CASPASE CASCADE

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]

Science Direct Journals

Scientific informations could be best viewed from journals available in the following link.

http://www.science-direct.com

Hydrostatic pressure induces apoptosis in human chondrocytes

Hydrostatic pressure induces apoptosis in human chondrocytes from osteoarthritic cartilage through up-regulation of tumor necrosis factor-, inducible nitric oxide synthase, p53, c-myc, and bax-, and suppression of bcl-2
Najmul Islam 2, Tariq M. Haqqi 1, Karl J. Jepsen 2, Matthew Kraay 2, Jean F. Welter 2, Victor M. Goldberg 2, Charles J. Malemud 1 3 4 *

Journal of Cellular Biochemistry
Volume 87 Issue 3, Pages 266 - 278
Published Online: 1 Oct 2002

AbstractHydrostatic pressure (HP) is thought to increase within cartilage extracellular matrix as a consequence of fluid flow inhibition. The biosynthetic response of human articular chondrocytes to HP in vitro varies with the load magnitude, load frequency, as well as duration of loading. We found that continuous cyclic HP (5 MegaPascals (MPa) for 4 h; 1 Hz frequency) induced apoptosis in human chondrocytes derived from osteoarthritic cartilage in vitro as evidenced by reduced chondrocyte viability which was independent of initial cell densities ranging from 8.1 × 104 to 1.3 × 106 cells ml-1. HP resulted in internucleosomal DNA fragmentation, activation of caspase-3, and cleavage of poly-ADP-ribose polymerase (PARP). At the molecular level, induction of apoptosis by HP was characterized by up-regulation of p53, c-myc, and bax- after 4 h with concomitant down-regulation of bcl-2 after 2 h at 5 MPa as measured by RT-PCR. In contrast, -actin expression was unchanged. Real-time quantitative RT-PCR confirmed a HP-induced (5 MPa) 1.3-2.6 log-fold decrease in bcl-2 mRNA copy number after 2 and 4 h, respectively, and a significant increase (1.9-2.5 log-fold) in tumor necrosis factor- (TNF-) and inducible nitric oxide synthase (iNOS) mRNA copy number after 2 and 4 h, respectively. The up-regulation of p53 and c-myc, and the down-regulation of bcl-2 caused by HP were confirmed at the protein level by Western blotting. These results indicated that HP is a strong inducer of apoptosis in osteoarthritic human chondrocytes in vitro. J. Cell. Biochem. 87: 266-278, 2002. © 2002 Wiley-Liss, Inc.