Caspase-activated DNase

Ataxia telangiectasia mutated (ATM), poly(ADP ribose) polymerase (PARP), DNA-dependent protein kinase, DNA replication factor C, DNA topoisomerase I, DNA fragmentation factor (DFF)45, inhibitor of caspase-activated DNAse (ICAD), lamins A, Bl, and C TRAF-1, Rafl, Ras, GAP, GDP dissociation inhibitor of Rho family GTPases, phospholipase A2, Statl... 

Wolf, BB., Schuler, M., Echeverri, F. and Green. DR. (1999) J. Biol. Chem., Caspase-3 is the primary activator of apoptotic DNA fragmentation via DNA fragmentation factor-45/inhibitor of caspase-activated DNase inactivation, 274, 30651-30556. 

Enari, M., Sakahira, H., Yokoyama, H., Okawa, K., Iwamatsu, A., Nagata, S., 1998, A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391 43-50. 

Other "upstream" caspases (caspases 2,9, and 10) also participate in initiation of apoptosis. In contrast, caspases 3,6, and 7, the "executioner caspases," are thought to participate directly in demolition of the cell.154 A caspase-activated DNase also participates by degrading DNA.166/167... 

Sikora E, Bielak-Zmijewska A, Magalska A, Piwocka K, Mosieniak G, Kalinowska M, Widlak P, Cymerman IA, Bujnicki JM. 2006. Curcumin induces caspase-3-dependent apoptotic pathway but inhibits DNA fragmentation factor 40/caspase-activated DNase endonuclease in human Jurkat cells. Mol Cancer Ther 5 927-934. 

Granzyme B will cleave proteins at aspartate residues and will therefore activate pro-caspase 10 and can cleave factors like ICAD (inhibitor of caspase-activated DNase). However, Granzyme B can also directly activate caspase 3. In this way, the upstream signaling pathways are bypassed and there is direct induction of the execution phase of apoptosis. Recent findings indicate that this method of granzyme B cytotoxicity is critical as a control mechanism for T-cell expansion of type 2 helper T (Th2) cells. Moreover, findings indicate that neither death receptors nor caspases... 

CAD Caspase-activated DNase DNA fragmentation factor subunit beta, DFF-40, caspase-activated nuclease, CP AN... 

Sustained elevations in intracellular Ca levels promote mitochondrial Ca uptake, which decreases the mitochondrial membrane potential and blocks the electron transport chain leading to ATP depletion. Large increases in mitochondrial Ca uptake also increase mitochondrial membrane permeability (Dubinsky and Levi, 1998) resulting in the release of proapoptotic factors such as cytochrome c and apoptosis inducing factor (AIL) (Luetjens et al, 2000). Cytochrome c binds to apoptotic protease-activation factor 1 (APAFl) and procaspase-9, forming a multiprotein complex known as the apoptosome that activates the caspase cascade. The apoptosome activates caspase-9, which in turn activates caspase-3. Caspase-3 activates caspase-activated DNase (CAD), resulting in DNA fragmentation, characteristic of apoptosis. 

Mnltifunctional protein which initiates and regnlates de novo pyrimidine biosynthesis caspases-activated DNAse Cdk-activating kinase... 

FMN flavin mononucleotide ICAD inhibitor of caspase-activates Dnase... 

In addition to cytochrome c, a second mitochondria-derived activator of caspases (SMAC) is also released from the mitochondrial intermembrane space. SMAC binds to an inhibitor of apoptosis protein (IAP) to prevent spontaneous caspase activation in a healthy cell. The IAP that binds to caspase-9 is called X-LAP. When SMAC binds to X-IAP, X-IAP is released from caspase-9. Autocleavage of the caspase-9 prodomain then exposes the catalytic site. Caspase-9 then activates caspase-3 which immediately cuts out the X-IAP binding domain from procaspase-9, preventing X-IAP inhibition and accelerating activation of both caspase-3 and caspase-9 (Fig. 13.11a), which digest all of the cell s proteins. The apoptotic cells also possess a caspase-activated DNase (CAD) that fragments chromosomal DNA. Other proteins from the mitochondrial intermembrane space can activate caspases by related mechanisms. The combination of mechanisms, or the overwhelming activation of any one of them, irreversibly propels a cell into apoptosis. 

Mukae, N., M. Enari, H. Sakahira, Y. Fukuda, J. Inazawa, H. Toh and S. Nagata. Molecular cloning and characterization of human caspase-activated DNase. Proc. Natl Acad. Sci. USA 95 9123-9128, 1998. 

So far, 13 caspases have been identified. In apoptosis they are involved as upstream initiators, such as cas-pase-2, -8, -9, and -10 or as downstream effectors directly responsible for the proteolytic cleavage that leads to cell disassembly (caspases-3, -6 or -7). The effector caspases are activated via proteolytic processing by the initiator caspases (Thomberry and Lazebnik, 1998). Death occurs, when the inhibitory subunit of caspase-activated Dnase (ICAD) is cleaved by e.g., caspase-3, which allows Dnase to translocate to the nucleus and to degrade DNA (Schulze-Osthoff et al., 1998). 

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