**3. Caspases: Executioners of the apoptotic process**

Caspases are the effector molecules of apoptosis in mammals. They were first discovered mediating programmed cell death during development in the nematode *Caenorhabditis elegans* [13]. The caspase family is characterized by their specificity for cleaving substrates after aspartic acid residues and for containing cystein in their active centre [14]. There are about fourteen caspases that used to be classified into two families: one involved in inflammation processes and the other taking part in apoptosis. However, some of the nonapoptotic caspases have some apoptotic roles, and conversely, some non-apoptotic caspases can induce pyroptosis [15]. They are synthesized as inactive precursors or zymogens (procaspases) that need to be proteolytically processed to become active. Once a caspase is activated, it can cleave another caspase creating thus an expansive hierarchical activating cascade that serves to amplify the apoptotic signal. Caspase activation is a complex and tightly regulated process. Within the apoptotic group, there are two types of caspases: upstream initiator or apical caspases and downstream effector or executioner caspases. The initiator group consists of caspases -2, -8, -9 and -10 and the effector group consists of -3, -6 and -7 caspases. Apical but not executioner caspases have long prodomains. Caspase-9 is considered the initiator of the mitochondrial pathway and caspase-8 is regarded as the originator of the dead receptor-mediated apoptotic pathway. Effector caspases carry out apoptotic programmes through direct processing of a variety of cellular substrates. The proteolytic cleavage of such substrates brings about a whole plethora of effects within the cell: disassembling of cytoskeleton, cytoplasm scaffolding, nuclear fragmentation as a consequence of laminin degradation, activation of endonucleases that cleave chromatin, inactivation of DNA damage repair proteins (PARP1, Rad9, etc.), phagocyte signalling, loss of cell-to-cell contact, etc. [16-18]


**Table 1.** Proteins substrates of caspases (Blank and Shiloh 2007; Cohen et al 1997)

Caspase activity can be regulated both in a positive and in a negative manner. Negative caspase regulators are called Inhibitors of Apoptosis Proteins (IAPs) that bind to the catalytic site of caspases neutralizing its activity [19], or targeting them to degradation by ubiquinitation [20,21]. Some examples of IAPs are: XIAP, c-IAP1, c-IAP2, NAIP and survivin. On the other hand, Smac/DIABLO and Omi/HtrA2 act as positive regulators by inactivating IAPs [22].
