Ceramide Activation of NFkB and Protection against Apoptosis

NF-kB is an inducible transcription factor classically implicated in the regulation of inflammatory response genes.106 NF-kB is activated by numerous stimuli including amyloid-beta peptides,107 reactive oxygen species,106,107 TNF,108 chemotherapeutic agents,20 NGF109 and ceramide.2,47,109 Intriguingly, the activation of NF-kB may elicit both apoptotic and antiapoptotic responses in neurons vs. glial cells.107,110-112 For example, activation of NF-kB in glial cells may be involved in apoptosis induced by amyloid-beta peptides, potentially through the activation of proinflammatory or cytotoxic genes such as nitric oxide synthase and interleukin-6.106,107 In contrast, activation of NF-kB in neurons may increase the expression of antioxidant genes and decrease neuronal apoptosis induced by amyloid-beta peptides44 or growth factor withdrawal.114 Moreover, previous studies had suggested that TNF could protect neurons from amyloid-beta-induced apoptosis by decreasing H2O2 production and activating NF-kB.115 Further, ceramide pretreatment mimicked the effect of TNF in protecting neurons from cell death induced by amyloid-beta peptides or glutamate.44 However, as previously discussed, ceramide can increase H2O2 production by directly inhibiting mitochondrial electron flow.65 These results raise the possibility that fundamental differences may exist in the effects of ceramide on mitochondria in different cell types. Alternatively, low levels of ceramide may induce sufficient generation of H2O2 to activate NF-kB and induce the expression of antioxidant genes but not be apoptotic. Indeed, recent data suggest that the production of H2O2 by low concentrations of Ap (0.1 pM) may induce a protective response in neurons through a transient activation of NF-kB.107 In contrast, doses of amyloid-beta peptides typically used to induce apoptosis (10 pM) generate significantly more H2O2 which inhibits NF-kB activation.107 Thus, depending upon the cell type and its genetic program, the nature of the specific activator, the magnitude and duration of the activation signal, as well an interaction with other signaling pathways, similar effector proteins may be involved in eliciting neurodegenerative or neuroprotective responses.

In summary, the dichotomous responses of neurons to ceramide are consistent with the hypothesis first put forth by Hannun and co-workers that ceramide may serve as a sensor of cellular stress involved in gauging the extent of cellular injury and initiating a response.19,36 If the stress is short term, transient ceramide production may promote an antiapoptotic response by affecting cell cycle progression and afford the cell an opportunity to recover from the stress. In contrast, if the stress endures, prolonged ceramide production in combination with other signals may initiate entry into apop-totic pathways. Understanding the circumstances and mechanisms whereby ceramide may activate antiapoptotic signals will undoubtedly provide basic insight into the relationships between lipid signaling pathways, cell cycle progression, and apoptosis. These efforts may provide novel approaches to regulating or slowing neurodegenerative processes.

Acknowledgments

This work was supported by grant MCB 9513596 from the National Science Foundation, a Career Development Award from the Juvenile Diabetes Foundation International, and by funds from the Higuchi Biosciences Center at the University of Kansas.

References

1. Kim, M., Linardic, C., Obeid, L., Hannun, Y. Identification of sphingomyelin turnover as an effector mechanism for the action of tumor necrosis factor-a and Y-interferon, J Biol Chem, 266, 484, 1991.

2. Schutze, S., Potthoff, K., Machleidt, T., Berkovic, D., Wegmann, K., Kronke, M. TNF activates NF-kB by phosphatidylcholine-specific phospholipase C-in-duced "acidic" sphingomyelin breakdown, Cell, 71, 765, 1992.

3. Mathias, S., Younes, A., Kan, C., Orlow, I., Joseph, C., Kolesnick, R.N. Activation of the sphingomyelin signaling pathway in intact EL4 cells and in a cell-free system by IL-1P, Science, 259, 519, 1993.

4. Dressler, K.A., Mathias, S., Kolesnick, R.N. Tumor necrosis factor-a activates the sphingomyelin signal transduction pathway in a cell-free system, Science, 255, 1715, 1992.

5. Masamune, A., Igarashi, Y., Hakomori, S. Regulatory role of ceramide in inter-leukin (IL)-1P-induced E-selectin expression in human umbilical vein endothelial cells, J Biol Chem, 271, 9368, 1996.

6. Belka, C., Weigmann, K., Dieter, A., Holland, R., Neuloh, M., Herrmann, F., Kronke, M., Brach, M.A. Tumor necrosis factor (TNF)-a activates c-raf-1 kinase via the p55 TNF receptor engaging neutral sphingomyelinase, EMBO J, 14, 1156, 1995.

7. Ballou, L.R., Chao, C.P., Holness, M.A., Barker, S.C., Raghow, R. Interleukin-1-mediated PGE2 production and sphingomyelin metabolism, J Biol Chem, 267, 20044, 1992.

8. Chen, J., Nikolova-Karakashian, M., Merrill, A.H., Morgan, E.T. Regulation of cytochrome P450 2C11 (CYP2C11) gene expression by interleukin-1, sphingomyelin hydrolysis, and ceramides in rat hepatocytes, J Biol Chem, 270, 25233, 1995.

9. Yanaga, F., Watson, S.P. Tumor necrosis factor a stimulates sphingomyelinase through the 55 kDa receptor in HL-60 cells, FEBS Lett, 314, 297, 1992.

10. Okazaki, T.O., Bell, R.M., Hannun, Y.A. Sphingomyelin turnover induced by vitamin D3 in HL-60 cells, J Biol Chem, 264, 19076, 1989.

11. Geilen, C.C., Bektas, M., Weider, T., Kodelja, V., Goerdt, S., Orfanos, C.E. 1 a,25-Dihydroxyvitamin D3 induces sphingomyelin hydrolysis in HaCaT cells via tumor necrosis factor a, J Biol Chem, 272, 8997, 1997.

12. Okazaki, T.O., Bielawska, A., Bell, R.M., and Hannun, Y.A. Role of ceramide as a lipid mediator of 1a,25-dihydroxyvitamin D3-induced HL-60 cell differentiation, J Biol Chem, 265, 15823, 1985.

13. Dobrowsky, R.T., Werner, M.H., Castellino, A.M., Chao, M.V., Hannun, Y.A. Activation of the sphingomyelin cycle through the low-affinity neurotrophin receptor, Science, 265, 1596, 1994.

14. Dobrowsky, R.T., Jenkins, G.M., Hannun, Y.A. Neurotrophins induce sphingomyelin hydrolysis: modulation by co-expression with trk receptors, J Biol Chem, 270, 22135, 1995.

15. Boucher, L., Wiegmann, K., Futterer, A., Pfeffer, K., Mahleidt, T., Schutze, S., Mak, T.W., Kronke, M. CD28 signals through acidic sphingomyelinase, J Exp Med, 181, 2059, 1995.

16. Bose, R., Verheji, M., Haimovitz-Friedman, A., Scotto, K., Fuks, Z., Kolesnick, R.N. Ceramide synthase mediates danorubicin-induced apoptosis: an alternative mechanism for generating death signals, Cell, 82, 405, 1995.

17. Jaffrezou, J., Levade, T., Bettaieb, A., Andrieu, N., Bezombes, C., Maestre, N., Vermeersch, S., Rousse, A., Laurent, G. Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis, EMBO J, 15, 2417, 1996.

18. Strum, J.C., Small, G.W., Pauig, S.B., Daniel, L.W. 1-ß-D-Arabinofuranosylcy-tosine stimulates ceramide and diglyceride formation in HL-60 cells, J Biol Chem, 269, 15493, 1994.

19. Zhang, J., Alter, N., Reed, J.C., Borner, C., Obeid, L.M., Bcl-2 interrupts the ceramide-mediated pathway of cell death, Proc Natl Acad Sci U.S.A., 93, 5325, 1996.

20. Boland, M.P., Foster, S.J., O'Neill, L.A.J. Daunorubicin activates NF-kB and induces KB-dependent gene expression in HL-60 promyelocytic and Jurkat T lymphoma cells, J Biol Chem, 272, 12952, 1997.

21. Chang, Y., Abe, A., Shayman, J.A. Ceramide formation during heat shock: a potential mediator of alpha B-crystallin transcription, Proc Natl Acad Sci U.S.A., 92, 12275, 1995.

22. Haimovitz-Friedman, A., Kan, C.C., Ehleiter, D., Persaud, R.S., McLoughlin, M., Fuks, Z., Kolesnick, R.N. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis, J Exp Med, 180, 525, 1994.

23. Obeid, L.M., Linardic, C.M., Karolak, L.A., Hannun, Y.A. Programmed cell death induced by ceramide, Science, 259, 1769, 1993.

24. Dbaibo, G.S., Perry, D.K., Gamard, C.J., Platt, R., Poirier, G.G., Obeid, L.M., Hannun, Y.A. Cytokine response modifier A (CrmA) inhibits ceramide formation in response to tumor necrosis factor (TNF)-a: CrmA and Bcl-2 target distinct components in the apoptotic pathway, J Exp Med, 185, 481, 1997.

25. Jarvis, W.D., Kolesnick, R.N., Fornari, F.A., Traylor, R.S., Gewirtz, D.A., Grant, S. Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway, Proc Natl Acad Sci U.S.A., 91, 73, 1994.

26. Verheij, M., Bose, R., Lin, X.H., Bei, Y., Jarvis, W.D., Grant, S., Birrer, M.J., Szabo, E., Zon, L.I., Kyriakis, J.M., Haimovitz-Friedman, A., Fuks, Z., Kolesnick, R.N. Requirement for ceramide-initiated SAPK/JNK signaling in stress-induced apoptosis, Nature, 380, 75, 1996.

27. Pronk, G.J., Ramer, K., Amiri, P., Williams, L.T. Requirement of an ICE-like protease for induction of apoptosis and ceramide generation by REAPER, Science, 271, 808, 1996.

Cassacia-Bonnefil, P., Carter, B.D., Dobrowsky, R.T., Chao, M.V. Nerve growth factor-mediated death of oligodendrocytes by the p75 neurotrophin receptor, Nature, 383, 716, 1996.

Tepper, C.G., Jayadev, S., Liu, B., Bielawska, A., Wolff, R., Yonehara, S., Hannun, Y.A., Seldin, M.F. Role for ceramide as an endogenous mediator of fas-induced cytotoxicity, Proc Natl Acad Sci U.S.A., 92, 8443, 1995.

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

Gamard, C., Dbaibo, G.S., Obeid, L.M., Hannun, Y.A. Selective involvement of ceramide in cytokine-induced apoptosis, J Biol Chem, 272, 16474, 1997. Sillence, D.J., Allan, D. Evidence against an early signaling role for ceramide in FAS-mediated apoptosis, Biochem J, 324, 29, 1997.

Cifone, M.G., De Maria, R., Roncaioli, P., Rippo, M.R., Azuma, M., Lanier, L.L., Santoni, A., Testi, R. Apoptotic signaling through CD95 (FAS/Apo-1) activates an acidic sphingomyelinase, J Exp Med, 177, 1547, 1993. Quintans, J., Kilkus, C.L., McShan, A.R., Dawson, G. Ceramide mediates the apoptotic response of WEHI 231 cells to anti-immunoglobulin, corticosteroids and irradiation, Biochem Biophys Res Comm, 202, 710, 1994. Weisner, D.A., Kilkus, J.P., Gottschalk, A.R., Quintans, J., Dawson, G. Anti-immunoglobulin-induced apoptosis in WEHI 231 Cells involves the slow formation of ceramide from sphingomyelin and is blocked by Bcl-xL, J Biol Chem, 272, 9868, 1997.

Hannun, Y.A. Functions of ceramide in coordinating cellular response to stress, Science, 274, 1855, 1996.

Sawai, H., Okazaki, T., Yamamoto, H., Okano, H., Takeda, Y., Tashima, M., Sawada, H., Okuma, M., Ishikura, H., Umehara, H., Domae, N. Requirement of AP-1 for ceramide-induced apoptosis in human leukemia HL-60 cells, J Biol Chem, 270, 27326, 1995.

Jarvis, W.D., Fornari, F.A.J., Browning, J.L., Gewirtz, D.A. Attenuation of cera-mide-induced apoptosis by diglyceride in human myeloid leukemia cells, J Biol Chem, 269, 31685, 1994.

Santana, P., Pena, L.A., Haimovitz-Friedman, A., Martin, S., Green, D., McLoughlin, E.H., Cordon-Cardo, C., Schuchman, E.H., Fuks, Z., Kolesnick, R. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis, Cell, 86, 189, 1996.

Hartfield, P.J., Mayne, G.C., Murray, A.W. Ceramide induces apoptosis in PC12 cells, FEBS Lett, 401, 148, 1997.

Casaccia-Bonnefil, P., Aibel, L., Chao, M.V. Central glial and neuronal populations display differential sensitivity to ceramide-dependent cell death, J Neu-rosci Res, 43, 382, 1996.

Wiesner, D.A., Dawson, G. Staurosporine induces programmed cell death in embryonic neurons and activation of the ceramide pathway, J Neurochem, 66, 1418, 1996.

Ito, A., Horigome, K. Ceramide prevents neuronal programmed cell death by NGF deprivation, J Neurochem, 65, 463, 1995.

Goodman, Y., Mattson, M.P. Ceramide protects hippocampal neurons against excitotoxic and oxidative insults, and amyloid P-peptide toxicity, J Neurochem, 66, 869, 1996.

Grazia Cifone, M., Roncaioli, P., De Maria, R., Camarda, G., Santoni, A., Ruberti, G., Testi, R. Multiple pathways originate at the FAS/APO-1 (CD95) receptor: sequential involvement of phosphatidylcholine-specific phospholipase C and acidic sphingomyelinase in the propagation of the apoptotic signal. EMBO J, 14, 5859, 1995.

Jayadev, S., Liu, B., Bielawska, A.E., Lee, J.Y., Nazaire, F., Pushkareva, M.Y., Obeid, L.M., Hannun, Y.A. Role for ceramide in cell cycle arrest, J Biol Chem, 270, 2047, 1995.

Weigmann, K., Schutze, S., Machleidt, T., Witte, D., Kronke, M. Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling, Cell, 78, 1005, 1994.

Chinnaiyan, A.R., Tepper, C.G., Seldin, M.F., O'Rourke, K., Kischkel, F.C., Hell-bardt, S., Krammer, P.H., Peter, M.E., Dixit, V.M. FADD/MORT1 is a common mediator of CD95 (FAS/APO-1) and tumor necrosis factor receptor-induced apoptosis, J Biol Chem, 271, 4961, 1996.

Chinnaiyan, A.M., Orth, K., O'Rourke, K., Duan, H., Poirer, G.G., Dixit, V.M. Molecular ordering of the cell death pathway, J Biol Chem, 271, 4573, 1996. Quillet-Mary, A., Jaffrezou, J., Mansat, V., Bordier, C., Naval, J., Laurent, G. Implication of mitochondrial hydrogen peroxide generation in ceramide-in-duced apoptosis, J Biol Chem, 272, 21388, 1997.

Tewari, M., Telford, W.G., Miller, R.A., Dixit, V.M. CrmA, a poxvirus-encoded serpin, inhibits cytotoxic T-lymphocyte-mediated apoptosis, J Biol Chem, 270, 22705, 1995.

Merrill, A.H.J., Jones, D.D. An update of the enzymology and regulation of sphingomyelin metabolism, Biochim Biophys Acta, 1044, 1, 1990. Michel, C., van Echten-Deckert, G., Rother, J., Sandhoff, K., Wang, E., Merrill, A.H.J. Characterization of ceramide synthesis, J Biol Chem, 272, 22432, 1997. Kok, J.W., Nikolova-Karakashian, M., Klappe, K., Alexander, C., Merrill, A.H.J. Dihydroceramide biology, J Biol Chem, 272, 21128, 1997. Merrill, A.H.J., van Echten, G., Wang, E., Sandhoff, K. Fumonisin B: inhibits sphingosine (sphinganine) N-acyltransferase and de novo sphingolipid biosynthesis in cultured neurons in situ, J Biol Chem, 268, 27299, 1993. Merrill, A.H.J., Schmelz, E., Dillehay, D.L., Spiegel, S., Shayman, J.A., Schroeder, J.J., Riley, R.T., Voss, K.A., Wang, E. Sphingolipids — the enigmatic lipid class: biochemistry, physiology and pathophysiology, Toxicol Appl Pharmacol, 142, 208, 1996.

Paumen, M.B., Ishida, Y., Muramatsu, M., Yamamoto, M., Honjo, T. Inhibition of carnitine palmitoyltransferase I augments sphingolipid synthesis and palm-itate-induced apoptosis, J Biol Chem, 272, 3324, 1997.

Barenholz, Y., Thompson, T.E. Sphingomyelins in bilayers and biological membranes, Biochim Biophys Acta, 604, 129, 1980.

Linardic, C.M., Hannun, Y.A. Identification of a distinct pool of sphingomyelin involved in the sphingomyelin cycle, J Biol Chem, 269, 23530, 1994. Andrieu, N., Salvayre, R., Levade, T. Comparative study of the metabolic pools of sphingomyelin and phosphatidylcholine sensitive to tumor necrosis factor, Eur J Biochem, 236, 738, 1996.

Liu, P., Ying, Y., Ko, Y., Anderson, R.G.W. Localization of platelet-derived growth factor-stimulated phosphorylation to caveolae, J Biol Chem, 271, 10299, 1996.

Bilderback, T.R., Grigsby, R.J., and Dobrowsky, R.T. Association of p75N™ with caveolin and localization of neurotrophin-induced sphingomyelin hydrolysis to caveolae. J Biol Chem, 272, 10922-7, 1997.

Zhang, P., Liu, B., Jenkins, G.M., Hannun, Y.A., Obeid, L.M. Expression of neutral sphingomyelinase identifies a distinct pool of sphingomyelin involved in apoptosis, J Biol Chem, 272, 9609, 1997.

Gudz, T.I., Tserng, K., Hoppel, C.L. Direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide, J Biol Chem, 272, 24154, 1997. Garcia-Ruiz, C., Colell, A., Maris, M., Morales, A., Fernandez-Checa, J.C. Direct effects of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species, J Biol Chem, 272, 11369, 1997. Zamzami, N., Marchetti, P., Castedo, M., Zanin, C., Vayssiere, J., Petit, P.X., Kroemer, G. Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo, J Exp Med, 181, 1661, 1995. Dobrowsky, R.T., Kamibayashi, C., Mumby, M.C., Hannun, Y.A. Ceramide activates heterotrimeric protein phosphatase 2A, J Biol Chem, 268, 15523, 1993. Mathias, S., Dressler, K.A., Kolesnick, R.N. Characterization of a ceramide-activated protein kinase: stimulation by tumor necrosis factor a, Proc Natl Acad Sci U.S.A., 88, 10009, 1991.

Lozano, J., Berra, E., Muncio, M.M., Diaz-Meco, M.T., Dominguez, I., Sanz, L., Moscat, J. Protein kinase C Z isoform is critical for KB-dependent promoter activation by sphingomyelinase, J Biol Chem, 269, 19200, 1994. Bernardi, P., Broekemeier, K.M., Pfeiffer, D.R. Recent progress on regulation of the mitochondrial permeability transition pore; A cyclosporin-sensitive pore in the inner mitochondrial membrane, J Bioenerget Biomembr, 26, 509, 1994. Susin, S.A., Zamzami, N., Castedo, M., Daugas, E., Wang, H., Geley, S., Fassy, F., Reed, J.C., Kroemer, G. The central executioner of apoptosis: multiple connections between protease activation and mitochondria in FAS/APO-1/CD95-and ceramide-induced apoptosis, J Exp Med, 186, 25, 1997. Zamzami, N., Marchetti, P., Castedo, M., Decaudin, D., Macho, A., Hirsch, T., Susin, S.A., Petit, P.X., Mignotte, B., Kroemer, G. Sequential reduction of mito-chondrial membrane transmembrane potential and generation of reactive oxygen species in early programmed cell death, J Exp Med, 182, 367, 1995. Liu, B., Hannun, Y.A. Inhibition of the neutral magnesium-dependent sphingomyelinase by glutathione, J Biol Chem, 272, 16281, 1997. Smyth, M.J., Perry, D.K., Zhang, J., Poirier, G.G., Hannun, Y.A., Obeid, L.M. prICE:a downstream target for ceramide-induced apoptosis and for the inhibitory action of Bcl-2, Biochem J, 316, 25, 1996.

Liu, X., Kim, C.N., Yang, J., Jemmerson, R., Wang, X. Induction of apoptotic program in cell free extracts: requirement for dATP and cytochrome c, Cell, 86, 147, 1996.

Adachi, S., Cross, A.R., Babior, B.M., Gottlieb, R.A. Bcl-2 and the outer mito-chondrial membrane in the inactivation of cytochrome c during FAS-mediated apoptosis, J Biol Chem, 272, 21878, 1997.

Kluck, R.M., Bossy-Wetzel, E., Green, D.R., Newmeyer, D.D. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apop-tosis, Science, 275, 1132, 1997.

Yang, J., Liu, X., Bhalla, K., Kim, C.N., Ibrado, A.M., Cai, J., Peng, T., Jones, D.P., Wang, X. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked, Science, 275, 1129, 1997.

Susin, S.A., Zamzami, N., Castedo, M., Hirsch, T., Marchetti, P., Macho, A., Daugas, E., Geuskens, M., Kroemer, G. Bcl-2 inhibits the mitochondrial release of an apoptogenic protease, J Exp Med, 184, 1331, 1996.

Reed, J.C. Double identity for proteins of the Bcl-2 family, Nature, 387, 773, 1997. Perry, D.K., Smyth, M.J., Wang, H., Reed, J.C., Duriez, P., Poirier, G.G., Obeid, L.M., Hannun, Y.A. Bcl-2 acts upstream of the PARP protease and prevents its activation, Cell Death Differ, 4, 29, 1997.

Hockenberry, D.M., Oltvai, Z.N., Yin, X., Milliman, C.L., Korsmeyer, S.J. Bcl-2 functions in an antioxidant pathway to prevent apoptosis, Cell, 75, 241, 1993. Wang, H., Rapp, U.R., Reed, J.C. Bcl-2 targets the protein kinase Raf-1 to mitochondria, Cell, 87, 629, 1996.

Park, J., Kim, I., Jun Oh, Y., Lee, K., Han, P., Choi, E. Activation of c-Jun N-terminal kinase antagonizes an antiapoptotic action of Bcl-2, J Biol Chem, 272, 16725, 1997.

Zha, J., Harada, H., Yang, E., Jockel, J., Korsmeyer, S. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not Bcl-XL, Cell, 87, 619, 1996.

Zhang, Y.L, Yao, B., Delikat, S., Bayoumy, S., Lin, X., Basu, S., McGinley, M., Cahn-hui, P., Lichenstein, H., Kolesnick, R. Kinase suppressor of Ras is cera-mide-activated protein kinase, Cell, 89, 63, 1997.

Yao, B., Zhang, Y., Delikat, S., Mathias, S., Basu, S., Kolesnick, R. Phosphorylation of Raf by ceramide-activated protein kinase, Nature, 378, 307, 1995. Karasavvas, N., Erukulla, R.K., Bittman, R., Lockshin, R., Zakeri, Z. Stereospe-cific induction of apoptosis in U937 cells by N-octanoyl-sphingosine stereoisomers and N-octyl-sphingosine, Eur J Biochem, 236, 729, 1996. Robinson, M.J., Cobb, M.H. Mitogen-activated protein kinase pathways, Curr Opin Cell Biol, 9, 181, 1997.

Kyriakis, J.M., Banerjee, P., Nikolakaki, E., Dal, T., Rubie, E., Ahmad, M.F., Avruch, J., Woodgett, J.R. The stress-activated protein kinase subfamily of c-Jun kinases, Nature, 369, 156, 1994.

Westwick, J.K., Bielawska, A., Dbaibo, G., Hannun, Y.A., Brenner, D.A. Cera-mide activates the stress-activated protein kinase, J Biol Chem, 270, 22689, 1995. Xia, Z., Dickens, M., Raingeaud, J., Davis, R.J., Greenberg, M.E. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis, Science, 270, 1326, 1996. Brenner, B., Koppenhoefer, U., Weinstock, C., Linderkamp, O., Lang, F., Gul-bins, E. Fas- or ceramide-induced apoptosis is mediated by a Rac1-regulated activation of Jun N-terminal kinase/p38 kinases and GADD 153, J Biol Chem, 272, 22173, 1997.

Shirakabe, K., Yamaguchi, K., Shibuya, H., Irie, K., Matsuda, S., Moriguchi, T., Gotoh, Y., Matsumoto, K., Nishida, E. TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase, J Biol Chem, 272, 8141, 1997.

Rani, C.S.S., Abe, A., Chang, Y., Rosenzweig, N., Saltiel, A.R., Radin, N.S., Shayman, J.A. Cell cycle arrest induced by an inhibitor of glucosylceramide synthase, J Biol Chem, 270, 2859, 1995.

Evan, G.I., Brown, L., Whyte, M., Harrington, E. Apoptosis and the cell cycle, Curr Opin Cell Biol, 7, 825, 1995.

Deshaies, R.J. The self-destructive personality of a cell cycle in transition, Curr Opin Cell Biol, 7, 781, 1995.

98. Park, D.S., Farinelli, S.E., Greene, L.A. Inhibitors of cyclin-dependent kinases promote survival of postmitotic neuronally differentiated PC12 cells and sympathetic neurons, J Biol Chem, 271, 8161, 1996.

99. Rukenstein, A., Rydel, R.E., Greene, L.A. Multiple agents rescue PC12 cells from serum-free cell death by translation- and transcription-independent mechanisms, J Neurosci, 11, 2552, 1991.

100. Farinelli, S.E., Greene, L.A. Cell cycle blockers mimosine, ciclopirox, and deferoxamine prevent the death of PC12 cells and postmitotic sympathetic neurons after removal of trophic support, J Neurosci, 16, 1150, 1996.

101. Sherr, C.J. G1 phase progression:cycling on cue, Cell, 79, 551, 1994.

102. Freeman, R.S., Estus, S., Johnson, E.M.J. Analysis of cell cycle-related gene expression in postmitotic neurons: selective induction of cyclin D1 during programmed cell death, Neuron, 12, 343, 1994.

103. Kranenburg, O., van der Eb, A.J., Zantema, A. Cyclin D1 is an essential mediator of apoptotic neuronal cell death, EMBO J, 15, 46, 1996.

104. Lee, K., Helbing, C.C., Choi, K., Johnston, R.N., Wang, J.H. Neuronal Cdc-2like kinase (Nclk) binds and phosphorylates the retinoblastoma protein, J Biol Chem, 272, 5622, 1997.

105. Dbaibo, G., Pushkareva, M.Y., Jayadev, S., Schwarz, J.K., Horowitz, J.M., Obeid, L.M., Hannun, Y.A. Retinoblastoma gene product as a downstream target for a ceramide-dependent pathway of growth arrest, Proc Natl Acad Sci U.S.A., 92, 1347, 1995.

106. Baeuerle, P., Henkel, T. Function and activation of NF-kB in the immune system, Annu Rev Immunol, 12, 141, 1994.

107. Kaltschmidt, B., Uherek, M., Volk, B., Baeuerle, P., Kalschmidt, C. Transcription factor NF-kB is activated in primary neurons by amyloid ß peptides and in neurons surrounding early plaques from patients with Alzheimer disease, Proc Natl Acad Sci U.S.A., 94, 2642, 1997.

108. Hsu, H., Shu, H., Pan, M., Goeddel, D.V. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways, Cell, 84, 299, 1996.

109. Carter, B.D., Kaltschmidt, C., Kaltschmidt, B., Offenhauser, N., Bohm-Matthaei, R., Baeuerle, P.A., Barde, Y. Selective activation of NF-kB by nerve growth factor through the neurotrophin receptor p75, Science, 272, 542, 1996.

110. Beg, A.A., Baltimore, D. An essential role for NF-Kb in preventing TNF-a-induced cell death, Science, 274, 782, 1996.

111. Wang, C., Mayo, M.W., Baldwin, A.S.J. TNF and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kB, Science, 274, 784, 1996.

112. Van Antwerp, D.J., Martin, S.J., Kafri, T., Green, D.R., Verma, I.M. Suppression of TNF-a-induced apoptosis by NF-kB, Science, 274, 787, 1996.

113. Bayaert, R., Fiers, W. Molecular mechanism of tumor necrosis factor-induced cytotoxicity, FEBS Letts, 340, 9, 1994.

114. Greenlund, L.L.S., Deckwerth, T.L., Johnson, E.M.J. Superoxide dismutase delays neuronal apoptosis: a role for reactive oxygen species in programmed neuronal death, Neuron, 14, 303, 1995.

115. Barger, S.W., Horster, D., Furukawa, K., Goodman, Y., Krieglstein, J., Mattson, M.P. Tumor necrosis factor a and ß protect neurons against amyloid ß-peptide toxicity: Evidence for involvement of a KB-binding factor and attenuation of peroxide and Ca2+ accumulation, Proc Natl Acad Sci U.S.A., 92, 9328, 1995.

Section B

Methods

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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