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Schauspiel Dinner

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Fedor Ivankov
Fedor Ivankov

V V-Katsu Activation Keygenl WORK



In the extrinsic pathway upon ligand binding to specific receptors the DISC complex is formed and caspase 8 activated. In the intrinsic pathway release of cyt c from the mitochondria result in the formation of the apoptosome and activation of caspase 9. Caspase 8 and 9 then activate downstream caspases such as caspase 3 resulting in cell death. The two pathways are connected through the cleavage of the BH3 only protein BID.




V V-Katsu Activation Keygenl



Extrinsic apoptosis indicates a form of death induced by extracellular signals that result in the binding of ligands to specific trans-membrane receptors, collectively known as death receptors (DR) belonging to the TNF/NGF family. All death receptors function in a similar way: upon ligand binding several receptor molecules are brought together and undergo conformational changes allowing the assembly of a large multi-protein complex known as Death Initiation Signalling Complex (DISC) that leads to activation of the caspase cascade. In the FAS/CD95 signalling complex, that can be used as a prototype of this form of death, upon ligand binding FAS recruits, through a highly conserved 80 amino acid domain, known as death domain (DD), an adaptor molecule: Fas-associated protein with a DD (FADD). FADD contains another conserved protein interaction domain known as Death Effector Domain (DED) that binds to an homologous domain in caspase 8 leading to its activation. Active caspase 8 will activate additional caspase 8 molecules as well as downstream caspases such as caspase 3 [7].


The intrinsic pathway is activated in response to a number of stressing conditions including DNA damage, oxidative stress and many others. In all cases this multiple forms of stress converge on the mitochondria and determine mitochondrial outer membrane permeabilization (MOMP) this in turn results in dissipation of the mitochondrial membrane potential and therefore in cessation of ATP production as well as release of a number of proteins that contribute to caspase activation. At least two molecular mechanisms (not mutually exclusive) have been proposed to explain how different signals converge at the mitochondria resulting in MOMP. One involves the pore forming ability of some of the BCL-2 family proteins in the outer mitochondrial membrane [8] and the other is the result of the opening in the inner membrane of the permeability transition pore complex (PTPC), that would require the Adenine Nucleotide Transporter (ANT) and the Voltage Dependent Anion Channel (VDAC) [9, 10]. The Bcl-2 family proteins are essential regulators of this type of apoptosis and are all characterized by the presence of at least one Bcl-2 Homology (BH) domain. From a functional point of view they can be classified in anti-apoptotic members containing three or four BH domains (such as Bcl-2, Bcl-xl, Bcl-w, Mcl-1) and pro-apoptotic members with two or three BH domains (such as Bax, Bak, Bcl-xs, Bok) or with just one (such as Bad, Bik, Bid, Bim, Noxa, Puma). Pro-apoptotic members of the family mediate apoptosis by disrupting membrane integrity either directly forming pores or by binding to mitochondrial channel proteins such as VDAC or ANT, while anti-apoptotic members would prevent apoptosis by interfering with pro-apoptotic member aggregation. The different apoptotic signals are sensed by BH3 only proteins that are induced or activated and migrate to the mitochondria where they bind the pro-survival members of the family removing their block or to the pro-apoptotic members promoting their aggregation [11].


Altered caspase function can also be a consequence of modified expression of their specific inhibitors, as an example cFLIPs that competes with caspase 8 for FADD binding, thus preventing its activation, is often elevated in tumours, while its down-regulation can sensitize tumour cells to therapy. Among caspase inhibitors an important role is played by IAPs. Indeed alterations of IAPs are found in a variety of human cancers and are associated with poor prognosis and resistance to therapy. In some cases however loss of IAPs correlates with tumour progression complicating the issue and suggesting that the role of IAPs has to be carefully evaluated based on cell context. While initially described as caspase inhibitors now IAPs have been recognized to regulate a multitude of other cellular functions including regulation of the immune response cell migration, mitosis and proliferation [43]. As many of these processes are often modified in cancer it is clear how alteration of IAPs can play a role in tumorigenesis not only as a consequence of altered apoptosis. In fact probably the most important pathway regulated by IAPs that contributes to cancer development is the NF-kB signaling pathway. XIAP, cIAP1 and cIAP2 have been shown to regulate this pathway and as a consequence inflammation, immunity and cell survival. Moreover cIAPs protect from TNF killing. In addition, recent findings show a role for IAPs in metastatization as a XIAP/survivin complex would trigger NF-kB pathway leading to activation of cell motility kinases [43]. This however is still a controversial issue and other studies show a suppressive effect of IAPs on cell mobility.


Neuronal apoptosis plays an important role in AD pathogenesis and caspases seem to be involved also in some of the upstream pathological events. Exposure of cultured hippocampal neurons to β results in caspase 3 activation and apoptosis [50]. Aβ is generated following sequential cleavage of the amyloid precursor protein (APP), and caspase 3 is considered the predominant caspase involved in APP cleavage [51, 52]. Tau protein is also a substrate for caspase 3; cleavage of tau at its C-terminus would promote tau hyper-phosphorylation and accumulation of NFTs. Moreover, β-induced caspase 3 activation causes abnormal processing of the tau protein in models of AD [53]. APP is also cleaved by caspase 6 in vivo [54], moreover the N-terminal APP fragment is a ligand for death receptor 6 (DR6 also known as TNFRSF21) activation of which triggers caspase 6 dependent axonal degeneration [55].


The potential benefit of inhibiting the intrinsic apoptotic pathway has been suggested through the use of a triple transgenic AD mouse model wherein overexpression of the anti-apoptotic Bcl-2 gene blocked activation of caspases 9 and 3; in these conditions, the degree of caspase cleavage of tau was limited, the formation of plaques and tangles was inhibited, and memory retention was improved [56, 57].


Parkinson's disease (PD) is considered the 2nd most common chronic neurodegenerative disorder after AD, it is associated with movement disorders, tremors, and rigidity and is characterized by a specific loss of dopaminergic neurons of the substantia nigra. This degeneration leads to the formation of fibrillar cytoplasmic inclusions known as Lewy bodies. A preponderant role of the aberrant activation of intrinsic and extrinsic apoptotic pathways in PD pathogenesis has been suggested. The involvement of caspases 1 and 3 in apoptotic cell death has been proved using PD animal models [58]. PD has been linked to mutations in several genes such as parkin [59], DJ-1, and a gene codifying for a mitochondrial kinase, (PTEN)-induced kinase 1 (PINK1) [60]. PINK1 function is related to the inhibition of mitochondria-dependent apoptosis [61]. In human and mouse neurons deleted for PINK1 Bax translocation to the mitochondria and cytochrome c release to the cytoplasm occur earlier than in control cells. Furthermore loss of PINK1 results in elevated levels of caspase activation (caspases 3 and 9) [61]. Gene-expression profiling studies performed on material from patients affected by PD confirmed down-regulation of PINK1 as well as other anti-apoptotic proteins such as Bcl-2 but also found evidence for the involvement of the extrinsic pathway. Indeed death receptors such as FAS, TNFRSF10B and TNFRSF21 were up-regulated in PD-affected neurons [62, 63].


Huntington's disease (HD) is a disorder characterized by a degenerative process, which affects medium spiny striatal and cortical neurons. HD is an autosomal dominant disease caused by a mutation in the gene encoding the huntingtin protein (htt); this mutation is responsible for abnormal expansion of a trinucleotide CAG repeat encoding polyglutamine tract expansion in the N terminus of htt [64]. The expanded polyglutamine alters protein folding, leading to generation of aggregates in neurons that seem to be crucial for the neurodegenerative process [65, 66]. Mutant htt is cleaved by different proteases including caspases [67] and accumulation of caspase cleaved fragments is an early pathological finding in brains of HD patients [68]. Moreover transgenic mice models have demonstrated that caspase 6 cleavage of mutant htt is required for the development of the characteristic behavioral and neuro-pathological symptoms. In addition activation of caspase 6, is observed before the onset of motor abnormalities in HD brains, suggesting that these activation could be used as an early marker of the disease [69].


Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by muscle atrophy, paralysis, and, death due to progressive loss of motor neurons [72]. About 10% of cases are familial as a result of mutations in the copper-zinc superoxide dismutase (SOD1) gene [73], whereas the majority of them are sporadic. SOD1 catalyzes conversion of the superoxide anion to hydrogen peroxide, however the mechanism by which SOD1 mutations cause ALS is still not completely understood. Several alterations have been identified in ALS and are thought to play a role in motor neuron death, including: neurofilament abnormalities, aggregate formation, oxidative stress, and inflammatory processes [74]. Mice overexpressing a human mutant SOD1 develop neuron degeneration, and have been used as a model [75, 76]. These mice show increased p38 activity that determines increased NO production that in turn results in increased FasL expression and activation of the extrinsic pathway [77]. In addition mutated SOD would localize to the mitochondria and directly trigger CYTC release and therefore neuronal death [78].


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