Molecular Basis of Cell and Developmental Biology
Rapid Turnover of Mcl-1 Couples Translation to Cell Survival and Apoptosis*

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Inhibition of translation plays a role in apoptosis induced by a variety of stimuli, but the mechanism by which it promotes apoptosis has not been established. We have investigated the hypothesis that selective degradation of anti-apoptotic regulatory protein(s) is responsible for apoptosis resulting from translation inhibition. Induction of apoptosis by cycloheximide was detected within 2–4 h and blocked by proteasome inhibitors, indicating that degradation of short-lived protein(s) was required. Caspase inhibition and overexpression of Bcl-xL blocked cycloheximide-induced apoptosis. In addition, cycloheximide induced rapid activation of Bak and Bax, which required proteasome activity. Mcl-1 was degraded by the proteasome with a half-life of ∼30 min following inhibition of protein synthesis, preceding Bak/Bax activation and the onset of apoptosis. Overexpression of Mcl-1 blocked apoptosis induced by cycloheximide, whereas RNA interference knockdown of Mcl-1 induced apoptosis. Knockdown of Bim and Bak, downstream targets of Mcl-1, inhibited cycloheximide-induced apoptosis, as did knockdown of Bax. Apoptosis resulting from inhibition of translation thus involves the rapid degradation of Mcl-1, leading to activation of Bim, Bak, and Bax. Because of its rapid turnover, Mcl-1 may serve as a convergence point for signals that affect global translation, coupling translation to cell survival and the apoptotic machinery.

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This work was supported by Grant RO1 CA18689 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Present address: Alzheimer's Disease Research Center, Massachusetts General Hospital, Charlestown, MA 02129.