Hypoxia-induced neuronal apoptosis is mediated by de novo synthesis of ceramide through activation of serine palmitoyltransferase

Kang, Mi Sun; Ahn, Kyong Hoon; Kim, Seok Kyun; Jeon, Hyung Jun; Ji, Jung Eun; Choi, Jong Min; Jung, Kwang-Mook; Jung, Sung Yun; Kim, Dae Kyong

doi:10.1016/j.cellsig.2009.11.015

Cited by 34 publications

(27 citation statements)

References 65 publications

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“…Cer then serves as the metabolic and structural precursor for complex sphingolipids, which are composed of hydrophilic head groups, such as sphingomyelin (SM), Cer-1-phosphate and glucosylceramide (GlcCer), which is the precursor for glycolipids and gangliosides[65]. Endogenous Cer can be generated via a de novo pathway, which begins with condensation of serine and palmitoyl CoA by serine-palmitoyl CoA transferase (SPT)[68,69]. Cer can be also generated by the metabolism of other complex sphingolipids, which is tightly regulated by many specialized enzymes[65,66,70].…”

Section: Regulation Of Autophagy By Cermentioning

confidence: 99%

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Autophagy paradox and ceramide

Jiang

Öğretmen

2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Sphingolipid molecules act as bioactive lipid messengers and exert their actions on the regulation of various cellular signaling pathways. Sphingolipids play essential roles in numerous cellular functions, including controlling cell inflammation, proliferation, death, migration, senescence, tumor metastasis and/or autophagy. Dysregulated sphingolipid metabolism has been also implicated in many human cancers. Macroatuophagy (referred to here as autophagy) “self-eating”, is characterized by nonselective sequestering of cytosolic materials by an isolation membrane, which can be either protective or lethal for cells. Ceramide (Cer), a central molecule of sphingolipid metabolism, has been extensively implicated in the control of autophagy. The increasing evidence suggests Cer is highly involved in mediating two opposing autophagic pathways, which regulate either cell survival or death, autophagy paradox. However, the underlying mechanism that regulates the autophagy paradox remains unclear. Therefore, this review focuses on recent studies with regard to the regulation of autophagy by Cer and elucidate the roles and mechanisms of action of Cer in controlling autophagy paradox.

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Section: Regulation Of Autophagy By Cermentioning

confidence: 99%

“…CerS and SPT primarily function to generate Cer de novo[69,84]. CerS was originally identified as the yeast longevity assurance gene 1 (LAG1), known to regulate life-span/longevity in Saccharomyces cerevisiae , and its deletion prolonged the replicative life-span of yeast[85,86].…”

Section: Regulation Of Autophagy By Cermentioning

confidence: 99%

Autophagy paradox and ceramide

Jiang

Öğretmen

2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…Each of these pathways involves a number of specialized enzymes [2]. In addition to the activation of sphingomyelinases (SMases) [5–7], which hydrolyze SM to yield ceramide, endogenous ceramide can be generated via the de novo pathway [8,9] after condensation of serine and palmitoyl CoA by serine-palmitoyl CoA transferase (SPT) [10,11], leading to the synthesis of dihydroceramide by dihydroceramide synthases (CerS) [3]. Dihydroceramide is then converted to ceramide by desaturase (DES), which inserts the double bond between carbons 4 and 5 in the sphingosine backbone [12,13].…”

Section: Structure and Metabolism Of Ceramidementioning

confidence: 99%

“…Ceramide generation by the function of SPT [11] and/or CerS [23] was implicated in inducing apoptosis in various cancer cell types. CerS, identified as the yeast longevity assurance gene 1 ( LAG1 ), is known to regulate lifespan/longevity in Saccharomyces cerevisiae , and its deletion prolongs the replicative lifespan of yeast [24,25].…”

Section: Cers and De Novo Generation Of Ceramidementioning

confidence: 99%

Sphingolipids and Cancer: Ceramide and Sphingosine-1-Phosphate in the Regulation of Cell Death and Drug Resistance

et al. 2010

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Sphingolipids have emerged as bioeffector molecules, controlling various aspects of cell growth and proliferation in cancer, which is becoming the deadliest disease in the world. These lipid molecules have also been implicated in the mechanism of action of cancer chemotherapeutics. Ceramide, the central molecule of sphingolipid metabolism, generally mediates antiproliferative responses, such as cell growth inhibition, apoptosis induction, senescence modulation, endoplasmic reticulum stress responses and/or autophagy. Interestingly, recent studies suggest de novo-generated ceramides may have distinct and opposing roles in the promotion/suppression of tumors, and that these activities are based on their fatty acid chain lengths, subcellular localization and/or direct downstream targets. For example, in head and neck cancer cells, ceramide synthase 6/C 16 -ceramide addiction was revealed, and this was associated with increased tumor growth, whereas downregulation of its synthesis resulted in ER stress-induced apoptosis. By contrast, ceramide synthase 1-generated C 18 -ceramide has been shown to suppress tumor growth in various cancer models, both in situ and in vivo. In addition, ceramide metabolism to generate sphingosine-1-phosphate (S1P) by sphingosine kinases 1 and 2 mediates, with or without the involvement of G-protein-coupled S1P receptor signaling, prosurvival, angiogenesis, metastasis and/or resistance to drug-induced apoptosis. Importantly, recent findings regarding the mechanisms by which sphingolipid metabolism and signaling regulate tumor growth and progression, such as identifying direct intracellular protein targets of sphingolipids, have been key for the development of new chemotherapeutic strategies. Thus, in this article, we will present conclusions of recent studies that describe opposing roles of de novo-generated ceramides by ceramide synthases and/or S1P in the regulation of cancer pathogenesis, as well as the development of sphingolipid-based cancer therapeutics and drug resistance. † Author for correspondence: 86 Jonathan Lucas Street, Room 512A, Charleston, SC, 29425, USA, Tel.: +1 843 792 0941, Fax: +1 843 792 2556, ogretmen@musc.edu. For reprint orders, please contact: reprints@futuremedicine.com Financial & competing interests disclosureThis work was supported by research grants (CA088932, DE016572 and CA097132) from the NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. NIH Public Access Structure & metabolism of ceramideSphingolipids are structural components of biological membranes that were first described by Thudichum, and the chemical structures of various sphingolipid molecules, including sphingosine and ceramide, were later resolved by Carter [1]. The term 'sphingosine' originates from a Greek word, ...

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“…The rate-limiting step in the de novo synthesis of ceramide is known to be at the level of the enzyme serine palmitoyltransferase (SPT) (Perry et al, 2000). Hypoxia is reported to increase the SPT enzyme activity (Kang et al, 2010), thus shifting the rate-limiting step to the enzyme DHC-DS under hypoxic conditions. This is illustrated in neuronal ceroid lipofuscinosis, specifically the CLN9 type.…”

Section: Introductionmentioning

confidence: 99%

Regulation ofDe NovoCeramide Synthesis: The Role of Dihydroceramide Desaturase and Transcriptional Factors NFATC and Hand2 in the Hypoxic Mouse Heart

Azzam

Hariri

El-Hachem

et al. 2013

DNA and Cell Biology

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We have previously shown that ceramide, a proapoptotic molecule decreases in the mouse heart as it adapts to hypoxia. We have also shown that its precursor, dihydroceramide, accumulates with hypoxia. This implicates the enzyme dihydroceramide desaturase (DHC-DS), which converts dihydroceramide to ceramide, in a potential regulatory checkpoint in cardiomyocytes. We hypothesised that the regulation of de novo ceramide synthesis plays an important role in the cardiomyocyte adaptation to hypoxia. We used an established mouse model to induce acute and chronic hypoxia. Cardiac tissues were extracted and quantitative real-time polymerase chain reaction (qRT-PCR) was used to evaluate the expression levels of DHC-DS. Electrophoretic Mobility Shift Assays (EMSAs) and qRT-PCR were used to evaluate the activity and expression levels of an array of transcription factors that might regulate DEGS1 gene expression. We demonstrated that DEGS1 mRNA levels decrease with time in hypoxic mice concurrent with the decrease in HAND2 transcripts. Interestingly, the DEGS1 promoter harbors overlapping sites for Hand2 and Nuclear Factor of Activated T-cells (NFATC) transcription factors. We have demonstrated a physical interaction between NFATC1 and the E-Box proteins with EMSA and coimmunoprecipitation assays. The regulation of de novo ceramide synthesis in response to hypoxia and this newly described interaction between E-box and NFATC transcription factors will pave the way to identify new pathways in the adaptation of the cardiomyocyte to stress. The elucidation of these pathways will in the longterm provide insights into potential targets for novel therapeutic regimens.

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Hypoxia-induced neuronal apoptosis is mediated by de novo synthesis of ceramide through activation of serine palmitoyltransferase

Cited by 34 publications

References 65 publications

Autophagy paradox and ceramide

Autophagy paradox and ceramide

Sphingolipids and Cancer: Ceramide and Sphingosine-1-Phosphate in the Regulation of Cell Death and Drug Resistance

Regulation ofDe NovoCeramide Synthesis: The Role of Dihydroceramide Desaturase and Transcriptional Factors NFATC and Hand2 in the Hypoxic Mouse Heart

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