Abstract
The sphingolipid ceramide mediates various cellular processes in response to several extracellular stimuli. Some genotoxic stresses are able to induce p53-dependent ceramide accumulation leading to cell death. However, in other cases, in the absence of the tumor suppressor protein p53, apoptosis proceeds partly due to the activity of this “tumor suppressor lipid”, ceramide. In the current review, we describe ceramide and its roles in signaling pathways such as cell cycle arrest, hypoxia, hyperoxia, cell death, and cancer. In a specific manner, we are elaborating on the role of ceramide in mitochondrial apoptotic cell death signaling. Furthermore, after highlighting the role and mechanism of action of p53 in apoptosis, we review the association of ceramide and p53 with respect to apoptosis. Strikingly, the hypothesis for a direct interaction between ceramide and p53 is less favored. Recent data suggest that ceramide can act either upstream or downstream of p53 protein through posttranscriptional regulation or through many potential mediators, respectively.
Highlights
Ceramide is a key sphingolipid that acts as a second messenger for multiple extracellular stimuli to mediate many cellular processes
Additional studies revealed that variation in free Mg2+ causes sustained changes in membrane phospholipids and second messengers resulting in the activation of intracellular signal transcription molecules such as nuclear factor-κB (NF-κB), proto-oncogenes c-fos and c-jun, MAPK and MAPKK in vascular smooth muscle cells in vitro [7]
The activation of Bax depends upon the presence of Bak because the latter was described to elevate the activity of ceramide synthase in the mitochondrial outer membrane of mammalian cells in response to irradiation [70]
Summary
Ceramide is a key sphingolipid that acts as a second messenger for multiple extracellular stimuli to mediate many cellular processes. Ceramide signaling, conserved throughout evolution, was found to be involved in death signaling in many systems. Since yeast cells undergo a cell death mechanism that resembles apoptosis, the sphingomyelin pathway appears evolutionarily older than the caspase-mediated death programs described in higher organisms [1]. Most DNA damaging agents and genotoxic stressors induce apoptosis in p53-dependent pathways. In the absence of p53, programmed cell death proceeds and is partly mediated by the “tumor suppressor lipid”, ceramide. Many stimuli can cause p53-dependent ceramide accumulation leading to cell death. We intend to focus on the role of ceramide in signaling pathways of apoptosis and try to shed light on its relation with p53
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