-8, -9, and -3 were measured. Serum creatinine and BUN levels increased significantly in Gly group compared with control group. Both levels decreased after fasudil treatment. The renal tubular damage score was significantly lower and cell apoptosis was significantly less in fasudil group compared with Gly group. The expression levels of ROCK1, PTEN, and caspase-8, -9, and -3 were upregulated significantly in Gly group, and their expression was reduced in the fasudil group. The P-Akt level was decreased in Gly group and upregulated significantly in fasudil group. Early application of fasudil reduced rhabdomyolysis-associated renal injury by inhibiting Rho kinase and thereby activating the PI-3K/Akt pathway, which decreased cell apoptosis via both the intrinsic and extrinsic apoptotic pathways.
 ...
PMID:Fasudil ameliorates rhabdomyolysis-induced acute kidney injury via inhibition of apoptosis. 2179 20