Ceramide and the Regulation of Apoptosis and the Stress Response

doi:10.1016/1050-1738(96)00044-8

Trends in Cardiovascular Medicine

Volume 6, Issue 5, July 1996, Pages 158-162

https://doi.org/10.1016/1050-1738(96)00044-8 Get rights and content

Abstract

The process of apoptosis or programmed cell death has been the subject of intense study due to the realization of its importance in a wide variety of biological and pathological conditions, including development, ischemia, cancer, and neurodegenerative disorders. Although a vast number of inducers of this process and several critical components have been identified, the signal transduction pathways regulating apoptosis are poorly understood. Recently, a pathway involving sphingolipid turnover and the production of the lipid mediator, ceramide, has emerged as a candidate regulator of apoptosis. This review provides a summary of the evidence implicating ceramide as a mediator of apoptosis and the stress response. (Trends Cardiovasc Med 1996;6:158-162).

Section snippets

• Introduction

Apoptosis (or programmed cell death) is a term given by Kerr et al. (1972)to represent a cellular process marked by characteristic morphological changes and culminating in cell death. It is conserved across species ranging from the nematode, Caenorhabditis elegans, to humans. Furthermore, apoptosis is thought to play a vital role in a vast number of biological and pathological conditions, including development and tissue remodeling, cancer, ischemia and infarction, immune disorders, and

• Known Components in the Apoptotic Response

Much of what we know concerning the apoptotic process and the components involved therein has been elucidated from studies on Caenorhabditis elegans (Hengartner and Horvitz 1994a). Genetic studies have identified two genes, ced-3 and ced-4, that are required for apoptosis. A third gene, ced-9, antagonizes the effects of ced-3 and ced-4, in that mutations in ced-9 cause cells that would normally live to undergo apoptosis.

The mammalian homologues of ced-3 and ced-9 have recently been identified

• Overview of Lipid Signal Transduction

Whereas signaling through glycerophospholipids is well established, the observation of signaling through sphingolipids is relatively recent. Sphingolipids are much more diverse than glycerolipids in their structures, particularly in the head-group moiety. However, they have been considered largely as structural components of cell membranes. The discovery of the inhibition of PKC by sphingosine led to the hypothesis that sphingolipid turnover may be involved in cellular signaling events (Hannun

• The Sphingomyelin Cycle and Ceramide

The sphingomyelin cycle is initiated by agents that cause a transient decrease in plasma membrane sphingomyelin content. This reaction is catalyzed by a specific phospholipase C, sphingomyelinase, resulting in the liberation of both ceramide and phosphocholine. The cycle is completed by the resynthesis of sphingomyelin via the transfer of phosphatidylcholine-derived phosphocholine to ceramide, catalyzed by a hitherto poorly characterized sphingomyelin synthase.

The inducers of sphingomyelin

• Role of Ceramide in Apoptosis/Stress

Early studies conducted to determine the role of ceramide in cellular biology were complicated by the toxicity of ceramide on cells. Further observation in U937 cells, however, revealed that ceramide treatment resulted in DNA fragmentation, and that this effect was specific for ceramide in that the closely related dihydroceramide and diacylglycerol were without effect (Obeid et al. 1993). Similar results were observed with TNF-α treatment and suggested that ceramide may be an intracellular

• Regulation of the Sphingomyelinase/Ceramide Pathway

The sphingomyelinases, which catalyze the formation of ceramide from sphingomyelin, are a diverse group of enzymes and are characterized based on their cellular localization, cation dependencies, and pH optima. The most widely studied member of this group is an acid sphingomyelinase that is localized to the lysosomes. It has been postulated that this enzyme is activated by TNF-α secondary to phospholipase C-catalyzed diacylglycerol (DAG) production and transmits at least some aspects of

• Conclusions

This review has provided a short summary of studies implicating ceramide as a second messenger involved in regulating apoptosis and stress responses. From preliminary experiments identifying ceramide as an inducer of cell death to the determination of both upstream and downstream effector mechanisms of ceramide, much has been learned of the role of ceramide in apoptosis. Wide gaps exist, however, in the understanding of the regulatory events in this pathway.

The mechanisms determining the

Acknowledgements

We thank Dr. Supriya Jayadev for the preparation of figures.

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Multiple novel agents that modulate SL metabolism have been studied and at least in one instance applied therapeutically for cancer treatment (Adan-Gokbulut et al., 2013). Ceramide (Cer), is responsible for several intracellular signals and is considered the parent SL molecule (Hannun, 1996; Jayadev and Hannun, 1996; Perry et al., 1996; Lee et al., 1996). Ceramides are a family of lipids with a sphingosine (So) backbone N-acylated with a variety of fatty acids, creating a diverse group of molecules (Fig. 1).
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BRIEF REVIEWSCeramide and the Regulation of Apoptosis and the Stress Response

Abstract

Section snippets

• Introduction

• Known Components in the Apoptotic Response

• Overview of Lipid Signal Transduction

• The Sphingomyelin Cycle and Ceramide

• Role of Ceramide in Apoptosis/Stress

• Regulation of the Sphingomyelinase/Ceramide Pathway

• Conclusions

Acknowledgements

FEBS Lett

Trends Biochem Sci

J Biol Chem

J Biol Chem

J Biol Chem

Trends Biochem Sci

Cell

Cell

Cell

J Biol Chem

Cell

Cell

Selectivity of ceramide-mediated biology

J Biol Chem

Thymocyte apoptosis induced by p53-dependent and independent pathways

Nature

Retinoblastoma gene product as a downstream target for a ceramide-dependent pathway of growth arrest

Proc Natl Acad Sci USA

ICE-LAP3, a novel mammalian homolog of the Caenorhabditis elegans cell death protein CED-3 is activated during Fas- and tumor necrosis factor-induced apoptosis

J Biol Chem

CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1β-converting enzyme

J Biol Chem

Functions of sphingolipids and sphingolipid breakdown products in cellular regulation

Science

Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets

J Biol Chem

The ins and outs of programmed cell death during C. elegans development

Philos Trans R Soc Lond

C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2.

Cell

Normal and abnormal consequences of apoptosis in the human heart

Circulation

Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics

Br J Cancer

BRIEF REVIEWS
Ceramide and the Regulation of Apoptosis and the Stress Response