When Do Lasses (Longevity Assurance Genes) Become CerS (Ceramide Synthases)?

Pewzner-Jung, Yael; Ben‐Dor, Shifra; Futerman, Anthony H.

doi:10.1074/jbc.r600010200

Cited by 406 publications

(373 citation statements)

References 55 publications

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“…The activities for acylation of long chain bases (both dihydrosphingosine and sphingosine) have been found to reside in microsomes. In mammals, six genes that encode (dihydro)ceramide synthase have been recently cloned and termed longevity-assurance homologues (LASSs: LASS1-6)/ceramide synthases (CerSs; CerS1-6) [30][31][32][33]. Biochemically, individual ceramide synthase isoforms show substrate preference for specific chain length fatty acyl CoAs, thus generating distinct ceramides with distinct acyl-chain lengths.…”

Section: -1 Sphingolipid Biosynthesismentioning

confidence: 99%

The sphingolipid salvage pathway in ceramide metabolism and signaling

Kitatani

Idkowiak‐Baldys

Hannun

2008

Cellular Signalling

517

436

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Sphingolipids are important components of eukaryotic cells, many of which function as bioactive signaling molecules. Of these, ceramide is a central metabolite and plays key roles in a variety of cellular responses, including regulation of cell growth, viability, differentiation, and senescence. Ceramide is composed of the long-chain sphingoid base, sphingosine, in N-linkage to a variety of acyl groups. Sphingosine serves as the product of sphingolipid catabolism, and it is mostly salvaged through re-acylation, resulting in the generation of ceramide or its derivatives. This recycling of sphingosine is termed the "salvage pathway", and recent evidence points to important roles for this pathway in ceramide metabolism and function. A number of enzymes are involved in the salvage pathway, and these include sphingomyelinases, cerebrosidases, ceramidases, and ceramide synthases. Recent studies suggest that the salvage pathway is not only subject to regulation, but it also modulates the formation of ceramide and subsequent ceramide-dependent cellular signals. This review focuses on the salvage pathway in ceramide metabolism, its regulation, its experimental analysis, and emerging biological functions.

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Section: -1 Sphingolipid Biosynthesismentioning

confidence: 99%

The sphingolipid salvage pathway in ceramide metabolism and signaling

Kitatani

Idkowiak‐Baldys

Hannun

2008

Cellular Signalling

517

436

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“…The acylation of sphinganine (dihydrosphingosine) by ceramide synthases (CerSs) is required to form dihydroceramide, which is subsequently converted to ceramide. Six CerS isoforms are present in mammalian cells, each with its own fatty acyl-CoA preference (33). Thus, specific CerS isoforms are responsible for the generation of ceramides of specific chain lengths.…”

Section: Bak Is Necessary For Generation Of Long-chain Ceramides-mentioning

confidence: 99%

The BCL-2 Protein BAK Is Required for Long-chain Ceramide Generation during Apoptosis

Siskind

Mullen

Rosales

et al. 2010

Journal of Biological Chemistry

113

102

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The BCL-2 family members BAK and BAX are required for apoptosis and trigger mitochondrial outer membrane permeabilization (MOMP). Here we identify a MOMP-independent function of BAK as a required factor for long-chain ceramide production in response to pro-apoptotic stress. UV-C irradiation of wild-type (WT) cells increased long-chain ceramides; blocking ceramide generation prevented caspase activation and cell death, demonstrating that long-chain ceramides play a key role in UV-C-induced apoptosis. In contrast, UV-C irradiation did not increase long-chain ceramides in BAK and BAX double knock-out cells. Notably, this was not specific to the cell type (baby mouse kidney cells, hematopoietic) nor the apoptotic stimulus employed (UV-C, cisplatin, and growth factor withdrawal). Importantly, long-chain ceramide generation was dependent on the presence of BAK, but not BAX. However, ceramide generation was independent of the known downstream actions of BAK in apoptosis (MOMP or caspase activation), suggesting a novel role for BAK in apoptosis. Finally, enzymatic assays identified ceramide synthase as the mechanism by which BAK regulates ceramide metabolism. There was no change in CerS expression at the message or protein level, indicating regulation at the post-translational level. Moreover, CerS activity in BAK KO microsomes can be reactivated upon addition of BAKcontaining microsomes. The data presented indicate that ceramide-induced apoptosis is dependent upon BAK and identify a novel role for BAK during apoptosis. By establishing a unique role for BAK in long-chain ceramide metabolism, these studies further demonstrate that the seemingly redundant proteins BAK and BAX have distinct mechanisms of action during apoptosis induction.Programmed cell death (apoptosis) is a complex, multistep process essential for normal tissue homeostasis and development. A key event in apoptotic signaling is mitochondrial outer membrane permeabilization (MOMP), 3 whereby pro-apoptotic factors are released from the mitochondrial intermembrane space into the cytosol resulting in the activation of caspases and triggering the execution phase of apoptosis. Multiple cell death pathways converge on MOMP, and it is considered a necessary step for the commitment of cells to apoptosis. Anti-apoptotic BCL-2 proteins like BCL-2 and BCL-X L can block MOMP and cell death when overexpressed. On the other hand, the proapoptotic BCL-2 proteins BAK and BAX are necessary for MOMP in response to a wide variety of death-inducing signals. In fact, cells lacking both BAK and BAX are highly resistant to apoptotic stimuli (1-4).Sphingolipids have been extensively implicated in the apoptotic response. Ceramide, a central molecule of sphingolipid metabolism, has been shown to be involved in programmed cell death through several lines of evidence. First, cellular levels of ceramide are elevated by a variety of apoptotic stimuli. Second, blocking ceramide generation delays or abrogates cell death in response to many different signals (5-9). Moreover, cancer cells ...

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“…Ceramides are synthesized either de novo by ceramide synthase genes (CerS1-6) or by breakdown of sphingomyelin by sphingomyelinase enzyme [19]. Different length of ceramides were synthesized by different CerS genes [20]. While CerS1 is responsible for synthesis of C18-ceramide [21], CerS2 and CerS4 increase the levels of C24-ceramides and C22-ceramides, respectively [22,23].…”

Section: Introductionmentioning

confidence: 99%

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

et al. 2011

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Sphingolipids are bioeffector molecules that control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramides, the central molecule of sphingolipid metabolism, are inducer of apoptosis and inhibitors of proliferation. Sphingosine-1-phosphate (S1P) and glucosyleceramide, converted from ceramides by sphingosine kinase-1 (SK-1) and glucosyleceramide synthase (GCS) enzymes, respectively, inhibit apoptosis and develop resistance to chemotherapeutic drugs. In this study, we examined the therapeutic potentials of bioactive sphingolipids in chronic myeloid leukemia (CML) alone and in combination with dasatinib in addition to investigate the roles of ceramide-metabolizing genes in dasatinib-induced apoptosis. Cytotoxic effects of dasatinib, C8:ceramide, PDMP, and SK-1 inhibitor were determined by XTT cell proliferation assay. Changes in caspase-3 enzyme activity and mitochondrial membrane potential (MMP) were measured using caspase-3 colorimetric assay and JC-1 MMP detection kit. Expression levels of ceramide-metabolizing genes were examined by qRT-PCR. Application of ceramide analogs and inhibitors of ceramide clearance genes decreased cell proliferation and induced apoptosis. Targeting bioactive sphingolipids towards generation/accumulation of ceramides increased apoptotic effects of dasatinib, synergistically. It was shown for the first time that dasatinib induces apoptosis through downregulating expression levels of antiapoptotic SK-1 but not GCS, and upregulating expression levels of ceramide synthase (CerS) genes, especially CerS1, in K562 cells. On the other hand, dasatinib downregulates expression levels of both GCS and SK-1 and upregulate apoptotic CerS2, −5 and −6 genes in Meg-01 cells. Increasing endogenous ceramide levels and decreasing prosurvival lipids, S1P, and GC, can open the way of more effective treatment of CML.

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When Do Lasses (Longevity Assurance Genes) Become CerS (Ceramide Synthases)?

Cited by 406 publications

References 55 publications

The sphingolipid salvage pathway in ceramide metabolism and signaling

The sphingolipid salvage pathway in ceramide metabolism and signaling

The BCL-2 Protein BAK Is Required for Long-chain Ceramide Generation during Apoptosis

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

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