Sphingosine-dependent apoptosis: A unified concept based on multiple mechanisms operating in concert
Abstract
Exposure of 3T3/A31 cells to serum-free medium, one type of apoptotic stimulus, causes a rapid increase in the sphingosine (Sph) level, which initiates a series of processes: (i) activation of caspase 3 through an enhanced "cascade" of caspases, (ii) release of the C-terminal-half kinase domain of PKCδ (PKCδ KD) by caspase 3, and (iii) activation of Sph-dependent kinase 1 (SDK1), which was previously identified as PKCδ KD. The activation of caspase 3 and release of PKCδ KD are inhibited strongly by the incubation of cells with the ceramidase inhibitor D-erythro-2-tetradecanoylamino-1-phenyl-1-propanol and, to a much lesser extent, by l-cycloserine, an inhibitor of de novo ceramide synthesis. Exogenous addition of Sph or N,N-dimethyl-Sph to U937 cells causes caspase 3 activation and release of PKCδ KD (SDK1), leading to apoptosis. The Sph-induced apoptotic process associated with activation of caspase 3 and release of PKCδ KD (SDK1) may promote the proapoptotic effect of BAD or BAX through an increase of phosphorylated 14-3-3. In addition, Sph induces apoptosis through a separate process: the blocking of "survival signal" through the Akt kinase pathway induced by α3β1-mediated cell adhesion to laminin 10/11 in extracellular matrix. We hereby propose a unified concept of Sph-dependent apoptosis based on these multiple mechanisms operating in concert.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- October 2004
- DOI:
- 10.1073/pnas.0406536101
- Bibcode:
- 2004PNAS..10114788S
- Keywords:
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- CELL BIOLOGY