Pro-apoptotic properties

A large and growing body of literature indicates that certain oxysterols, under given experimental conditions, exhibit strong pro-apoptotic properties against all types of vascular cells implicated in atheroma formation and development (Berthier et al. 2004 Pedruzzi et al. 2004 Poll et al. 2009 Vejux and Lizard 2009). 

Bcl2 and Bax are mitochondrial proteins possessing anti-apoptotic and pro-apoptotic properties, respectively. Overexpression of Bcl2 prevents apoptosis and cytochrome c release induced by various stimuli (36,37). However, in our study, we did not observe changes of Bcl2/Bax ratio in carnosic acid-, carnosol-,... 

Quiney, C., Billard, C., Faussat, A.M., Salanoubat, C., Ensaf, A., Nait-Si, Y, Foumeron, J.D., and Kolb, J.R (2006). Pro-apoptotic properties of hyperforin in leukemic cells from patients with B-cell chronic lymphocytic leukemia. Leukemia 20,491 97. 

Like Cer, SPH acts as a pro-apoptotic signal (Hung et al., 1999 Sakakura et al., 1998 Sweeney et al., 1998) as well as an inhibitor of protein kinase C (PKC) (Hannun et al., 1986), phospholipase D (PLD) (Natarajan et al., 1994), and calmodulin-dependent kinase (Jefferson and Schulman, 1988) in diverse cell types. SPH has also been shown to activate diacylglycerol (DAG) kinase (Yamada and Sakane, 1993). SIP is involved in cell survival and proliferation (Olivera et al., 1999 Olivera and Spiegel, 1993 Spiegel and Milstien, 2002). In contrast to Cer, which is membrane-bound, SIP can diffuse into the cytosol and be secreted into the extracellular space, where it can exert its signaling properties by binding to cell surface receptors (reviewed in ref. (Kihara et al.,... 

This family of proteins plays a central role in the early life/death decisions of cells. The first family member discovered was Bcl-2 itself (identified as being overexpressed in B cell lymphoma) but since its discovery many other family members have been identified on the basis of the presence of conserved sequence motifs or BH domains (Bcl-2 homology domains) within their structures [66, 67]. Curiously, members belonging to this family can have anti-apoptotic effects (e.g. Bcl-2, Bc1-Xl) or pro-apoptotic effects (e.g. Bax, Bak, Bid, Bak) [68]. The niunber and types of BH domains present within these family members dictate their properties and function in the apoptotic process. Some family members possess 4 domains, whereas others contain only one. 

The hallmark feature of the Bcl-2 proteins is their ability to form hetero-or homodimers [69-71], The BH domains are the key to this property and form a-helical structures that serve as protein protein interaction motifs. For example, the BH4 domain (found in most, but not all anti-apoptotic family members) may be responsible for molecular interactions with calcineurin and Raf-1 [72, 73], The importance of the BH4 domain is emphasised by the fact that in cells transfected with a mutant or truncated form of Bcl-2 (an anti-apoptotic protein) apoptosis is accelerated [74,75], There is also some evidence that this BH4 domain may be involved in control of the voltage-dependent anion channel of mitochondria [76], Some pro-apoptotic proteins (e.g. Bik, Bid and Bad) only possess the BH3 domain. Consequently, this has led to the idea that this domain is the minimal death domain required for the activity of some pro-apoptotic proteins. 

It has been reported that NO can have both pro- and anti-apoptotic properties (Li and Billiar 1999 Weller et al. 2002 Liu et al. 1998 Pervin et al. 2001a, b, 2003a, b). Inhibition of apoptosis by NO is reported in endothelial cells, hepatocytes, and other tumor cells (Li and Billiar 1999 Weller et al. 2002 Liu and Stamler 1999). NO induces S-nitrosylation of active site cysteines in caspases and other related proteins leading to inhibition of apoptosis and the formation of 5-nitrosothiols leading to the oxidation of thiol proteins, which might act as switches in cell survival and apoptotic signaling pathway (Mannick et al. 2001 Azad et al. 2006 Marshall et al. 2000). 

The structure of Bc1-Xl provides support for this idea (Plate 27). (Refs. 27—37 provide more information on the properties of pro- and anti-apoptotic proteins which control the fate of the cell). 

If neutrophils do express neither Bcl-2 nor Bc1-Xl, then how is their survival regulated The answer lies in the fact that they express Mcl-l [31, 100], an anti-apoptotic protein of the Bcl-2 family that has some unusual properties compared to other members of the family. These properties of Mcl-l make it ideally suited to its function in the survival of neutrophils, cells which must respond very quickly to either pro- or anti-inflammatory signals in their environment so that their role in infections and inflammation is tightly controlled. 

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