Tuesday, July 21, 2009


Caspase cascade

[Source: http://en.wikipedia.org/wiki/Caspase#Caspase_cascade]

Caspases are regulated at a post-translational level, ensuring that they can be rapidly activated. They are first synthesized as inactive pro-caspases, that consist of a prodomain, a small subunit and a large subunit. Initiator caspases possess a longer prodomain than the effector caspases, whose prodomain is very small. The prodomain of the initiator caspases contain domains such as a CARD domain (e.g. caspases-2 and -9) or a death effector domain (DED) (caspases-8 and -10) that enables the caspases to interact with other molecules that regulate their activation. These molecules respond to stimuli which cause the clustering of the initiator caspases. Such clustering allows them to activate automatically, so that they can proceed to activate the effector caspases.

The caspase cascade can be activated by granzyme B (released by cytotoxic T lymphocytes and NK cells) which is known to activate caspase-3 and -7
death receptors (like FAS, TRAIL receptors and TNF receptor) which can activate caspase-8 and -10 the apoptosome (regulated by cytochrome c and the Bcl-2 family) which activates caspase-9.
Some of the final targets of caspases include: nuclear lamins
ICAD/DFF45 (inhibitor of caspase activated DNase or DNA fragmentation factor 45)
PARP (poly-ADP ribose polymerase)
PAK2 (P 21-activated kinase 2).

what is the role of the cleavage of caspase substrates in the morphology of apoptosis is still not clear till date. However, ICAD/DFF45 acts to restrain CAD (caspase activated DNase). The cleavage and inactivation of ICAD/DFF45 by a caspase allows CAD to enter the nucleus and fragment the DNA, causing the characteristic 'DNA ladder' in apoptotic cells.

In 2009 Queensland researchers announced caspase 1 and 3 in macrophages are regulated by p202 (a double-stranded DNA binding protein) reducing caspase response, and AIM2 (another double-stranded DNA binding protein) increasing caspase activation.
[Source: http://en.wikipedia.org/wiki/Caspase#Caspase_cascade]


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