An update of the enzymology and regulation of sphingomyelin metabolism

Merrill, Alfred H.; Jones, Dean

doi:10.1016/0005-2760(90)90211-f

Cited by 433 publications

(202 citation statements)

References 175 publications

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“…In this study, we found for the first time that Jaspine B-induced inhibition of sphingomyelin synthesis likely contributes to the modification of SL pattern, including SM decrease and ceramide increase, and cell death induction. The biosynthesis of SM is catalyzed by SMS, an enzyme that transfers the phosphocholine moiety from phosphatidylcholine onto the primary hydroxyl group of ceramide generating SM and diacylglycerol [37]. There are two isoforms of mammalian SMS genes [19,38].…”

Section: Page 17 Of 43mentioning

confidence: 99%

The natural marine anhydrophytosphingosine, Jaspine B, induces apoptosis in melanoma cells by interfering with ceramide metabolism

Salma

Lafont

Therville

et al. 2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 AbstractMarine environment has frequently afforded a variety of biologically active compounds with strong anticancer and cytotoxic properties. In the present study, the mechanism of action of Jaspine B, an anhydrophytosphingosine derivative isolated from the marine sponge Jaspis sp., was investigated. Jaspine B was able to doseand time-dependently decrease the viability of murine B16 and human SK-Mel28 melanoma cells. On these cells, Jaspine B treatment triggered cell death by typical apoptosis as illustrated by phosphatidylserine externalization, the release of cytochrome c and caspase processing. These effects were associated with increased intracellular ceramide levels owing to perturbed ceramide metabolism. Indeed, Jaspine B exposure strongly inhibited the activity of sphingomyelin synthase (SMS), an enzyme that converts de novo ceramide into the membrane lipid sphingomyelin.Moreover, whereas Jaspine B-induced cell death was enhanced in SMS1-depleted cells, it was strongly inhibited in cells that stably overexpress human SMS1. Finally, the cytotoxic effects of Jaspine B truncated analogs were also shown to be dependent on SMS activity.Altogether, Jaspine B is able to kill melanoma cells by acting on SMS activity and consequently on ceramide formation, and may represent a new class of cytotoxic compounds with potential applications in anticancer melanoma therapy.

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Section: Page 17 Of 43mentioning

confidence: 99%

The natural marine anhydrophytosphingosine, Jaspine B, induces apoptosis in melanoma cells by interfering with ceramide metabolism

Salma

Lafont

Therville

et al. 2009

Biochemical Pharmacology

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Section: Introductionmentioning

confidence: 99%

“…In particular, ceramides induce cell cycle arrest and are potent inducers of apoptosis. Also, ceramides play crucial roles in the regulation of cell differentiation, and inflammation (Hannun et al, 1986;Hannun, 1994;Hannun and Obeid, 1995;Hannun, 1996;Hannun and Obeid, 2002;Kolesnick, 1994;Kolesnick, 1987;Kolesnick and Hemer, 1990;Kolesnick et al, 2000;Merrill and Jones, 1990;Merrill et al, 1997;Merrill, 2002;Spiegel and Merrill, 1996).Ceramides are generated either by de novo synthesis, or by the action of different sphingomyelinases (SMases), whose activities, enzymology, and compartmentalization have been thoroughly reviewed by others (Cremesti et al, 2002;Goni and Alonso, 2002;Kolesnick et al, 2000). A major metabolite of ceramide is ceramide-1-phosphate (C1P, Fig.…”

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confidence: 99%

Distinct receptor-mediated activities in macrophages for natural ceramide-1-phosphate (C1P) and for phospho-ceramide analogue-1 (PCERA-1)

Levi

Meijler

Gómez-Muñoz

et al. 2010

Molecular and Cellular Endocrinology

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. Distinct receptor-mediated activities in macrophages for natural ceramide-1-phosphate (C1P) and for phospho-ceramide analogue-1 (PCERA-1). Molecular and Cellular Endocrinology, Elsevier, 2009, 314 (2) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 Ceramide-1-phosphate (C1P) is known as a second messenger regulating a multitude of processes including cell growth, apoptosis and inflammation. Exciting recent findings now suggest that C1P can stimulate macrophages migration in an extra-cellular manner via a G protein-coupled receptor (GPCR). Interestingly, a synthetic C1P analog, named phospho-ceramide analogue-1 (PCERA-1), was recently described as a potent in-vivo anti-inflammatory agent, and was suggested to act on macrophages in an extra-cellular manner via a GPCR. Here we summarize and compare the receptor-mediated as well as receptor-independent activities of natural C1P and its synthetic analog. We also provide experimental data in support of distinct C1P and PCERA-1 receptors.Page 3 of 20A c c e p t e d M a n u s c r i p t 3 IntroductionIt is well-established that sphingolipids are crucial metabolites for controlling cell and tissue homeostasis. In particular, ceramides induce cell cycle arrest and are potent inducers of apoptosis. Also, ceramides play crucial roles in the regulation of cell differentiation, and inflammation (Hannun et al., 1986;Hannun, 1994;Hannun and Obeid, 1995;Hannun, 1996;Hannun and Obeid, 2002;Kolesnick, 1994;Kolesnick, 1987;Kolesnick and Hemer, 1990;Kolesnick et al., 2000;Merrill and Jones, 1990;Merrill et al., 1997;Merrill, 2002;Spiegel and Merrill, 1996).Ceramides are generated either by de novo synthesis, or by the action of different sphingomyelinases (SMases), whose activities, enzymology, and compartmentalization have been thoroughly reviewed by others (Cremesti et al., 2002;Goni and Alonso, 2002;Kolesnick et al., 2000). A major metabolite of ceramide is ceramide-1-phosphate (C1P, Fig. 1), which is generated through direct phosphorylation of ceramide by ceramide kinase (CERK) (Bajjalieh et al., 1989;Kolesnick and Hemer, 1990). This enzyme was first shown to be confined to the microsomal fraction, but its location in the cytosol has also been reported (Mitsutake et al., 2004). Recently, Chalfant and co-workers demonstrated that CERK utilizes ceramide transported to the trans-Golgi apparatus by the ceramide transport protein (CERT). Of note, down-regulation of CERT by RNA interference resulted in strong inhibition of newly synthesized C1P, suggesting that CERT plays a critical role in C1P formation . However, this observation contrasts with that of Bornancin and...

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“…These lipids have also been shown to be important for the understanding of a number of biological processes such as cell growth, differentiation, stress and apoptosis (Hannun and Bell, 1989;Hannun, 1996;Kolesnick and Kronke, 1998). Several studies have shown that the action of a number of agonists leads to the activation of sphingomyelinases, and sphingomyelin hydrolysis leads to ceramide generation (Merrill and Jones, 1990;Zhang et al, 1997). It has been reported that once generated, ceramide acts through a ceramide-activated protein phosphatase 2A (CAPP) to elicit some of its downstream effects (Dobrowsky and Hannun, 1992;Galadari et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Effects of cations on ceramide-activated protein phosphatase 2A

Galadari

Hago²,

Patel³

2001

Exp Mol Med

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Characterization of ceramide-effector(s), which includes protein phosphatase 2A (PP2A) is an important prelude to understanding the molecular basis of sphingolipid-mediated biological effects such as cell growth, differentiation and apoptosis. Recently, the existence of a metal-dependent form of PP2A has been reported (Cai et al., 1995). In this study, we investigated the effects of metal ions and chelators on ceramide-activated PP2A (CAPP). Our study demonstrates that at 0.5 mM concentration, Mg 2+ appears to have no significant effect on either basal or ceramide-stimulated phosphatase activities, whereas Ca 2+ stimulated the basal phosphatase activity, but was inhibitory towards CAPP. Moreover, the divalent cations Cr 2+ , Mn 2+ , Fe 2+ , Ni 2+ , Cu 2+ and Zn 2+ were tested and all were found to be inhibitory towards both CAPP and basal phosphatase activities. By contrast, Cs + and Li + had almost no effect on CAPP, although both stimulated basal phosphatase activity. The effects of EDTA and EGTA were tested and it was observed that EDTA decreased CAPP activity in a dose-dependent fashion, but had no effect upon basal phosphatase activity. These results suggest that CAPP is a metal-dependent protein, but, because Ca 2+ inhibitied CAPP and EGTA was much less potent than EDTA in inhibiting CAPP, Ca 2+ is unlikely to be its metal cofactor.

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An update of the enzymology and regulation of sphingomyelin metabolism

Cited by 433 publications

References 175 publications

The natural marine anhydrophytosphingosine, Jaspine B, induces apoptosis in melanoma cells by interfering with ceramide metabolism

The natural marine anhydrophytosphingosine, Jaspine B, induces apoptosis in melanoma cells by interfering with ceramide metabolism

Distinct receptor-mediated activities in macrophages for natural ceramide-1-phosphate (C1P) and for phospho-ceramide analogue-1 (PCERA-1)

Effects of cations on ceramide-activated protein phosphatase 2A

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