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Papers In Press, published online ahead of print January 8, 2001
Shands Cancer Center, University of Florida, Health Science Center, Gainesville, FL 32610-0232
Corresponding Author: pruvolo{at}ufscc.ufl.edu
The sphingolipid, ceramide, is an important second signal molecule and potent apoptogenic agent. The production of ceramide is associated with virtually every known stress stimuli, 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. IL-3 withdrawal, sodium arsenite treatment, and peroxide treatment) is the activation of the dsRNA activatable protein kinase (PKR1) resulting in the inhibition of protein synthesis (Ito, Jagus, and May, Proc. Natl. Acad. Sci. USA 1994, 91: 7455 - 7459). The recently discovered cellular PKR activator, RAX, is phosphorylated in association with PKR activation (Ito, Yang, and May J. Biol. Chem. 1999, 274: 15427 - 15432). Since RAX is phosphorylated by an as yet undetermined stress-activated protein kinase (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 eIF2a 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.
J. Biol. Chem, 10.1074/jbc.M011400200
Submitted on December 18, 2000
Revised on January 5, 2001
Accepted on January 7, 2001
Ceramide Regulates Protein Synthesis By A Novel Mechanism Involving The Cellular PKR Activator RAX
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