Ceramide-mediated regulation

The membrane-associated kinase KSR plays an important role in ceramide-mediated regulation of BAD, a pro-apoptotic protein belonging to the Bcl-2-like protein family (Basu et al, 1998). Ceramide indirectly activates BAD via a pathway involving KSR, Ras, c-Raf-1, and MEK-1. Stimulation of this pathway results in Akt inactivation. Since the kinase activity of Akt maintains Bad in the inactive form, inhibition of Akt in turn releases BAD and, finally, permits BAD-triggered cell death. 

While the exact mechanism of ceramide-mediated regulation of most of the above proteins is still unknown, ASM-released ceramide binds directly to PLAa and cathepsin D (Huwiler et al, 2001 Heinrich et al., 1999). Binding of ceramide to cathepsin D in endosomes triggers autocatalytic cleavage of cathepsin to its active form (Heinrich et al, 1999). However, the physiological role of ceramide binding to cathepsin D and PLA2 for apoptosis stiU remains to be determined. 

Ruvolo PP, Clark W, Mumby M et al (2002) A functional role for the B56 alpha-subunit of protein phosphatase 2A in ceramide-mediated regulation of Bcl2 phosphorylation status and function. J Biol Chem 277 22847-22852... 

Lavrentiadou, SN, Chan, C, Kawcak, T, Ravid, T, Tsaba, A, van der Vliet, A, Rasooly, R and Goldkom, T (2001) Ceramide-mediated apoptosis in lung epithelial cells is regulated by glutathione. Am J Respir Cell Mol Biol, 25, 676-684. 

Once apoptosis is triggered, a stereotyped sequence of premitochondrial events occurs that executes the cell death process. In many cases proteins and/or lipid mediators that induce changes in mitochondrial membrane permeability and calcium regulation are produced or activated. For example, the pro-apoptotic Bcl-2 family members Bax, Bad and Bid may associate with the mitochondrial membrane and modify its permeability. Membrane-derived lipid mediators such as ceramide and 4-hydroxynonenal can also induce mitochondrial membrane alterations that are critical for the execution of apoptosis. 

Ballou, L.R., Chao, C.P., Holness, M.A., Barker, S.C., and Raghow, R., 1992, Interleukin-1-mediated PGE2 production and sphingomyelin metabolism. Evidence for the regulation of cyclooxygenase gene expression by sphingosine and ceramide. J.Biol.Chem. 267 20044-20050. 

Brenner, B., Koppenhoefer, U., Weinstock, C., Linderkamp, O., Lang, F. and Gulbins, E., 1997, Fas- or ceramide-induced apoptosis is mediated by a Rad-regulated activation of Jun N-terminalkinase/p38 kinases and GADD153./. Biol. Chem. 272 22173-22181... 

Figure 15.4 Mechanisms of apoptosis induction by resveratrol. Resveratrol selectively induces apoptosis in various cancer cells in culture by several mechanisms including activation of death receptor-mediated signaling, mitochondria-dependent cytochrome c release and caspase activation, induction of p53 and p53-regulated proapototic genes, activation of MAP kinase-mediated p53 phosphorylation, blockade of Akt-mediated cell survival pathways, and accumulation of intracellular ceramide level.

Hannun, Y.A., Obeid, L.M. 2002. The ceramide-centric universe of lipid-mediated cell regulation Stress encounters of the lipid kind. J. Biol Chem. 277, 25847-25850. 

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