Download preview PDF. Skip to main content. This service is more advanced with JavaScript available. Advertisement Hide. This is a preview of subscription content, log in to check access. Cell , 86 , — J Biol Chem , , — Biochem Soc Trans , 32 , — Drugs Exp Clin Res , 29 , 5— PubMed Google Scholar.
Free Radic Biol Med , 37 , — Mol Pharmacol , 63 , — Faseb J , 15 , — Chatterjee S Neutral sphingomyelinase: past, present and future. Chem Phys Lipids , , 79— Genomics , 9 , — Eur J Biochem , , — Antioxid Redox Signal , 2 , — Cancer Res , 64 , — FEBS Lett , , 38— Gulbins E, Grassme H Ceramide and cell death receptor clustering. While ceramide stimulates signal transduction pathways that are associated with cell death or at least are inhibitory to cell growth eg stress-activated protein kinase, SAPK, pathways , DAG activates the classical and novel isoforms of the protein kinase C PKC family.
These PKC isoforms are associated with cell growth and cell survival. Thus, ceramide and DAG generation may serve to monitor cellular homeostasis by inducing pro-death or pro-growth pathways, respectively. The production of ceramide is emerging as a fixture of programmed cell death. Consistent with this notion, ceramide itself is a potent apoptogenic agent. Ceramide activates stress-activated protein kinases like c-jun N-terminal kinase JNK and thus affects transcription pathways involving c-jun.
Ceramide activates protein phosphatases such as protein phosphatase 1 PP1 and protein phosphatase 2 PP2A. A new role has recently emerged for ceramide in the regulation of protein synthesis. Ceramide-induced activation of double-stranded RNA-dependent protein kinase PKR , a protein kinase important in anti-viral host defense mechanisms and recently implicated in cellular stress pathways, results in the inhibition of protein synthesis as a prelude to cell death.
Taken together, these properties of ceramide suggest that this important second-signal molecule may have useful properties as an anti-neoplastic agent. Thus, strategies to promote ceramide metabolism or use of ceramide analogs directly may one day become useful in the treatment of diseases like leukemia.
Ceramide is a naturally occurring sphingolipid that is a key component in the sphingomyelin cycle. During growth conditions, ceramide and phosphatidylcholine are converted to sphingomyelin by sphingomyelin synthase. In contrast, stress stimuli promote the breakdown of sphingomyelin by phospholipases known as sphingomyelinases SMase and ceramide is produced.
Like DAG, ceramide has emerged as an important second messenger molecule, except that ceramide-mediated signaling usually involves stress pathways. Since each effector is able to transmodulate the signaling pathways regulated by the other, it is possible that net expression of DAG vs ceramide may create a sort of cellular rheostat.
This review will focus on ceramide as a stress second signal molecule and the stress signaling pathway this important sphingolipid regulates including a novel pathway that regulates protein synthesis. Ceramide activates both protein kinases and protein phosphatases. Since a number of different substrates are involved, ceramide is a potent effector molecule. Considerable interest has developed in ceramide metabolism over the past few years.
Ceramide is actually a family of highly hydrophobic molecules that contain a variable length fatty acid containing 2 to 28 carbons linked to sphingosine or a related long chain base.
Ceramide is an important intermediate in sphingomyelin biosynthesis. Ceramide can be generated 1 as a byproduct of sphingomyelin hydrolysis, 2 via de novo pathways involving ceramide synthase, or 3 by the breakdown of complex glycosphingolipids. Cellular generation of ceramide appears to involve some level of topological control since the various metabolic enzymes involved appear to have preferred sub-cellular compartments.
The sphingomyelin pathway for ceramide generation demonstrates the versatility of effector responses that can be generated by ceramide. In fact, divergent responses from a single receptor may be generated depending on whether neutral SMase or acidic SMase is involved. The influences of other effectors that oppose or support ceramide-regulated signal pathways also seem to be important in the regulation of the SMase pathway. The effect of DAG, a molecule that antagonizes ceramide's actions and is oppositely regulated from ceramide in the sphingomyelin cycle, is discussed above.
Another molecule that can apparently antagonize ceramide-mediated signaling is glutathione. It has recently been discovered that neutral SMase is inhibited by glutathione. Like DAG, effectors that antagonize ceramide action are sometimes byproducts of ceramide metabolism.
Deacylation of ceramide by ceramidases yields sphingosine. A number of ceramidases have been identified in various subcellular locations including lysosomes and membranes. Ceramide promotes Jun phosphorylation while sphingosine does not. Likewise, modifications of ceramide also alter effector activity.
Phosphorylation of ceramide results in a molecule that supports growth. Glycosylation of ceramide inactivates the molecule's negative growth effects and thus glycosylation may serve as a mechanism for the cell to tolerate excess ceramide levels. The mechanism by which ceramide activates JNK is not yet clear.
For instance, AP-1 appears to be required in ceramide-induced apoptosis in human leukemia HL cells and U cells. One candidate that has emerged is cyclooxygenase-2 Cox2 85 , However, while over-expression of Cox2 has been shown to impede cell cycle progression, 87 Cox2 inhibits apoptosis.
This novel ceramide regulatory mechanism will be discussed in greater detail later. PP2A has also been implicated in Akt inactivation 35 , 36 Thus the regulation of Bad pro-apoptotic function appears to involve both protein phosphatases and protein kinases. It is known, however, that protein phosphatases play a critical role in ceramide-mediated processes.
Ceramide has been shown to promote dephosphorylation of Rb in association with growth arrest. Since ceramide can be produced by multiple mechanisms in different subcellular compartments, ceramide has the potential to regulate diverse signal transduction pathways. In addition, since there is a fair level of interaction between the various ceramide metabolic pathways and pathways regulated by effectors that transmodulate ceramide action, downstream effects in response to stress will be complex and varied.
In effect, the dominance of a particular pathway eg ceramide-mediated anti-growth signaling vs DAG-mediated pro-growth signaling in a cell will probably determine the outcome of how that cell responds to the stress challenge. Recent studies focusing on de novo synthesis of ceramide in the mitochondria have found that carnitine palmitoyltransferase I CPT I may have a role in ceramide-mediated apoptosis.
The complexity of regulation at the level of just one cellular regulatory molecule becomes clear in the example of ceramide's effects on Bcl2 Figure 2. In addition, the levels of ceramide produced in the mitochondria vs competing levels of antagonistic effectors eg DAG would influence the function of these proteins at this subcellular location.
Model of how ceramide may regulate apoptosis in the mitochondria. Bcl2 heterodimerizes with and inactivates Bax. Bax is free and promotes cytochrome C cyto C release from the pore complex prior to cell death. It is more than likely that other mechanisms involving regulators of mitochondrial integrity will be affected by alterations in ceramide metabolism. The regulation of apoptosis by signal transduction pathways is complex. Meanwhile, other important regulatory proteins localized in the membranes of other organelles and in the plasma membrane would undergo similar regulation.
Taken as a whole, the capacity of a cell to survive stress stimuli will probably come down to how well the cell's survival signaling pathways can weather a challenge by ceramide. It is logical that inhibition of protein synthesis may precede apoptosis in cells that are challenged by stress responses.
Recently, the inhibition of protein synthesis has been shown to be a prelude to cell death following growth factor withdrawal in ILdependent murine myeloid cells by a mechanism involving the double-stranded RNA-activated protein kinase, PKR. It is clear that ceramide regulates diverse stress signaling pathways that determine the cell's fate in response to stress stimuli Figure 3.
Therefore, defects in ceramide metabolism could potentially affect the cellular response to chemotherapy or other anti-cancer regimens by rendering the cells more resistant to cell killing, and as has been suggested, could contribute to multi-drug resistance. In the case of adriamycin-resistant cells, ceramide is converted to a non-toxic form ie glucosylceramide by glucosylceramide synthase GCS Ceramide regulates diverse cellular processes.
Ceramide regulates diverse stress signaling pathways by affecting transcription through Jun , translation through RAX , and the apoptotic machinery through Bcl2 and Bad.
In addition, ceramide promotes inactivation of pro-growth signaling pathways mediated by PKC and Akt. While defects in ceramide metabolism may be detrimental to patients with diseases such as leukemia, manipulation of ceramide metabolism in patients to promote ceramide production may be of use in remission-induction chemotherapy regimens. Common components of cancer treatment strategy regimens such as chemotherapeutic drug treatment and irradiation promote ceramide production.
Novel strategies to deliver ceramide directly to malignant cells have yet to be exploited. Currently, strategies being used to target ceramide metabolism focus on GCS activity. Hannun YA. The sphingomyelin cycle and the second messenger function of ceramide J Biol Chem : — CAS Google Scholar.
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Sphingomyelin SM and its metabolic products are now known to have second messenger functions in a variety of cellular signaling pathways. Particularly, the sphingolipid metabolites, ceramide Cer and sphingosinephosphate S1P , have emerged as a new class of potent bioactive molecules.
Ceramide can be generated de novo or by hydrolysis of membrane sphingomyelin by sphingomyelinase SMase.
Ceramide is subsequently metabolized by ceramidase to generate sphingosine Sph which in turn produces S1P through phosphorylation by sphingosine kinases 1 and 2 SphK1, 2. Both ceramide and S1P regulate cellular responses to stress, with generally opposing effects.
S1P functions as a growth and survival factor, acting as a ligand for a family of G protein-coupled receptors, whereas ceramide activates intrinsic and extrinsic apoptotic pathways through receptor-independent mechanisms. PMID: Principles of bioactive lipid signalling: lessons from sphingolipids.
A house divided: ceramide, sphingosine, and sphingosinephosphate in programmed cell death. A review of ceramide analogs as potential anticancer agents. Sphingosinephosphate regulation of mammalian development.
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