Neutral sphingomyelinases activation

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. 

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. 

Hanada, K., Mitamura, T., Fukasawa, M., Magistrado, P. A., Horii, T., and Nishijima, M. (2000). Neutral sphingomyelinase activity dependent on Mg2+ and anionic phospholipids in the intraerythrocytic malaria parasite Plasmodium falciparum. Biochem. ]. 346(Pt 3), 671-677. 

Yoshimura, S., Banno, Y.. Nakashima, S., Hayashi. K.. Ya-makawa, H., Sawada, M.. Sakai, N.. and Nozawa, Y. (1999) Inhibition of Neutral Sphingomyelinase Activation and Ceramide Formation hy Glutathione in Hypoxic PC 12 Cell Death, /. Neurochem. 73,675-683. 

Berliner, J.A. 2006. A role for neutral sphingomyelinase activation in the inhibition of LPS action by phospholipid oxidation products. 47, 1967-1974. 

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.

Chmura, S. J., Nodzenski, E., Weichselbaum, R. R., and Quintans, J., 1996, Protein kinase C inhibition induces apoptosis and ceramide production through activation of a neutral sphingomyelinase. Cancer Res. 56 2711-2714. 

Wu, M., Harvey, K., Ruzmeto, N., Welch, Z., Sech, L., Jackson, K., Stillwell, W., Zaloga, G., and Siddiqui, R. (2005). Omega-3 polyunsaturated fatty acids attenuate breast cancer growth through activation of a neutral sphingomyelinase-mediated pathway. Int.. Cancer 117, 340-348. 

The fungal metabolite scyphostatin (Fig. 7) is a potent, reversible inhibitor of membrane-bound Mg +-dependent neutral sphingomyelinase (nSMase), thereby interfering with the generation of ceramide (102, 103). The activity of nSMases is sensitive to the cellular redox state, for example, the ratio of glutathione in the reduced versus the oxidized form (104, 105). The famesyltransferase inhibitor manumycin A, a polyenamide produced by the Streptomyces species, also inhibits nSMase irreversibly (106). 

Nara F, Tanaka M, Masuda-Inoue S, Yamasato Y, Doi-Yoshioka 119. H, Suzuki-Konagai K, Kumakura S, Ogita T. Biological activities of scyphostatin, a neutral sphingomyelinase inhibitor from... 

Claus RA, Wtistholz A, Muller S, Bockmeyer CL, Riedel NH, Kinscherf R, Deigner HP. Synthesis and antiapoptotic activity of a novel analogue of the neutral sphingomyelinase inhibitor scyphostatin. ChemBioChem 2005 6 726-737. 

Lee JT, Xu J, Lee JM, Ku G, Han X, Yang DI, Chen S, Hsu CY (2004) Amyloid-beta peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway. J Cell Biol 164 123-131. 

Jana A, Pahan K (2004a) Fibrillar amyloid-beta peptides kill human primary neurons via NADPH oxidase-mediated activation of neutral sphingomyelinase. Implications for Alzheimer s disease. J Biol Chem 279 51451-51459. 

Jana A, Pahan K (2004b) Human immunodeficiency vims type 1 gpl20 induces apoptosis in human primary neurons through redox-regulated activation of neutral sphingomyelinase. J Neurosci 24 9531-9540. 

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