UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
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Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine known to activate macrophages and T cells. In this study, we demonstrate that recombinant MIF delays apoptosis of neutrophils in vitro. MIF action is dose and time dependent as well as specific since it was abolished with a neutralizing anti-MIF antibody. MIF, like G-CSF, delayed cleavage of the proapoptotic members of the Bcl-2 family Bid and Bax in neutrophils, suggesting that MIF inhibits apoptosis pathways proximal to mitochondria activation. Indeed, MIF also prevented release of cytochrome c and Smac from the mitochondria and subsequent activation of the critical effector caspase-3 in these cells. Moreover, we observed increased MIF plasma levels in patients with cystic fibrosis, a heterogeneous recessive genetic disorder associated with bacterial infections and delayed neutrophil apoptosis. In conclusion, MIF is a survival cytokine for human neutrophils, a finding with potential pathologic relevance in infectious diseases.
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PMID:Macrophage migration inhibitory factor delays apoptosis in neutrophils by inhibiting the mitochondria-dependent death pathway. 1465 84

Oxidized low-density lipoprotein (ox-LDL) induces apoptosis in endothelial cells. However, steps leading to ox-LDL-induced apoptosis remain unclear. We examined the role of ox-LDL and its newly described receptor LOX-1 in the expression of intracellular pro- and antiapoptotic proteins and caspase pathways in human coronary artery endothelial cells (HCAECs). Cells were cultured and treated with different concentrations (10 to 80 microg/mL) of ox-LDL for different times (2 to 24 hours). Ox-LDL induced apoptosis in HCAECs in a concentration- and time-dependent manner. Ox-LDL also activated caspase-9 and caspase-3, but not caspase-8. After ox-LDL treatment, there was a significant release of activators of caspase-9, including cytochrome c and Smac from mitochondria to cytoplasmic compartment, and their release was not affected by treatment of cells with inhibitors of either caspase-8 or caspase-9. Ox-LDL also decreased expression of antiapoptotic proteins Bcl-2 and c-IAP (inhibitory apoptotic protein)-1, which are involved in the release of cytochrome c and Smac and activation of caspase-9, in a concentration- and time-dependent manner. On the other hand, ox-LDL did not change the expression of Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (FLIP) and proapoptotic protein Fas, which are required for the activation of caspase-8. Further, ox-LDL did not cause the truncation of Bid, which implies the activation of caspase-8. In other experiments, pretreatment of HCAECs with the caspase-9 inhibitor z-LEHD-fmk, but not the caspase-8 inhibitor z-IETD-fmk, blocked ox-LDL-induced activation of caspase-3 and apoptosis. As expected, pretreatment with the caspase-3 inhibitor DEVD-CHO inhibited ox-LDL-induced activation of caspase-3 and resultant apoptosis. The proapoptotic effects of ox-LDL were mediated by its receptor LOX-1, because pretreatment of HCAECs with antisense-LOX-1, but not sense-LOX-1, blocked these effects of ox-LDL. These findings suggest that ox-LDL through its receptor LOX-1 decreases the expression of antiapoptotic proteins Bcl-2 and c-IAP-1. This is followed by activation of apoptotic signaling pathway, involving release of cytochrome c and Smac and activation of caspase-9 and then caspase-3.
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PMID:Role of caspases in Ox-LDL-induced apoptotic cascade in human coronary artery endothelial cells. 1497 36

Apicidin, a histone deacetylase inhibitor, is a novel cyclic tetrapeptide with potent antiproliferative activity against various cancer cells. We examined whether apicidin potentiates the imatinib-induced apoptosis of Bcr-Abl-positive human leukaemia cells. In K562 cells, the co-administration of minimally toxic concentrations of imatinib and apicidin (imatinib/apicidin) for 48 h produced a marked increase in mitochondrial damage, processing of caspase cascades and apoptosis. Similar results were observed in leukaemic blasts obtained from patients with chronic myeloid leukaemia in blast crisis. Imatinib/apicidin co-treatment for 48 h resulted in a near complete loss of the full-length XIAP (X-linked inhibitor of apoptosis) protein, with a corresponding increase in the 29-kDa XIAP cleavage product. Both the degradation of XIAP and increased release of second mitochondria-derived activator of caspase/direct IAP-binding protein with low pI (Smac/DIABLO) into the cytosol were abrogated by pretreatment with the caspase-3 inhibitor DEVD-CHO. Imatinib/apicidin co-treatment for 48 h produced a prominent decrease in Bcr-Abl protein levels in a caspase-dependent manner. In summary, these data indicate that apicidin potentiates the imatinib-induced apoptosis of Bcr-Abl-positive leukaemia cells through the enhanced activation of the mitochondria-dependent caspase cascades, accompanied by caspase-dependent downregulation of Bcr-Abl and XIAP. These findings generate a rationale for further investigation of apicidin and imatinib as a potential therapeutic strategy in Bcr-Abl-positive leukaemias.
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PMID:Apicidin potentiates the imatinib-induced apoptosis of Bcr-Abl-positive human leukaemia cells by enhancing the activation of mitochondria-dependent caspase cascades. 1468 26

Many environmental and therapeutic agents initiate apoptotic cell death by inducing the release of cytochrome c from the mitochondria, which activates Apaf-1 (apoptotic protease-activating factor-1). This large (approximately 130kD) protein is a mammalian homologue of CED-4, an essential protein involved in programmed cell death in the nematode C. elegans. Cytochrome c activates Apaf-1, which oligomerizes to form an approximately 700-1400-kDa caspase-activating complex known as the Apaf-1 apoptosome. Caspase-9, an initiator caspase, is then recruited to the complex by binding to Apaf-1 through CARD-CARD (caspase recruitment domain) interactions to form a holoenzyme complex. Subsequently, the Apaf-1/caspase-9 holoenzyme complex recruits the effector caspase-3 via an interaction between the active site cysteine in caspase-9 and the critical aspartate, which is the cleavage site for generating the large and small subunits of caspase-3 that constitute the activated form of caspase-3. This initiates the caspase cascade that is responsible for the execution phase of apoptosis. Intracellular levels of K+, XIAP an inhibitor of apoptosis protein, and at least two mitochondrial released proteins, Smac/DIABLO and Omi/Htra 2 a serine protease, tightly regulate formation and function of the apoptosome. Thus, a number of physiological mechanisms ensure that the apoptosome complex is only fully assembled and functional when the cell is irrevocably committed to die. It is interesting that more recent studies show that a variety of small molecules can directly activate or inhibit caspase activation by interfering with the formation and function of the apoptosome complex. The cytotoxicity of many conventional chemotherapeutic drugs rests on their ability to induce apoptosome formation and apoptosis. Defects in this pathway can result in drug resistance, and the discovery that small molecules can directly activate or inhibit the apoptosome may provide new alternative treatments for cancer.
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PMID:Chemical-induced apoptosis: formation of the Apaf-1 apoptosome. 1470 65

Overexpression of inhibitors of apoptosis (IAP) is one potential mechanism for tumor cells to evade immune surveillance. To determine whether immune-mediated killing of tumor cells can be enhanced by neutralization of IAP proteins, 2 novel eGFP-Smac fusion proteins (pro-Smac) were introduced into the poorly immunogenic mouse melanoma cell line, B16BL6-D5 (D5). Each fusion protein contained Smac and a cleavage site specific for granzyme B (GrB) or caspase 8, thereby targeting the 2 major killing mechanisms of cytotoxic T-lymphocyte (CTL) and NK cells. Expression of a pro-Smac fusion protein by D5 tumor cells greatly enhanced the susceptibility to killing by lymphokine-activated killer (LAK) cells or purified GrB. GrB-mediated killing was increased to a much greater extent when tumor cells expressed the eGFP-Smac fusion protein with a GrB cleavage site compared to a caspase 8 cleavage site. In contrast, perforin-deficient LAK cells, which lack GrB-mediated cytotoxicity but process normal ligands for death receptors, killed D5 tumor cells expressed pro-Smac with caspase 8 cleavage site more efficiently. Enhanced killing by GrB was also accompanied by processing of the fusion protein and increased caspase-3-like activity. These results indicate that killing of tumor cells can be amplified by targeting cell-mediated cytotoxic mechanisms via expression of pro-Smac fusion proteins.
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PMID:Targeting and amplification of immune killing of tumor cells by pro-Smac. 1473 72

Paracetamol (also known as acetaminophen) causes acute and chronic renal failure. While the mechanisms leading to hepatic injury have been extensively studied, the molecular mechanisms of paracetamol-induced nephrotoxicity are poorly defined. Paracetamol induced cell death with features of apoptosis in murine proximal tubular epithelial cells. While paracetamol increased the expression of the death receptor Fas on the cell surface, the Fas pathway was not involved in the paracetamol-induced apoptosis of tubular cells. The mitochondrial pathway was not activated during paracetamol-induced apoptosis; there was no dissipation of mitochondrial potential or release of apoptogenic factors such as cytochrome c or Smac/DIABLO. However, paracetamol-induced apoptosis is a caspase-dependent process that involves activation of caspase-9 and caspase-3 in the absence of cytosolic cytochrome c or Smac/DIABLO. The authors also detected induction of endoplasmic reticulum (ER) stress, characterized by GADD153 upregulation and translocation to the nucleus, as well as caspase-12 cleavage. Interestingly, after treatment of murine tubular cells with paracetamol and calpain inhibitors, the caspase-12 cleavage product was still detectable, and calpain inhibitors were unable to protect tubular cells from paracetamol-induced apoptosis. The results suggest that induction of apoptosis may underlie the nephrotoxic potential of paracetamol and identify ER stress as a therapeutic target in nephrotoxicity.
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PMID:Paracetamol-induced renal tubular injury: a role for ER stress. 1474 84

In this issue of Cancer Cell, Schimmer et al. report the identification of small molecule antagonists of XIAP that overcome its inhibition of caspase-3. It was remarkable that the compounds directly induced cell death in tumor cells while having little toxicity on normal cells. This suggests that caspases are already activated in tumor cells, which is different from the caspase activation status in normal mammalian cells. In comparison with Smac peptides targeting XIAP-mediated caspase-9 inhibition, which do not directly induce cell death, it appears that liberating downstream caspases rather than upstream caspases may be a preferred strategy for cancer drug discovery.
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PMID:Antagonizing XIAP-mediated caspase-3 inhibition. Achilles' heel of cancers? 1474 24

Apoptosis is an evolutionarily conserved process critical to tissue development and tissue homeostasis in eukaryotic organisms and, when dysregulated, causes inappropriate cell death. Global ischemia is a neuronal insult that induces delayed cell death with many features of apoptosis. Ischemic preconditioning affords robust protection of CA1 neurons against a subsequent severe ischemic challenge. The molecular mechanisms underlying ischemic tolerance are unclear. Here we show that ischemia induces pronounced caspase-3 activity in naive neurons that die and in preconditioned neurons that survive. Preconditioning intervenes downstream of proteolytic processing and activation of caspase-3 (a protease implicated in the execution of apoptosis) and upstream of the caspase-3 target caspase-activated DNase (CAD, a deoxyribonuclease that catalyzes DNA fragmentation) to arrest neuronal death. We further show that global ischemia promotes expression of the pro-survival inhibitor-of-apoptosis (IAP) family member cIAP, but unleashes Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI), a factor that neutralizes the protective actions of IAPs and promotes neuronal death. Preconditioning blocks the mitochondrial release of Smac/DIABLO, but not the ischemia-induced upregulation of IAPs. In the absence of Smac/DIABLO, cIAP halts the caspase death cascade and arrests neuronal death. These findings suggest that preconditioning preserves the integrity of the mitochondrial membrane, enabling neurons to survive in the face of caspase activation.
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PMID:Ischemic preconditioning: neuronal survival in the face of caspase-3 activation. 1502 68

Present studies demonstrate that treatment with the histone deacetylases inhibitor LAQ824, a cinnamic acid hydroxamate, increased the acetylation of histones H3 and H4, as well as induced p21(WAF1) in the human T-cell acute leukemia Jurkat, B lymphoblast SKW 6.4, and acute myelogenous leukemia HL-60 cells. This was associated with increased accumulation of the cells in the G(1) phase of the cell cycle, as well as accompanied by the processing and activity of caspase-9 and -3, and apoptosis. Exposure to LAQ824 increased the mRNA and protein expressions of the death receptors DR5 and/or DR4, but reduced the mRNA and protein levels of cellular FLICE-inhibitory protein (c-FLIP). As compared with treatment with Apo-2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or LAQ824 alone, pretreatment with LAQ824 increased the assembly of Fas-associated death domain and caspase-8, but not of c-FLIP, into the Apo-2L/TRAIL-induced death-inducing signaling complex. This increased the processing of caspase-8 and Bcl-2 interacting domain (BID), augmented cytosolic accumulation of the prodeath molecules cytochrome-c, Smac and Omi, as well as led to increased activity of caspase-3 and apoptosis. Treatment with LAQ824 also down-regulated the levels of Bcl-2, Bcl-x(L), XIAP, and survivin. Partial inhibition of apoptosis due to LAQ824 or Apo-2L/TRAIL exerted by Bcl-2 overexpression was reversed by cotreatment with LAQ824 and Apo-2L/TRAIL. Significantly, cotreatment with LAQ824 increased Apo-2L/TRAIL-induced apoptosis of primary acute myelogenous leukemia blast samples isolated from 10 patients with acute myelogenous leukemia. Taken together, these findings indicate that LAQ824 may have promising activity in augmenting Apo-2L/TRAIL-induced death-inducing signaling complex and apoptosis of human acute leukemia cells.
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PMID:Cotreatment with histone deacetylase inhibitor LAQ824 enhances Apo-2L/tumor necrosis factor-related apoptosis inducing ligand-induced death inducing signaling complex activity and apoptosis of human acute leukemia cells. 1505 15

The mitochondrial apoptosis pathway mediates cell death through the release of various pro-apoptotic factors including cytochrome c and Smac, the second mitochondrial activator of caspases, into the cytosol. Smac was shown previously to inhibit IAP proteins and to facilitate initiation of the caspase cascade upon cytochrome c release. To investigate Smac function during apoptosis and to explore Smac as an experimental cancer therapeutic, we constructed an expression system based on a single adenoviral vector containing Smac under control of the Tet-off system supplied in cis. Conditional expression of Smac induced apoptosis in human HCT116 and DU145 carcinoma cells regardless of the loss of Bax or overexpression of Bcl-x(L). Nevertheless, apoptosis induced by Smac was associated with cytochrome c release and breakdown of the mitochondrial membrane potential. This indicates that Smac acts independently of Bax and Bcl-x(L) during initiation of apoptosis and triggers a positive feedback loop that results in Bax/Bcl-x(L)-independent activation of mitochondria. In caspase-proficient cells, Smac-induced apoptosis could be inhibited partially by cell-permeable LEHD (caspase-9 inhibitor) and DEVD (caspase-3 inhibitor) peptides. Furthermore, loss of caspase-3 expression in MCF-7 cells carrying a caspase-3 null mutation completely abrogated the sensitivity for Smac-induced apoptotic or nonapoptotic, necrosis-like cell death, while re-expression of caspase-3 conferred sensitivity. Altogether, caspase-3 but not caspase-9 activation was necessary for execution of Smac-induced cell death. Notably, Smac did not induce caspase-9 processing in the absence of caspase-3. Thus, caspase-9 processing occurs secondary to caspase-3 activation during Smac-induced apoptosis. Altogether, Smac is capable of circumventing defects in mitochondrial apoptosis signaling such as loss of Bax or overexpression of Bcl-x(L) that are frequently observed in tumor cells resistant to anticancer therapy. Consequently, Smac appears to be a promising therapeutic target in anticancer treatment.
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PMID:Smac induces cytochrome c release and apoptosis independently from Bax/Bcl-x(L) in a strictly caspase-3-dependent manner in human carcinoma cells. 1506 10

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