Editors' ChoiceApoptosis

Two Messengers in Balance

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Science's STKE  16 May 2000:
Vol. 2000, Issue 32, pp. tw5
DOI: 10.1126/stke.2000.32.tw5

Apoptosis induced by tumor necrosis factor-alpha (TNF-α) occurs through the activation of the death receptor p55, followed by recruitment of the cytosolic adapter protein TRADD to p55, and the subsequent activation of caspase 8. In addition, the neutral sphingolipid ceramide is a downstream effector of death receptors. De Nadai et al. show that while ceramide potentiates the ability of TNF-α to recruit TRADD to p55, the intracellular messenger nitric oxide (NO) inhibits both this recruitment and the production of intracellular ceramide in cells, thus blocking the apoptotic effect of TNF-α. The effect of NO was dependent on cGMP. The authors propose that the sensitivity of a cell to TNF-α-induced apoptosis may depend on a cell's ability to regulate the signaling systems that generate the second messengers NO and ceramide. It is not yet clear how NO blocks ceramide production.

De Nadai, C., Sestili, P., Cantoni, O., Lièvremont, J.-P., Sciorati, C., Barsacchi, R., Moncada, S., Meldolesi, J., and Clementi, E. (2000) Nitric oxide inhibits tumor necrosis factor-α-induced apoptosis by reducing the generation of ceramide. Proc. Natl. Acad. Sci. U.S.A. 97: 5480-5485. [Abstract] [Full Text]