CERAMIDE: From intermediary metabolism to cell regulation

Ceramide functions as the key intermediate in sphingolipid metabolism and serves as the lipid backbone in mammalian sphingolipids. Recent studies have demonstrated an essential role for ceramide in the mammalian stress response and in cell regulation. A number of extracellular stimuli of stress and/or injury such as tumor necrosis factor α, fas, dexamethasone, serum withdrawal , and chemotherapeutic agents cause significant and persistent accumulation of ceramide. Addition of exogenous ceramides or metabolic generation of endogenous ceramide mimics the ability of these extracellular agents in inducing various forms of growth suppression such as apoptosis, cell cycle arrest, terminal cell differentiation, or cell senescence. In vitro, ceramide activates a protein phosphatase of the PP2A family which may serve as a proximal target mediating its cellular activities. In the cell, ceramide regulates the activity of the retinoblastoma gene product which mediates cell cycle arrest in response to ceramide. Ceramide also activates proteases of the ICE-like family which mediate its apoptotic activity. These two pathways represent distinct outcomes of ceramide accumulation, suggesting that ceramide may act as a proximal biosensor of stress and injury with the particular outcome dictated by downstream components.