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

Previously we showed that teratogen-induced cell death in mouse embryos is apoptotic in nature, i.e., involves the release of cytochrome c from mitochondria and the subsequent activation of caspase-3, cleavage of poly (ADP-ribose) polymerase (PARP), and internucleosomal DNA fragmentation. Herein we show that hyperthermia, 4-hydroperoxycyclophosphamide, and staurosporine also activate caspase-9, the apical caspase in the mitochondrial apoptotic pathway. Activation of procaspase-9 is associated with the cleavage of this proenzyme and the generation of two forms of the large subunit, primarily a 39-kDa subunit (p39) but also a lesser amount of a 37-kDa subunit (p37). We also present data that support the idea that the teratogen-induced formation of the p37 subunit in vivo occurs by the cytochrome c-mediated processing of procaspase-9, whereas the p39 subunit is formed by an amplification loop involving caspase-3. We also previously showed that the release of cytochrome c, activation of caspase-3, cleavage of PARP, and DNA fragmentation are blocked in cells of the developing heart, which are resistant to teratogen-induced cell death. We now show that this block in the mitochondrial apoptotic pathway in heart cells extends to the activation of procaspase-9. Thus, our cumulative data indicate that hyperthermia, 4-hydroperoxycyclophosphamide, and staurosporine induce cell death in Day 9 mouse embryos by activating the mitochondrial apoptotic pathway. In addition, our data suggest that cells of the Day 9 mouse embryo that are resistant to teratogen-induced cell death possess multiple mechanisms for inhibiting the mitochondrial apoptotic pathway after a teratogenic exposure.
 ...
PMID:Teratogen-induced activation of caspase-9 and the mitochondrial apoptotic pathway in early postimplantation mouse embryos. 1205 98

Caspases are responsible for a cascade of events controlling the disassembly of apoptotic cells. We now demonstrate that caspase-9 is activated at an early stage of apoptosis in epithelial cells and all its detectable, catalytically active large subunits (both the p35 and p37) are concentrated on cytokeratin fibrils. Immunolabeling of distinctive neoepitopes, exposed by cleavage of procaspase-9 at either Asp315 or Asp330, was co-localized on these fibrils with active caspase-3, caspase-cleaved cytokeratin-18, death-effector-domain containing DNA-binding protein and ubiquitin. Cytokeratin filaments may thus provide a scaffold whereby active subunits of caspase-9 can activate caspase-3 which, in turn, can activate more caspase-9 so forming an amplification loop to facilitate cleavage of cytokeratin-18, disruption of the cytoskeleton and the ensuing formation of cytoplasmic inclusions. These inclusions, formed from the collapse of fibrils, together with their associated components, also contain ubiquitinated proteins, vimentin, heat-shock protein 72, and tumor necrosis factor receptor type-1-associated death domain protein. Many of their constituents, including active caspases, remain sequestered within these inclusions, even after detergent treatment and isolation. Thus, such inclusions do not merely accumulate disrupted cytokeratins but also sequestrate potentially noxious proteins that could injure healthy neighboring cells.
 ...
PMID:Intermediate filaments control the intracellular distribution of caspases during apoptosis. 1474 46

Sf-caspase-1 is the principal effector caspase in Spodoptera frugiperda cells. Like the caspases in other organisms, Sf-caspase-1 is processed by upstream caspases to form an active heterotetramer composed of the p19 and p12 subunits. The regulation of active caspases is crucial for cellular viability. In mammal cells, the subunits and the active form of caspase-3 were rapidly degraded relative to its proenzyme form. In the present study, the S. frugiperda Sf9 cells were transiently transfected with plasmids encoding different fragments of Sf-caspase-1: the pro-Sf-caspase-1 (p37), a prodomain deleted fragment (p31), a fragment containing the large subunit and the prodomain (p25), the large subunit (p19), and the small subunit (p12). Flow cytometry and Western blot analysis revealed that p12, p19, and p25 were unstable in the transfected cells, in contrast to p37 and p31. Lactacystin, a proteasome inhibitor, increased the accumulation of the p19 and p12 subunits, suggesting that the degradation is performed by the ubiquitin-proteasome system. During the activation, the Sf-caspase-1 produces an intermediate form and then undergoes proteolytic processing to form active Sf-caspase-1. We found that both the active and the intermediate form were unstable, indicating that once activated or during its activation, the Sf-caspase-1 was unstable.
...
PMID:The Spodoptera frugiperda effector caspase Sf-caspase-1 becomes unstable following its activation. 2374 Jun 63