Sphingolipids and apoptosis

From LipidomicsWiki

Apoptosis is a physiological form of cell death required to control cell populations during processes such as embryogenesis, the immune response, wound healing and other examples of normal tissue differentiation and homeostasis (Kolesnik and Kronke, 1998). It includes appearance of phosphatidylserine on the external cell membrane, loss of leukocyte EC platelet EDG? EDG? platelet PC-PLD PC PA LPA is formed by PLA1 and PLA2 mediated cleavage of PA Platelets lack Sph-1-P-lyase Platelets store Sph-1-P in α-granules Enabling Technologies 95 mitochondrial transmembrane potential, activation of caspases, nuclear chromatin condensation and DNA fragmentation (Blatt and Glick, 2001). Apoptosis induced by ceramide through either caspase-dependent or caspase-independent mechanisms (Fig. 38) has been reported (Zhao et al. 2004). Caspases are a group of aspartate-specific cysteine proteases, and it has been demonstrated in vitro that caspase-independent cell death is inducible by short-time ceramide treatment. Apoptosis induced in such conditions appears without typical apoptotic phenotypes such as DNA fragmentation or caspase activation and cannot be blocked by caspase inhibitors (Zhao et al. 2004). TNFα, radiation, FAS ligand or cell-permeable ceramide-induced elevated levels of cellular ceramide lead to caspase-dependent cell death (Cuvillier et al. 1998). Binding via death domains of receptors and adaptor proteins recruits caspase-8 to the plasma membrane resulting in autocatalytic activation of the caspase cascade. The substrates for caspases are enzymes associated with DNA repair (poly ADP-ribose polymerase - PARP) and nuclear lamins. The degradation of nuclear lamins is required for formation of apoptotic bodies, a typical morphological change observed during the last stage of apoptosis. The apoptotic effect of ceramide is blocked by addition of phorbol esters (TPA) or diacylglycerol (DAG), both known activators of protein kinase C (PKC). Stimulation of PKC results in the activation of sphingosine kinase and intracellular accumulation of S1P. Another mechanism implicated in the inhibition of apoptosis by TPA and DAG suggests inhibition of sphingomyelinase activation (Santana et al. 1995).

fig to added 30 may 2011 noragon

Co-treatment with S1P not only inhibits the appearance of the key feature of apoptosis, namely intranucleosomal DNA fragmentation and morphological changes induced by FAS antibody or exogenous ceramide, but also prevents SAPK/JNK activation, another signalling pathway leading to apoptosis ( Cuvillier et al. 1998). The stress-activated protein kinase (SAPK/JNK) pathway is required for ceramide-mediated apoptosis, a process that can be also induced by FAS ligation and is independent from the caspase cascade. It is now clear that ceramide and sphingosine-1-phosphate have opposing effects on cell fate, which is regulated by the balance between both compounds (rheostat model, Fig. 35) and their regulatory effects on members of the mitogen-activated protein kinase family. More recently, it has been demonstrated that this ceramide/sphingosine-1-phosphate rheostat is an evolutionary conserved stress regulatory mechanism influencing growth and survival also in yeast. Sphingosine-1-phosphate has been recently shown to stimulate endothelial cell survival by increasing NO production (Kwon et al. 2001), through the activation of the S1P1 receptor/Gi pathway. This pathway is also involved in the activation of MAP kinase ERK-2 and inhibition of apoptosis in endothelial cells (Lee et al. 1999). In macrophages, S1P is a potent inhibitor of SMase activity and ceramide formation, thereby promoting cell survival (Gomez-Munoz et al. 2003). This cytoprotective effect of S1P may be a receptor-independent event and involves the PI-3 Kinase/PKB signalling cascade.


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