Caspase-3 protease

Gunasekar, PG., Borowitz, J.L., and Isom, G.E., Cyanide-induced apoptosis involves NMDA receptor-mediated oxidative stress and NF-, B linked activation of caspase-3 protease, submitted for publication. 

Kumi-Diaka J, Sanderson NA, Hall A. The mediating role of caspase-3 protease in the intracellular mechanism of genistein-induced apoptosis in human prostatic carcinoma cell hnes, DU145 and LANCaP. Biol Cell 2000 92 595-604. 

Enzyme activation. In addition to DNA/RNA chains, peptides can also be used to construct molecular beacons, termed peptide-based photodynamic molecular beacons (PPMBs), where the PS and quencher, initially held close together by the peptide conformation, separate by the action of specific enzymes that cleave the linking sequence. The most-used peptide is caspase-3 ° (GDEVDGSGC) which is cleaved at the underlined sequence by caspase-3 protease. Similar peptides containing the DEVD sequence have been used as well. Another example is FAPMB, a molecular beacon for the fibroblast activation protein, cell-surface... 

Pervaiz S, Hirpara JL, Clement M-V (1998) Caspase proteases mediate apoptosis induced by anticancer preactivated MC540 in human tumor lines. Cancer Lett 128 11-22... 

Recently, a SAMDI-MS assay was described by means of which endogenous caspase protease activities in cell lysates can be determined [26], Similar to the assay used to determine anthrax lethal factor inhibitors, peptide substrate SAMs for either caspase-3 or -8 were treated with cell lysates. In contrast to fluorescence assays, also longer peptide substrates could be used, thus enabling a better resolution of the two caspase activities. 

Figure 7.11 Activation of the caspase proteases during apoptosis. Caspases are implicated in both the induction and execution of the apoptotic process. Following the apoptotic stimuli, initiator caspases (caspase 8 or 9) are activated by autocatalysis. The initiator caspases then activate the effector caspases (caspase 3, 6, and 7), which are responsible for most of the protein cleavage during apoptosis.

Apoptosis (programmed cell death) is characterized by a complex series of biochemical changes that culminate in cell death without inflammation or swelling, which are signs of necrosis. Embryonic, fetal, and postnatal development involve cell death by apoptosis, which serves to eliminate excessive cell proliferation and migration. Apoptosis is initiated by a variety of external stimuli and molecular events such as oxidative stress, mitochondrial permeability transition, mitochondrial cytochrome c release, activation of caspase proteases, activation of endonucleases, transglutaminase activation, and poly(ADP-ribose) polymerase cleavage. 

Exposure of cells to anthracyclines leads to apoptosis mediators of this process include the p53 DNA-damage sensor and activated caspases (proteases), although ceramide, a lipid breakdown product, and the fas receptor-ligand... 

Various fluorescence based kits, e.g. those using annexin V conjugates Caspase protease activity... 

Antoku K, Liu Z, Johnson DE. Inhibition of caspase proteases by CrmA enhances the resistance of human leukemic cells to multiple chemotherapeutic agents. Leukemia 1997 11 1665-1672. 

In the execution phase of apoptosis, caspase proteases are activated by various apoptotic stimuli. Caspases belong to the cysteine protease family and were originally identified as homologues of the ced- i (cell death abnormal) gene product (an executor of apoptosis in Caenorhabdi-tis elegans). Indeed, most caspases induce apoptosis if they are overexpressed in growing cells and cell death can be blocked by caspase-specific inhibitors. Therefore, caspases are accepted as executors for apoptosis in mammals and this pathway appears to be conserved between species. 

Some death receptors also activate caspase proteases by ligation with their cognate ligands. Like in TNFRI signaling, DD regions of activated death receptors including... 

Apoptotic executioner caspases (caspase-3, -6, -7) constitute a subgroup of the caspase family. These proteases are the workhorses of the apoptotic process as they are responsible for cleaving many down-stream substrates important for cellular morphology, organelle homeostasis, cell cycle arrest, and regulation of transcription and translation. 

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

YU R, mandlekar s, HARVEY K J, UCKER D s and KONG A N (1998) Chemopreveutive isothiocyanates induce apoptosis and caspase-3-like protease activity . Cancer Res, 58 402-8. 

Some new 3-alkoxy-7-amino-4-chloroisocoumarins have been found recently to be poor inhibitors of a-chymotrypsin, trypsin, caspase 3, and HIV protease and to... 

Antiapoptotic proteins. There are many different intracellular proteins that can prevent apoptosis by inhibiting specific steps in the cell death process. These include Bcl-2 family members such as Bcl-2 and Bcl-xL which can stabilize (mitochondrial, ER and plasma) membranes (Bcl-2 may also have intrinsic antioxidant activity). Other proteins, IAPs such as XIAP (X-linked) and NIAP (neuronal), which can directly inhibit caspases [31]. Additional examples of antiapoptotic proteins include protease inhibitors such as calpastatin, and protein chaperones such as GRP-78 and heat shock protein (HSP)-70. 

Necrosis is a dramatic and very rapid form of cell death in which essentially every compartment of the cell disintegrates. Necrosis is characterized by marked dysregulation of ion homeostasis resulting in cell swelling, dilation of mitochondria and the ER and the formation of vacuoles in the cytoplasm [33], Proteases play important roles in the degradation of cells during necrosis. In contrast to apoptosis, where caspases are the key death proteases, calpains and lysosomal proteases (cathepsins B and D, in particular) are major players in necrosis. Caspases may be activated in response to mitochondrial damage and... 

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