Small stress proteins: novel negative modulators of apoptosis induced independently of reactive oxygen species.

The execution phase of the apoptotic cell death process occurs throughout the proteolytic activation of proteolytic enzymes called caspases (Nicholson and Thornberry 1997; Thornberry and Lazebnik 1998). Several different pathways can lead to the activation of caspases, among them, one can cite the death receptors (i.e. Fas) (Scaffidi et al. 1998) and mitochondria pathways (Reed 1997; Green and Reed 1998). When activated by ligand binding, death receptors (i.e. Fas) recruit adapter polypeptides (i.e. FADD) that interact with and subsequently activate pro-caspases (i.e. pro-caspase 8) or trigger a signal transduction pathway that activates specific genes (i.e. the DAXX/ASK1/JNK pathway). In contrast, in the mitochondria pathway, different inducers have the ability to induce the release in the cytoplasm of different proteins present in mitochondria, such as cytochrome c, apoptosis-inducing factor (AIP), Hsp60, HsplO, adenylate kinase, Smac/Diablo as well as the fraction of pro-caspase 2,3,8, and 9 present in mitochondria (Kluck et al. 1997; Reed 1997; Yang et al. 1997; Kohler et al. 1999; Samali et al. 1999a; Susin et al. 1999a,1999b; Xanthoudakis et al. 1999; Du et al. 2000; Verhagen et al. 2000). Once it has been released from the mitochondria, cytochrome c interacts with Apaf-1 in the presence of ATP/dATP. This results in the formation of the apoptosome complex which recruits and activates pro-caspase 9 which subsequently activates pro-caspase 3 (Li et al. 1997; Saleh et al. 1999). The release of cytochrome c from the mitochondria is a caspase-independent early phenomenon that precedes mitochondrial membrane potential loss (Bossy-Wetzel et al. 1998). This phenomenon may be induced by conformational changes of Bax (Desagher et al. 1999) or by BAK oligomerization induced by tBID, a membrane-targeted death ligand (Wei et al. 2000). Stress-induced apoptosis usually occurs through the activation of the mitochondria pathway. This is particularly the case when mild oxidative or heat stresses are considered (Samali et al. 2000).