SPHINGOLIPID METABOLISM AND CELL-GROWTH REGULATION

Sphingolipids have been implicated in the regulation of cell growth, d ifferentiation, and programmed cell death. The current paradigm for th eir action is that complex sphingolipids such as gangliosides interact with growth factor receptors, the extracellular matrix, and neighbori ng cells, whereas the backbones-sphingosine and other long-chain or '' sphingoid'' bases, ceramides, and sphingosine 1-phosphate-activate or inhibit protein kinases and phosphatases, ion transporters, and other regulatory machinery. Tumor necrosis factor-alpha, interleukin Ip, and nerve growth factor, for example, induce sphingomyelin hydrolysis to ceramide. Other agonists, such as platelet-derived growth factor, trig ger further hydrolysis of ceramide to sphingosine and activate sphingo sine kinase to form sphingosine 1-phosphate. These metabolites either stimulate or inhibit growth and may be cytotoxic (in some cases via in duction of apoptosis), depending on which products are formed (or adde d exogenously), the cellular levels (and possibly intracellular locali zation), and the cell type. In Swiss 3T3 cells, for example, sphingosi ne and sphingosine 1-phosphate are growth stimulatory at low concentra tions via calcium mobilization from intracellular stores and activatio n of the mitogen-activated protein kinase (MAP kinase) pathway and tra nscription factors (AP-1), but are toxic at high concentrations. High levels of endogenous sphingoid bases are also produced by inhibition o f ceramide synthase by fumonisins, mycotoxins produced by Fusarium mon iliforme, resulting in growth stimulation or toxicity. Thus, sphingoli pid metabolites appear to serve as second messengers for growth factor s, cytokines, and other ''physiological'' agonists and, when elevated abnormally, to lead to disease.