Ceramide regulates cellular homeostasis via diverse stress signaling pathways

Abstract

The sphingolipid ceramide is an important second signal molecule that regulates diverse signaling pathways involving apoptosis, cell senescence, the cell cycle, and differentiation. For the most part, ceramide's effects are antagonistic to growth and survival. Interestingly, ceramide and the pro-growth agonist, diacylglycerol (DAG) appear to be regulated simultaneously but in opposite directions in the sphingomyelin cycle. While ceramide stimulates signal transduction pathways that are associated with cell death or at least are inhibitory to cell growth (eg stress-activated protein kinase, SAPK, pathways), DAG activates the classical and novel isoforms of the protein kinase C (PKC) family. These PKC isoforms are associated with cell growth and cell survival.

PKC α mediates chemoresistance in acute lymphoblastic leukemia through effects on Bcl2 phosphorylation

“…9,28,48 Interestingly, both PKC a and Bcl2 are dephosphorylated by PP2A during stress stimuli, thus suggesting a complex level of regulation of the entire Bcl2 pathway during apoptosis. 25,26 Whether a similar but opposite regulatory mechanism for the Bcl2 pathway during survival conditions exists is currently unknown. Such a novel mechanism may exist, since the overexpression of PKC a in the REH cells results in the suppression of PP2A activity while promoting chemoresistance.…”

“…This finding suggests a complex level of regulation of the entire Bcl2 pathway during apoptosis. [23][24][25][26] Whether a similar but opposite regulatory mechanism for the Bcl2 pathway during survival conditions exists is currently unknown. In this study, we show evidence for such a novel mechanism, since the overexpression of PKC a in the acute lymphoblastic leukemia (ALL)-derived cell line REH results in the suppression of PP2A activity while promoting chemoresistance against the chemotherapeutic drug etoposide.…”

Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines

“…CAPK will phosphorylate important MAP kinase signal pathway members Raf-1, MEK, PLA2, and ERK-2 (Maziere et al, 2001;Willaime et al, 2001). Ceramide is a catalyst for the activation of stress response proteins MEKK1, SEK1, SAPK, and c-Jun (Smith et al, 1997;Basu and Kolesnick, 1998;Ruvolo, 2001). Interestingly, ceramide can activate PP2A (Ruvolo, 2001).…”

“…Ceramide is a catalyst for the activation of stress response proteins MEKK1, SEK1, SAPK, and c-Jun (Smith et al, 1997;Basu and Kolesnick, 1998;Ruvolo, 2001). Interestingly, ceramide can activate PP2A (Ruvolo, 2001). PP2A is a phosphatase involved in a diverse number of pathways, such as cell cycle control.…”

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.…”