Differential Effects of Sphingomyelin Hydrolysis and Resynthesis on the Activation of NF-κB in Normal and SV40-transformed Human Fibroblasts

Luberto, Chiara; Yoo, David; Suidan, Hana S.; Bartoli, Gianna Maria; Hannun, Yusuf A.

doi:10.1074/jbc.275.19.14760

Cited by 70 publications

(66 citation statements)

References 31 publications

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“…Indeed, it has been reported that downregulation of SMS1 reduces the amount of SM in lipid rafts and reduces the rate of cell apoptosis induced by alkyl-lysophospholipid (10). It has also been reported that D609 exposure inhibits TNF-a- (27,14) or phorbol ester-mediated (14) NFkB activity. A critical question remains to be answered: are both SMS1 and SMS2 responsible for the production of plasma membrane-associated SM?…”

Section: Discussionmentioning

confidence: 99%

“…Whether the DAG generated by SMS regulates cellular processes is, in fact, not known. In mammalian cells, SMS activation correlates with the activation and nuclear translocation of NFkB (14); these events are often regulated by DAG-dependent PKC (15). Cerbon and del Carmen Lopez-Sanchez (16) reported that exposure to D609 (an SMS inhibitor) significantly reduces cellular DAG levels, thereby reducing cell proliferation.…”

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confidence: 99%

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SMS overexpression and knockdown: impact on cellular sphingomyelin and diacylglycerol metabolism, and cell apoptosis

Ding

Hailemariam

et al. 2008

Journal of Lipid Research

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Sphingomyelin synthase (SMS), the last enzyme in the sphingomyelin (SM) biosynthetic pathway, uses ceramide and phosphatidylcholine as substrates to produce SM and diacylglycerol (DAG). To evaluate the role of SMS in apoptosis, we generated Chinese hamster ovary cells that stably express human SMS1 or SMS2. We found that SMS1 or SMS2 overexpression results in a significant increase in cellular levels of SM (24% or 20%) and DAG (35% or 31%), respectively, compared with controls. Cells overexpressing SMS1 or SMS2 were more likely to undergo lysis mediated by lysenin (a protein that causes lysis through its affinity with SM-rich microdomains in the plasma membrane) than were controls, indicating SM enrichment of the plasma membrane. SMS1 and SMS2 overexpression also led to higher retention of DiIC16 fluorescence compared with wild-type cells, indicating an increased number of detergentinsoluble microdomains and significantly increased tumor necrosis factor-a-mediated apoptosis. To further evaluate the relationship between SMS activity and cell apoptosis, we used SMS1 and SMS2 small interfering RNA (siRNA) to knock down their mRNA in THP-1-derived macrophages. We found that SMS1 or SMS2 siRNA significantly reduces intracellular SM (by 20% or 23%), plasma membrane SM (as indicated by the rate of lysenin-mediated cell lysis), and DAG levels (24% or 20%), respectively, while significantly reducing lipopolysaccharide-mediated apoptosis compared with controls. These results indicate that SMS1 and SMS2 are key factors in the control of SM and DAG levels within the cell and thus influence apoptosis.-Ding, T., Z. Li, T. Hailemariam, S. Mukherjee, F. R. Maxfield, M-P. Wu, and X-C. Jiang. SMS overexpression and knockdown: impact on cellular sphingomyelin and diacylglycerol metabolism, and cell apoptosis. J. Lipid Res. 2008. 49: 376-385.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

SMS overexpression and knockdown: impact on cellular sphingomyelin and diacylglycerol metabolism, and cell apoptosis

Ding

Hailemariam

et al. 2008

Journal of Lipid Research

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“…In this respect, it is worth noting that SM synthase recently emerged as a negative regulator of endogenous ceramide levels involved in signaling processes (35)(36)(37). Moreover, it has been demonstrated that SV40-transformed lung fibroblasts contain a significantly higher SM synthase activity than normal lung fibroblasts, and a role for SM synthase in the regulation of cell growth has been suggested (23).…”

Section: Discussionmentioning

confidence: 99%

Basic Fibroblast Growth Factor-induced Proliferation of Primary Astrocytes

Riboni

Viani

Bassi

et al. 2001

Journal of Biological Chemistry

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We recently reported that the marked decrease in cellular ceramide in primary astrocytes is an early event associated with the mitogenic activity of basic fibroblast growth factor (bFGF) (Riboni, L., Viani, P., Bassi, R., Stabieini, A., and Tettamanti, G. (2000) GLIA 32, 137-145). Here we show that a rapid activation of sphingomyelin biosynthesis appears to be the major mechanism responsible for the fall in ceramide levels induced by bFGF. When quiescent astrocytes were treated with bFGF, an increased amount of newly synthesized ceramide (from either L-[ 3 H]serine or [ 3 H]sphingosine) was directed toward the biosynthesis of sphingomyelin. Conversely, bFGF did not appear to affect ceramide levels by other metabolic pathways involved in ceramide turnover such as sphingomyelin degradation and ceramide biosynthesis, degradation, and glucosylation. Enzymatic studies demonstrating a relevant and rapid increase in sphingomyelin synthase activity after bFGF treatment have provided a convincing explanation for the activation of sphingomyelin biosynthesis. The bFGF-induced increase in sphingomyelin synthase appears to depend on a post-translational activation mechanism. Moreover, in the presence of brefeldin A, the activation of sphingomyelin biosynthesis was abolished, suggesting that the enzyme is located in a compartment other than the Golgi apparatus. Also the phosphatidylcholine-specific phospholipase C inhibitor D609 exerted a potent inhibitory effect on sphingomyelin biosynthesis. Finally, we demonstrate that inhibition of sphingomyelin biosynthesis by brefeldin A or D609 led to a significant inhibition of bFGF-stimulated mitogenesis. All this supports that, in primary astrocytes, the early activation of sphingomyelin synthase is involved in the bFGF signaling pathway leading to proliferation.Ceramide, a key sphingolipid metabolite in both the biosynthesis and degradation of complex sphingolipids, is involved in the signal transduction of different extracellular stimuli that lead to cell proliferation, cell differentiation, cell cycle arrest, and apoptotic cell death (reviewed in Refs. 1-3). In all these events, the ceramide concentration, possibly at specific subcellular sites, is crucial. There is evidence that different activators such as cytokines, growth factors, and hormones elicit their biological effect by modulating the activity of sphingomyelinases, ceramide synthase, or neutral ceramidase (reviewed in Refs. 1 and 3-5) and thus affect ceramide levels.A role of ceramide as an intracellular mediator of specific extracellular agents has been recognized also in cells from the central nervous system (reviewed in Refs. 6 -8). In neuronal and glial cells, the administration of differentiating or apoptotic agents results in increased cellular levels of ceramide, which, in turn, participate in the cascade of events producing the final effects (9 -12). In a recent study (13), we demonstrated that ceramide plays a role in the growth control of glial cells by basic fibroblast growth factor (bFGF), 1 a factor stimul...

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“…It also was reported that the activity of GC synthase, which converts ceramide to GC, was more increased in apoptosis-resistant cells than in apoptosis-sensitive cells (12)(13)(14). The involvement of SM synthase in nuclear factor B activation of transformed fibroblast and basic fibroblast growth factor-induced proliferation of primary astrocytes was suggested recently, but the implication of SM synthase has yet to be clarified in Fas-induced apoptosis (15,16).…”

Section: Introductionmentioning

confidence: 99%

Increase of Nuclear Ceramide through Caspase-3-Dependent Regulation of the “Sphingomyelin Cycle” in Fas-Induced Apoptosis

Watanabe¹,

Kitano²,

Kondo³

et al. 2004

Cancer Research

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Regardless of the existence of ceramide-related molecules, such as sphingomyelin (SM), neutral sphingomyelinase (nSMase), and SM synthase, in the nucleus, the regulation of ceramide in the nucleus is poorly understood in stress-induced apoptosis. In Fas-induced Jurkat T-cell apoptosis, we found a time-and dose-dependent increase of ceramide content in the nuclear and microsomal fractions. Fas-induced increase of ceramide content in the nucleus also was detected by confocal microscopy using anticeramide antibody. Activation of nSMase and inhibition of SM synthase were evident in the nuclear fraction after Fas cross-linking, whereas nSMase was activated, but SM synthase was not affected, in the microsomal fraction. Pretreatment with D-609, a putative SM synthase inhibitor, enhanced Fas-induced increase of ceramide in the nucleus and induction of apoptosis along with increase of Fas-induced inhibition of nuclear SM synthase. Fas-induced activation of caspase-3 was detected in the nuclear fraction and in whole cell lysate. A caspase-3 inhibitor, acetyl-Asp-GluVal-Asp-chloromethyl ketone, blocked not only Fas-induced increases of apoptosis and ceramide content but also Fas-induced activation of nSMase and inhibition of SM synthase in the nuclear fraction. Taken together, it is suggested that the nucleus is a site for ceramide increase and caspase-3 activation in Fas-induced Jurkat T-cell apoptosis and that caspase-3-dependent regulation of the "SM cycle" consisting of nSMase and SM synthase plays a role in Fas-induced ceramide increase in the nucleus.

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Differential Effects of Sphingomyelin Hydrolysis and Resynthesis on the Activation of NF-κB in Normal and SV40-transformed Human Fibroblasts

Cited by 70 publications

References 31 publications

SMS overexpression and knockdown: impact on cellular sphingomyelin and diacylglycerol metabolism, and cell apoptosis

SMS overexpression and knockdown: impact on cellular sphingomyelin and diacylglycerol metabolism, and cell apoptosis

Basic Fibroblast Growth Factor-induced Proliferation of Primary Astrocytes

Increase of Nuclear Ceramide through Caspase-3-Dependent Regulation of the “Sphingomyelin Cycle” in Fas-Induced Apoptosis

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