Sphingomyelinase activation

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.

Machleidt, T., Wiegmann, K., Henkel, T., Schiitze, S., Baeuerle, P., and Kronke, M., 1994, Sphingomyelinase activates proteolytic iKB-a degradation in a ceU-free system. J. Biol. Chem. 269 13760-13765. 

Mansat, V., Laurent, G. Levade, T., Bettaieb, A., and Jaffrezou, J.P., 1997a, The protein kinase C inhibitors phorbol ester and phosphatidylserine block neutral sphingomyelinase activation, ceramide generation and apoptosis triggered by daunorubicin. Cancer Res. 57 5300-5304. 

Jaffrezou, J. P., Maestre, N., de Mas-Mansat, V., Bezomhes, C., Levade, T., and Laurent, G., 1998, Positive feedback control of neutral sphingomyelinase activity by cerattride. Faseb J 12 999-1006. 

Samet, D., and Barenholz, Y., 1999, Characterization of acidic and neutral sphingomyelinase activities in crude extracts of HL-60 cells. Chem Phys Lipids 102 65-77. 

Menon, G.K., Grayson, S., Elias, P.M. Cytochemical and biochemical localization of lipase and sphingomyelinase activity in mammalian epidermis. J. Invest. Dermatol. 86 591-597 (1986). 

Jensen, J.M., Folster-Holst, R., Baranowsky, A., Schunck, M., Winoto-Morbach, S., Neumann, C., Schutze, S., and Proksch, E., Impaired sphingomyelinase activity and epidermal differentiation in atopic dermatitis, J. Invest. Dermatol., 122, 1423-1431, 2004. 

Chen, H., Born, E., Mathur, S.N., Johlin, F.C., Jr., Field, F.J. 1992. Sphingomyelin content of intestinal cell membranes regulates cholesterol absorption. Evidence for pancreatic and intestinal cell sphingomyelinase activity. Biochem. J. 286, 771-777. 

The importance of alkaline sphingomyelinase and ceramides in colon cancer is suggested by studies that compared their levels in tumors with levels in normal colonic tissue. Hertervig et al. (1997) found that the activity of alkaline sphingomyelinase was 75% less in tissue from human colon carcinomas than in normal colonic tissue. In familial adenomatous polyposis patients, there was a 90% decrease in alkaline sphingomyelinase activity in colonic adenomas and in surrounding mucosa compared to healthy controls (Hertervig et al., 1999). Human colon carcinomas had a 50% decrease in cellular ceramide content compared to normal colon mucosa (Selzner et al., 2001). 

Hertervig, E., Nilsson, A., Bjork, J., Hultkrantz, R., Duan, R-D. 1999. Familial adenomatous polyposis is associated with a marked decrease in alkaline sphingomyelinase activity a key factor to the unrestrained cell proliferation Br. J. Cancer. 81, 232-236. 

Studies with JB6 mouse epidermal cells demonstrated that resveratrol agly-cone-induced apoptosis in these cells was through p53 and that it was not dependent upon normal sphingomyelinase activity as the induction of apoptosis was observed in sphingomyelinase deficient and sufficient cell lines. Studies by Lu,... 

Soeda S, Tsuji Y, Ochiai T, Mishima K, Iwasaki K, et al. Inhibition of sphingomyelinase activity helps to prevent neuron death caused by ischemic stress. Neurochem. Int. 2004 45 619-626. Hakogi T, Taichi M, Katsumura S. Synthesis of a nitrogen analogue of sphingomyelin as a sphingomyelinase inhibitor. Org. Lett. 2003 5 2801-2804. 

Kinnunen PKJ, Holopainen JM. Sphingomyelinase activity of LDL A link between atherosclerosis, ceramide, and apoptosis ... 

Morimoto S, Martin BM, Kishimoto Y, O Brien JS (1988) Saposin D a sphingomyelinase activator. Biochim Biophys Res Commun 156 403— 410... 

Chlorogentisylquinone 287, which was obtained from the culture broth of a marine fungal strain FOM-8108, inhibited neural sphingomyelinase activity of rat brain membranes (with IC50 value of 1.2 The strain FOM-8108 was considered to be a member of genus Phoma family. ... 

At least two obvious aspects must be considered here, namely the influence of the membrane lipids on sphingomyelinase activity, and the effects of the enzyme on the membrane properties. For the latter, we shall deal separately with enzyme effects on membrane permeability and effects on membrane architecture. 

Also relevant in this context is the observation by Jaffrezou et al. [120] that ceramide enhances neutral sphingomyelinase activity in myeloid leukemia cells and in normal skin fibroblasts. However, these results were obtained with short-chain, cell-permeant ceramides, whose physical effects on membranes may differ from the more frequent long-chain ones [9]. The subject is interesting enough to deserve a more detailed investigation. 

E. Activation of Sphingomyelinase Activities after CEES Exposure.253... 

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