Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate

Abstract

Ceramide is an important regulatory participant of programmed cell death (apoptosis) induced by tumour-necrosis factor (TNF)-alpha and Fas ligand, members of the TNF superfamily. Conversely, sphingosine and sphingosine-1-phosphate, which are metabolites of ceramide, induce mitogenesis and have been implicated as second messengers in cellular proliferation induced by platelet-derived growth factor and serum. Here we report that sphingosine-1-phosphate prevents the appearance of the key features of apoptosis, namely intranucleosomal DNA fragmentation and morphological changes, which result from increased concentrations of ceramide. Furthermore, inhibition of ceramide-mediated apoptosis by activation of protein kinase C results from stimulation of sphingosine kinase and the concomitant increase in intracellular sphingosine-1-phosphate. Finally sphingosine-1-phosphate not only stimulates the extracellular signal-regulated kinase (ERK) pathway, it counteracts the ceramide-induced activation of stress-activated protein kinase (SAPK/JNK). Thus, the balance between the intracellular levels of ceramide and sphingosine-1-phosphate and their regulatory effects on different family members of mitogen-activated protein kinases determines the fate of the cell.

Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras

“…Recent ®ndings indicate an important role for ERKs in the protection of di erentiated PC12 cells from growth factor withdrawal (Xia et al, 1995) and ceramide-induced apoptosis (Cuvillier et al, 1996). We have previously reported that Gas6 induces a transient activation of ERK (Goruppi et al, 1996): we therefore analysed here the role of ERK in Gas6 survival signalling.…”

Deregulation of sphingolipid metabolism in Alzheimer's disease

“…Notably, it has been suggested that S1P may be a potent neuroprotective factor against Aβ-induced neuronal apoptosis, and that it that acts by inhibiting ASM activation (GomezMunoz et al, 2003;Malaplate-Armand et al, 2006). Thus, during the past decade a model has been proposed in which the balance between the levels of ceramide and S1P, the 'ceramide/S1P rheostat', contributes to the fate of cells (Cuvillier et al, 1996). Based on this model, the regulation of sphingomyelinases and ceramidases, as well as sphingosine kinase, S1P phosphatase and lysase may play pivotal roles in the apoptotic signaling of cells by regulating the ratio between sphingomyelin, ceramide, sphingosine, and S1P.…”

v-Abl protein tyrosine kinase (PTK) mediated suppression of apoptosis is associated with the up-regulation of Bcl-XL

“…Inhibition and/or downregulation of PKC has been shown previously in many studies to induce apoptosis in many cell types although many of these studies su er from the use of compounds which inhibit other kinases in addition to PKC (reviewed by Dive et al, 1992a). More recently activation of PKC has been shown to suppress ceramide induced apoptosis (Cuvillier et al, 1996), and from our own studies appears to be important for v-Abl mediated suppression of apoptosis induced by cytokine deprivation and exposure to anticancer drugs (Evans et al, 1995;Chapman et al, 1995). The activity of PKC may either lead to regulation of Bcl-2 and Bclx L via e ects on transcription, and/or may a ect their function via posttranslational modi®cation.…”