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Originally published In Press as doi:10.1074/jbc.M011400200 on January 8, 2001

J. Biol. Chem., Vol. 276, Issue 15, 11754-11758, April 13, 2001
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Ceramide Regulates Protein Synthesis by a Novel Mechanism Involving the Cellular PKR Activator RAX*

Peter P. RuvoloDagger , Fengqin Gao, William L. Blalock, Xingming Deng, and W. Stratford May

From the Shands Cancer Center and the Department of Medicine, University of Florida, Gainesville, Florida 32610-0232

The sphingolipid ceramide is an important second signal molecule and potent apoptotic agent. The production of ceramide is associated with virtually every known stress stimulus, and thus, generation of this sphingolipid has been suggested as a universal feature of apoptosis. Recent studies suggest that an important component of cell death following diverse stress stimuli (e.g. interleukin-3 withdrawal, sodium arsenite treatment, and peroxide treatment) is the activation of the double-stranded RNA-activable protein kinase, PKR, resulting in the inhibition of protein synthesis (Ito, T., Jagus, R., and May, W. S. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 7455-7459). The recently discovered cellular PKR activator, RAX, is phosphorylated in association with PKR activation (Ito, T., Yang, M., and May, W. S. (1999) J. Biol. Chem. 274, 15427-15432). Since RAX is phosphorylated by an as yet undetermined SAPK and ceramide is a potent activator of SAPKs such as JNK, a role for ceramide in the activation of RAX might be possible. Results indicate that overexpression of exogenous RAX potentiates ceramide-induced killing. Furthermore, ceramide can potently inhibit protein synthesis. Since ceramide potently promotes RAX and eukaryotic initiation factor-2alpha phosphorylation, a possible role for ceramide in this process may involve the activation of PKR by RAX. Since 2-aminopurine, a serine/threonine kinase inhibitor that has previously been shown to inhibit PKR, blocks both the potentiation of ceramide killing by RAX and ceramide-induced inhibition of protein synthesis, ceramide appears to promote PKR activation, at least indirectly. Collectively, these findings suggest a novel role for ceramide in the regulation of protein synthesis and apoptosis.

* This work was supported by National Institutes of Health Grant HL54083.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Shands Cancer Center, University of Florida, P. O. Box 100232, Gainesville, FL 32610-0232. Tel.: 352-392-9017; Fax: 352-392-5802; E-mail: pruvolo@ufscc.ufl.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.