Ceramide mediated apoptosis signaling

Figure 1. Ceramide mediated apoptosis signaling, Recent investigations hypothesize that, at least for drug induced apoptosis, the src kinase Lyn is activated and recruited to plasma membrane rafts. There it binds to and activates a neutral sphingomyelinase (SMase) within minutes. This initial rise in ceramide levels initiates an apoptotic cascade. Howevo- several cellular events can inhibit ceramide production (by blocking sphingomyelinase activation or clearing out ceramide accumulation through increased metabolisation) and therefore contribute to cellular resistance/survival.

Gulbins, E, Bissoimette, R., Mahboubi, A., Martin, S., Nishioka, W., Bmnner, T., Baier, G., Baier-Bitterbch, G., Byrd, C., Lang, E, Kolesnick, R, Altman, A., Green, D., 1995, FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway. Immunity 2 341-351... 

One class of signaling pathways that has received considerable attention involves the action of cytokine-stimulated sphingomyelinase (SHM-ase) (Hannun and Obeid, 1997). Ceramide generated from SHM-ase activation plays a critical role in cytokine-mediated apoptosis, cellular differentiation, and senescence, each of which may be important in the inflammatory response. 

An additional regulatory pathway for this process is the system involved in the production of ceramide, which not only mediates apoptotic signals in some cells, but can also modulate apoptosis itself. 

Bose, R., Verheij, M., Haimovitz-Friedman, A., Scotto, K., Fuks, Z., and Kolesnick, R., 1995, Ceramide synthase mediates daunombicin-induced apoptosis an alternative mechanism for generating death signals. Cell 82 405-414. 

A signaling rheostat has been proposed where the relative level of SIP and ceramide determines cellular fate. This was based on the observation that ceramide, Fas and TNFa-mediated programmed cell death is suppressed by the addition of SIP (Cuvillier et al, 1996). The model assumes that ceramide is a physiological mediator of apoptosis although this is subject to controversy (Hofmann and Dixit, 1998 Kolesnick and Hannun, 1999). Indeed, sphingosine is also implicated as an apoptotic agent (see above). 

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