engleski

Lipid Second Messengers in the Regulation of Apoptosis

The regulation of cell survival is a central feature in animal development and in didseases such as cancer. When various extracellular signals including growth factors and cytokines bind to their cell-surface receptors, intracellular phosphoinositide 3-kinase becomes activated. This results in the generation of two lipid products (PtdIns-3,4P_2 and PtdIns-3,4,5-P_3), which act as second messenger molecules and activate serine/threonine kinases PDK1 and PKB/Akt. Activated PKB phosphorylates the pro-apoptotic factor Bad on a serine residue, resulting in its dissociation from Bcl-xl and its association with 14-3-3. Released Bcl-xl is then capable of suppressing cell-death pathways that involve the activity of Apaf-1, cytochrome c and the caspase protease cascade. On the other hand, it has been known that signaling systems engaged by ceramide are also involved in apoptosis. Activation of tumor necrosis factor receptor stimulates neutral and acidic sphingomyelinase isoforms, resulting in ceramide generation. Ceramide can stimulate ceramide-activated protein kinase in the plasma membrane to phosphorylate and activate Ras-Raf-1 pathway. Further downstream there is transcription activator NF-kB, who plays pivotal role in activation and expression of genes encoding antiapoptotic factors, which allow the cell to survive.

lipid second messengers; apoptosis

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