, 2005, Gorria et al., 2006, Podechard et al., 2011, Sandal et al., 2004 and Yilmaz et al., 2006). Also see Table 1 for a nonexhaustive list of environmental pollutants which may induce plasma membrane remodeling and cell death. Environmental pollutants have also been shown to affect the expression of major structural components of the plasma membrane like cav-1, which may be involved in cell death/survival signaling (Lim et al., 2007). Ceramide is an evolutionarily conserved second messenger that plays a ubiquitous role in biological processes as diverse as apoptosis, growth arrest, senescence and differentiation (Deng et al., 2008, Dickson
et al., 1997, Jenkins et al., 1997 and Menuz et al., 2009). Ceramide is an N-acylsphingosine
formed of a fatty acid bound to the amino group of the sphingoid base, sphingosine. The hydrolysis of sphingomyelin Ixazomib nmr to ceramide selleck is catalyzed by acid, neutral and alkaline sphingomyelinases that are named according to the optimum pH of their activity. In this review, we focus on acid sphingomyelinase (ASM) whose activity and role in the generation of ceramide have been described in more detail with regard to its implication in cell death. Moreover, ASM can translocate to the plasma membrane; in this context, the generation of ceramide can therefore directly affect plasma membrane composition, whereas neutral sphingomyelinase activity seems to be limited to the cytoplasm (Hannun and Obeid, 2008 and Kolesnick et al., 2000). ASM, can be activated via engagement of the TNF-receptor super-family members—Fas ( Cremesti et al., 2001, Grassme et al., 2001a and Grassme et al., 2001b), CD40 ( Grassme et al., 2002), DR5 ( Dumitru and Gulbins, 2006) and TNFα ( Garcia-Ruiz et al., 2003). Furthermore, a number of groups have demonstrated activation of ASM by various stress stimuli, such as LPS ( Pfeiffer et al., 2001), disruption of integrin signaling ( Erdreich-Epstein et al., 2005), engagement of the platelet-activating factor-receptor ( Goggel et al., 2004), UV-light (UV-A ( Zhang et al., 2001) and UV-C ( Kashkar et al., 2005)),
heat ( Chung et al., 2003), alcohol ( Reichel et al., 2010), oxidative stress ( Sanvicens and RANTES Cotter, 2006), chemotherapeutic agents like cisplatin ( Dimanche-Boitrel et al., 2011), gemcitabine ( Modrak et al., 2004), doxorubicin ( Morita and Tilly, 2000), or ionizing radiation ( Paris et al., 2001) and accumulation of Cu2+ ( Lang et al., 2007). All these stimuli may ultimately lead to ceramide production with further consequences on plasma membrane and cell fate. When cells and tumors are exposed to radiation or chemicals including cytostatics like cisplatin, ASM is activated. The activated ASM then translocates to the membrane surface and hydrolyzes sphingomyelin, which generates sphingosine and ceramide in lipid rafts (Grassme et al., 2001a).