Enhanced ceramide-induced apoptosis in ceramide kinase overexpressing cells

Gräf, Christine; Rovina, Philipp; Tauzin, Loïc; Schanzer, Andrea; Bornancin, Frédéric

doi:10.1016/j.bbrc.2006.12.208

Cited by 22 publications

(14 citation statements)

References 25 publications

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“…The latter findings are supported by recent work showing that downregulation of CERK in mammalian cells reduced growth, promoted apoptosis, and blocked epithelial growth factor (EGF)-induced cell proliferation (Mitra et al, 2007). However, contrary to these observations, Graf and co-workers reported that addition of the cell permeable C 2 -ceramide to cells over-expressing CERK led to C 2 -C1P formation and apoptosis (Graf et al, 2007). It should however be noted that in contrast to low concentrations of C1P, relatively high concentrations were toxic for fibroblasts or macrophages (Gomez-Munoz, 2006); obviously, over-expression of CERK would potently increase formation of intracellular C1P, particularly if cells were supplied with a high concentration of exogenous ceramide, resulting in cell toxicity.…”

Section: C1p Regulates Cell Growth and Deathmentioning

confidence: 78%

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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Section: C1p Regulates Cell Growth and Deathmentioning

confidence: 78%

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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“…In this regard, Högback et al ( 10 ) and Tornquist et al ( 11 ) showed that C 2 -C1P induced an increase in the intracellular Ca +2 levels in FRTL 5 cells and GH 4 C 1 rat pituitary cells. Using the same lipid, Graf et al ( 12 ) showed a correlation between apoptosis and enhanced C 2 -C1P formation upon C 2 -ceramide treatment of CERK overexpressing COS cells. C 2 , C 8 , and long chain C1P have also been demonstrated to cause 3 H thymidine incorporation into DNA ( 1, 2 ).…”

Section: Dispersion Of C1p In Etoh/dodecanementioning

confidence: 99%

Chain length specificity for activation of cPLA2α by C1P: use of the dodecane delivery system to determine lipid-specific effects

Wijesinghe

Subramanian

Lamour

et al. 2009

Journal of Lipid Research

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The fi rst report of a biological effect for ceramide-1-phosphate (C1P) was by , which demonstrated that short chain (not naturally found in cells) C1P induced DNA synthesis in Rat-1 fi broblasts. Later, treatment of T17 fi broblasts with long chain, natural C1P was also demonstrated to induce a potent increase in DNA synthesis ( 2 ) and the levels of proliferating nuclear antigen. Following this line of research, a recent report demonstrated that C1P prevented programmed cell death in bone marrow-derived macrophages after withdrawal of macrophage colony-stimulating factor ( 3 ). Treatment of these cells with C1P effectively blocked the activation of caspases and prevented DNA fragmentation upon serum removal.Abstract Previously, our laboratory demonstrated that ceramide-1-phosphate (C1P) specifi cally activated group IVA cytosolic phospholipase A 2 (cPLA 2 ␣ ) in vitro. In this study, we investigated the chain length specifi city of this interaction. C1P with an acyl-chain of ≥ 6 carbons effi ciently activated cPLA 2 ␣ in vitro, whereas C 2 -C1P, was unable to do so. Delivery of C1P to cells via the newly characterized ethanol/dodecane system demonstrated a lipid-specifi c activation of cPLA 2 ␣ , AA release, and PGE 2 synthesis (EC 50 = 400 nM) when compared to structurally similar lipids. C1P delivered as vesicles in water also induced a lipid-specifi c increase in AA release. Mass spectrometric analysis demonstrated that C1P delivered via ethanol/dodecane induced a 3-fold increase in endogenous C1P with little metabolism to ceramide. C1P was also more effi ciently delivered (>3-fold) to internal membranes by ethanol/dodecane as compared to vesiculated C1P. Using this now established delivery method for lipids, C 2 -C1P was shown to be ineffective in the induction of AA release as compared with C 6 -C1P, C 16 -C1P, and C 18:1 C1P. Here, we demonstrate that C1P requires ≥ 6 carbon acyl-chain to activate cPLA 2 ␣ . Thus, published reports on the biological activity of C 2 -C1P are not via eicosanoid synthesis. Furthermore, this study demonstrates that the alcohol/dodecane system can be used to effi ciently de-

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“…Early macular degeneration and cone and rod involvement are common outcomes of the two CERKL mutations identifi ed. Conversion of Cer by CerK to ceramide-1-phosphate (C1P), which has anti-apoptotic properties, is emerging as an important factor in the regulation of apoptosis (149)(150)(151). CerKL was initially expected to act as a second, specifi c retinal CerK; however, it does not phosphorylate Cer ( 152 ) and its deletion in mice affects neither Cer nor C1P levels in the retina, suggesting it might use a novel lipid substrate, which has proved elusive ( 153 ).…”

Section: Ceramide In the Retinamentioning

confidence: 99%

Regulating survival and development in the retina: key roles for simple sphingolipids

Rotstein

Miranda

Abrahan

et al. 2010

Journal of Lipid Research

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tions as structural membrane components and energetic fuels. However, the fi ndings of the previous half century have extended these roles, shedding light on their indisputable relevance as signaling molecules controlling key aspects of cellular life and development. The identifi cation of diacylglycerol and inositol 1,4,5 triphosphate ( 1 ) as second messengers seemed at the time a peculiarity of these lipids. The subsequent fi ndings of the roles of arachidonic acid metabolites ( 2 ), platelet activating factor ( 3 ), and other minor inositol lipids ( 4 ) in cell signaling began to establish that being intracellular messengers was not an oddity but a habitual task for lipids in cells. The family of lipid signaling molecules largely expanded in the last two decades, when several sphingolipids were successively shown to regulate a multiplicity of cell functions. Sphingosine (Sph) was the fi rst sphingolipid to be established as a bioactive lipid, involved in the regulation of protein kinase (PK)C activity ( 5 ). Ceramide (Cer) and sphingosine-1-phosphate (S1P) were next shown to signal a myriad of cell functions and the number of sphingolipid molecules with bioactive properties has gone on enlarging in recent years ( 6, 7 ).Though a vast literature exists on the functions of sphingolipids in several tissues, less is known concerning its roles in the eye, and in the retina in particular. Accumulation of sphingolipids originated in defects in the lysosomal Abstract Many sphingolipids have key functions in the regulation of crucial cellular processes. Ceramide (Cer) and sphingosine (Sph) induce growth arrest and cell death in multiple situations of cellular stress. On the contrary, sphingosine-1-phosphate (S1P), the product of Sph phosphorylation, promotes proliferation, differentiation, and survival in different cell systems. This review summarizes the roles of these simple sphingolipids in different tissues and then analyzes their possible functions in the retina. Alterations in proliferation, neovascularization, differentiation, and cell death are critical in major retina diseases and collective evidence points to a role for sphingolipids in these processes. Cer induces infl ammation and apoptosis in endothelial and retinal pigmented epithelium cells, leading to several retinopathies. S1P can prevent this death but also promotes cell proliferation that might lead to neovascularization and fibrosis. Recent data support Cer and Sph as crucial mediators in the induction of photoreceptor apoptosis in diverse models of oxidative damage and neurodegeneration, and suggest that regulating their metabolism can prevent this death. New evidence proposes a central role for S1P controlling photoreceptor survival and differentiation. Finally, this review discusses the ability of trophic factors to regulate sphingolipid metabolism and transactivate S1P signaling pathways to control survival and development in retina photoreceptors. When asked about the roles of cellular lipids, the fi rst thought usually coming to our minds re...

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Enhanced ceramide-induced apoptosis in ceramide kinase overexpressing cells

Cited by 22 publications

References 25 publications

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

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

Chain length specificity for activation of cPLA2α by C1P: use of the dodecane delivery system to determine lipid-specific effects

Regulating survival and development in the retina: key roles for simple sphingolipids

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