Apoptosis caspases

The caspases that are involved in apoptosis may be further classified as either initiators or effectors. Induction of apoptosis via death receptors results in the activation of an initiator caspase. Caspases-8, -9, and -10 are initiators because they initiate the cascade of biochemical events that culminates in apoptosis. Caspases-3, -6, and -7 propagate this cascade (the so-called doomsday signal), thus functioning as effectors. Although there is some overlap, caspases-1, -4, -5, -11, -12, and -13 are involved in processing cytokines, thus influencing immunoregulation. The various caspases are listed in table 8.2. 

Caspase-9 Apaf-3, ICE-LAP6, Mch6 Apoptosis Caspase-3... 

Caspase-10 FLICE-2, Mch4 Apoptosis Caspase-7 PARP pro-Caspase-9 Caspase-3... 

The TNF-a-induced DNA fragmentation may have been caused by caspase-activated deoxyribonuclease (CAD) in PC-12 cells. In non-apoptotic cells, CAD is present as an inactive complex with the inhibitor jOvd p3,24]. During apoptosis, caspase-3 inactivates ICAD, leaving CAD free to function as a nuclease [25]. Therefore, we used die fluorogenic substrate, Ac-DEVD-MCA, to determine whether the caspase-3 in PC-12 cells was activated by treatment with TNF-a and/or crocin. As shown in... 

Lee SC, Chan J, Clement MY, Pervaiz S. 2006. Functional proteomics of resveratrol-induced colon cancer cell apoptosis Caspase-6-mediated cleavage of lamin A is a major signaling loop. Proteomics 6 2386-2394. 

Biochemical execution of cell death depends on three major components caspases, mitochondrial factors, and the Bcl-2 family of proteins (Green 2005 Yuan 2006). Caspases are a group of cysteine proteases acting as the central effectors of apoptosis. Caspases are normally suppressed by the inhibitor of apoptosis (IAP) in... 

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.

LAP proteins prevent cell death through interactions between their BIR (baculoviral) IAP repeat domains and the proteases that are critical for the initiation and execution of apoptosis, caspase-3, caspase-7, and/or caspase-9 (23). X-chromosome... 

Cummings BS, Schnellmann RG. Cisplatin-induced renal cell apoptosis caspase 3-dependent and -independent pathways. J Pharmacol ExpTher 2002 302 8-17... 

Green, D., and Kroemer, G. (1998) The central executioners of apoptosis caspases or mitochondria Trends Cell Biol. 8(7) 267-271. 

It is well understood that caspases are critical for the process of apoptosis. Caspases are cysteinyl-containing active center proteases with specificity for protein cleavage after aspartyl residues. Thus the term caspase is derived from (ysteinyl-containing aij artate-specific proteinase. The caspases are responsible for many of the hallmarks of apoptosis defined in Table 18.1, mediated through their cleavage of specific polypeptide substrates. The caspases (e.g., caspase-2, -3, -6, -7, -8, -9, -10, and -12 in the mouse) are not the only proteases involved in PCD, as calpains have also been shown to play... 

Boulares H, Yakovlev A. Ivanova I et al. Role of PARP cleavage in apoptosis Caspase 3 resistant PARP mutant increases rates of apoptosis in transfected cells. J Biol Chem 1999 274 22932-22940. 

Apoptosis Caspase activation Cell membrane changes Changes of caspase activity DNA... 

Caspases are intracellular proteases and cleave their substrate proteins specifically behind an aspartate residue. Caspases are normally present as inactive proenzymes. However, during apoptosis, caspase activation is induced by cleavage at specific internal aspartate residues. Activation of the initiator caspases by pro-apoptotic signals leads to proteolytic activation of the execution caspases, which cleave a set of vital proteins and thus initiate and execute the apoptotic degradation phase. A self-contained on-chip cell culture and pretreatment microdevice system has been developed for the screening of caspase-3 expression in apoptotic cells. 

Dual-label TR-FRET substrates have also been used for simultaneous monitoring of the enzymes related to apoptosis caspases 1, 3, and 6 [44]. Kokko et al. utilized fluorescent terbium chelates as the donors for two different acceptors, Alexa Fluor 488 and 680, in a dual-label immtmoassay of free and total PSA [45]. Free, uncomplexed PSA were measured with TR-FRET from terbium labeled (universal) antibody to free-specific Alexa 488 labeled antibody, and the total PSA was quantified with TR-FRET from terbium to another generic antibody labeled with Alexa 680. Kupcho et al. followed nuclear receptor coactivator recruitment... 

Figure 13.2 Representation of two hypothetical conditions of abnormal cellular death (Apoptosis Caspase-3 active, PARP-1 Necrosis Caspase-3 inactive, PARP-1 hyper-activated). The example on the left consists of a large area of necrosis surrounded by a small penumbra of apoptosis. This condition would benefit greater from treatment with a PARP-1 inhibitor. The condition on the right consists of a large area of apoptosis surrounding a small necrotic core. This condition would benefit more from treatment with either a pancaspase inhibitor or a selective inhibitor of caspase-3.

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. 

A completely different example of the serpin CrmA (cytokine response modifier A), which expresses Cowpox virus. The targets of CrmA are members of the caspase family of proteases that either initiate the extrinsic pathway of apoptosis (caspases 8 and 10) or trigger activation of the pro-inflammatory cytokines interleukin-1 p and interleukin-18 (caspase 1). CrmA has the typical fold of a cleaved serpin, even though it lacks the N-terminal half of the A helix, the entire D helix, and a portion of the E helix that are present in all other known serpins. Thus, the inhibitory proteins can be not only drugs. They may also viral countermeasures to host defenses against infection may contribute significantly to the pathology associated with poxvirus infections (Renatus et al, 2000). 

Caspase-3 activation induction of apoptosis apoptosis protection radical scavenger DNA intercalation release of cytochrome c Bcl-XL inhibitor activation of caspase-3 DNA fragmentation depolarization DNA intercalation spindle poison activation of caspase-3 DNA fragmentation depolarization of mitochondrial membranes, apoptotic Spindle poison activation of caspase-3 DNA fragmentation apoptotic activation of JNK/SAPK ROS production inhibition of mitochondrial electron chain Protein, DNA and RNA synthesis inhibition DNA intercalation induction of apoptosis caspase-3 activation DNA fragmentation depolarization of mitochondrial membranes Apoptosis induction... 

Caspase-9 Apoptosis, caspase activation Cys-287 iNOS Decreased enzymatic activity Negative Mannick et al. 1999... 

Keywords Apoptosis Anti-apoptosis Caspase Bel Mitochondria TNF Fas TRAIL NF-kB S-nitrosylation Proteasome... 

Keywords Nitric oxide Apoptosis Caspase Leukemia Chronic lymphocytic leukemia... 

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