Activation of Acid Sphingomyelinase by Protein Kinase Cδ-mediated Phosphorylation

Zeidan, Youssef H.; Hannun, Yusuf A.

doi:10.1074/jbc.m609424200

Cited by 128 publications

(151 citation statements)

References 56 publications

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“…However, it has been recently shown that generation of reactive oxygen species an important step for aSMase activation in cells (Dumitru and Gulbins 2006;Charruyer et al 2005).The aSMase could be activated by the protein kinase Cδ (PKCδ), which is overexpressed under oxidative stress (Zeidan and Hannun 2007) and a premature aging disorderWerner syndrome (Massip et al 2010). Based on these results, reasonable assumption can be made that α-tocopherol prevents ceramide accumulation in the liver of old rats, at least in part, via the glutathionedependent nSMase and PKCδ-dependent aSMase inhibition.…”

Section: Discussionmentioning

confidence: 99%

Vitamin E prevents the age-dependent and palmitate-induced disturbances of sphingolipid turnover in liver cells

Babenko

Hassouneh

Kharchenko

et al. 2011

AGE

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Sphingolipid turnover has been shown to be activated at old age and in response to various stress stimuli including oxidative stress. Reduction of vitamin E content in the liver under the pro-oxidant action is associated with enhanced sphingolipid turnover and ceramide accumulation in hepatocytes. In the present paper, the correction of sphingolipid metabolism in the liver cells of old rats and in the palmitate-treated young hepatocytes using α-tocopherol has been investigated. 3-and 24-month-old rats, [ 14 C] palmitic acid, [methyl− 14 C-choline]sphingomyelin (SM), and [ 14 C]serine were used. α-Tocopherol administration to old rats or addition to the culture medium of old liver slices or hepatocytes prevented age-dependent increase of ceramide synthesis and lipid accumulation, and increased SM content in liver tissue and cells. α-Tocopherol treatment of old cells decreased the neutral and acid sphingomyelinase (SMase) activities in hepatocytes and serine palmitoyl transferase activity in the liver cell microsomes. Effect of α-or γ-tocopherol, but not of δ-tocopherol, on the newly synthesized ceramide content in old cells was correlated with the action of inhibitor of serine palmitoyl transferase (SPT) activity (myriocin) and SMase inhibitors (glutathione, imipramine). Addition of α-tocopherol as well as myriocin to the culture medium of young hepatocytes, treated by palmitate, abolished ceramide accumulation and synthesis. The data obtained demonstrate that α-tocopherol normalized elevated ceramide content in the old liver cells via inhibition of acid and neutral SMase activities and lipid synthesis de novo. α-Tocopherol, reducing ceramide synthesis, prevented palmitate-induced aging-like ceramide accumulation in young liver cells.

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Section: Discussionmentioning

confidence: 99%

Vitamin E prevents the age-dependent and palmitate-induced disturbances of sphingolipid turnover in liver cells

Babenko

Hassouneh

Kharchenko

et al. 2011

AGE

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“…Additional studies have implicated acid SMase in the generation of ceramide following PKC activation in MCF-7 cells, such that RNAi directed against acid SMase prevented phorbol esterinduced sphingomyelin hydrolysis and caused a significant reduction in the accumulating ceramide [72]. In light of previous studies demonstrating that lysosomal sphingomyelin degradation results in generation of sphingosine which is salvaged for ceramide synthesis [42], acid SMase appears to be a key component in PKC-dependent ceramide synthesis through the salvage pathway.…”

Section: Regulation Of the Salvage Pathway 4-1 The Salvage Pathway Amentioning

confidence: 95%

“…Studies conducted to determine which PKC isoform is involved in ceramide accumulation showed that specific pharmacologic inhibition or knock-down of the PKCδ isoform completely attenuated ceramide formation following phorbol ester treatment [72]. Additional studies showed that PKCδ activates acid SMase, in a process involving phosphorylation of acid SMase.…”

Section: Regulation Of the Salvage Pathway 4-1 The Salvage Pathway Amentioning

confidence: 99%

The sphingolipid salvage pathway in ceramide metabolism and signaling

Kitatani

Idkowiak‐Baldys

Hannun

2008

Cellular Signalling

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539

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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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“…Moreover, activation of ASM, leading to ceramide accumulation, has been linked to PKC␦ activity (9). Due to the interplay between PKC signaling and sphingolipids, it was of interest to define the roles of classical and novel PKCs in the context of IL-6 production.…”

Section: Differential Regulation Of Il-6 Production and P38mentioning

confidence: 99%

Defining a Role for Acid Sphingomyelinase in the p38/Interleukin-6 Pathway

Perry

Newcomb²,

Adada³

et al. 2014

Journal of Biological Chemistry

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Background: Sphingolipids are important in multiple biological processes, but there is a lack of understanding of the pathways that mediate these effects. Results: Acid sphingomyelinase is involved in p38 activation, interleukin-6 production, and cancer cell invasion. Conclusion: Acid sphingomyelinase plays a role in inflammatory, proinvasive signaling in cancer cells. Significance: This work expands the understanding of acid sphingomyelinase signaling and downstream biology.

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Activation of Acid Sphingomyelinase by Protein Kinase Cδ-mediated Phosphorylation

Cited by 128 publications

References 56 publications

Vitamin E prevents the age-dependent and palmitate-induced disturbances of sphingolipid turnover in liver cells

Vitamin E prevents the age-dependent and palmitate-induced disturbances of sphingolipid turnover in liver cells

The sphingolipid salvage pathway in ceramide metabolism and signaling

Defining a Role for Acid Sphingomyelinase in the p38/Interleukin-6 Pathway

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