Advances in the Signal Transduction of Ceramide and Related Sphingolipids

Abstract

Recently, the sphingolipid metabolites ceramide, sphingosine, ceramide 1-P, and sphingosine 1-P have been implicated as second messengers involved in many different cellular functions. Publications on this topic are appearing at a rapidly increasing rate and new developments in this field are also appearing rapidly. It is thus important to summarize the results obtained from many different laboratories and from different fields of research to obtain a clearer picture of the importance of sphingolipid metabolites. This article reviews the studies from the last few years and includes the effects of a variety of extracellular agents on sphingolipid signal transduction pathways in different tissues and cells and on the mechanisms of regulation. Sphingomyelin exists in a number of functionally distinct pools and is composed of distinct molecular species. Sphingomyelin metabolites may be formed by many different pathways. For example, the generation of ceramide from sphingomyelin can be catalyzed by at least five different sphingomyelinases. A large variety of stimuli can induce the generation of ceramide, leading to activation or inhibition of various cellular events such as proliferation, differentiation, apoptosis, and inflammation. The effect of ceramide on these physiological processes is due to its many different downstream targets. It can activate ceramide-activated protein kinases and ceramide-activated protein phosphatases. It also activates or inhibits PKCs, PLD, PLA2, PC-PLC, nitric oxide synthase, and the ERK and SAPK/JNK signaling cascades. Ceramide activates or inhibits transcription factors, modulates calcium homeostasis and interacts with the retinoblastoma protein to regulate cell cycle progression. Most of the work in this field has involved the study of ceramide effects, but the roles of the other three sphingomyelin metabolites is now attracting much attention. The complex interactions between signaling components and ceramide and the controls regulating these interactions are now being identified and are presented in this review.

An extensive microarray analysis of AAL-toxin-induced cell death in Arabidopsis thaliana brings new insights into the complexity of programmed cell death in plants

“…The AAL toxin triggers PCD through interference with sphingolipid metabolism, although the exact mechanism of activating the cell death machinery remains elusive [3,6]. The role of sphingolipids in promoting cell proliferation or death is well recognized in animals [19]. Recently, sphingolipids also emerged as important cell death players in plants.…”

Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies

“…One of the most studied of these signaling pathways that could modulate cell sensitivity to chemotherapeutic drugs and ionizing radiation is the sphingomyelin-ceramide pathway, a pathway which is activated within a few minutes after drug interaction with the target cell [203][204][205] ( Figure 6). Sphingomyelin was initially considered as a structural element in eukaryotic cell membranes.…”

TGF-β1 suppresses apoptosis via differential regulation of MAP kinases and ceramide production

“…The production of ceramide, a potent bioactive sphingolipid derivative, can be stimulated by stress, including tumor necrosis factor-a (TNF-a), chemotherapeutic reagents, and the deprivation of survival signals. [1][2][3][4] Increased intracellular ceramide formation in response to the above stimuli is followed by apoptotic and nonapoptotic cell death. Exogenous cell permeable ceramide analogs, C 2 -and C 8 -ceramide, are also able to induce apoptosis in a variety of cells.…”