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TSC1 Sets the Rate of Ribosome Export and Protein Synthesis through Nucleophosmin Translation

¹ Division of Molecular Oncology, Department of Internal Medicine, Siteman Cancer Center and Departments of ² Neurology and ³ Cell Biology, Washington University School of Medicine, St. Louis, Missouri

Request for reprints: Jason D. Weber, Division of Molecular Oncology, Department of Medicine, Washington University School of Medicine, Campus Box 8069, 660 South Euclid Avenue, St. Louis, MO 63110. Phone: 314-747-3896; Fax: 314-747-2797; E-mail: jweber{at}im.wustl.edu.

Nucleophosmin (B23) is a nucleolar phosphoprotein that has been implicated in numerous cellular processes. In particular, nucleophosmin interacts with nucleolar components of newly synthesized ribosomes to promote ribosome nuclear export. Nucleophosmin is a classic mitogen-induced protein, with changes in its expression correlating with growth factor stimulation. In this study, we examined the underlying mechanism of nucleophosmin induction and showed that hyperproliferative signals emanating from oncogenic H-Ras^V12 cause tremendous increases in nucleophosmin protein expression. Nucleophosmin protein accumulation was dependent on mammalian target of rapamycin (mTOR) activation, as rapamycin completely prevented nucleophosmin induction. Consistent with this finding, genetic ablation of Tsc1, a major upstream inhibitor of mTOR, resulted in nucleophosmin protein induction through increased translation of existing nucleophosmin mRNAs. Increases in nucleophosmin protein accumulation were suppressed by reintroduction of TSC1. Induction of nucleophosmin through Tsc1 loss resulted in a greater pool of actively translating ribosomes in the cytoplasm, higher overall rates of protein synthesis, and increased cell proliferation, all of which were dependent on efficient nucleophosmin nuclear export. Nucleophosmin protein accumulation in the absence of Tsc1 promoted the nuclear export of maturing ribosome subunits, providing a mechanistic link between TSC1/mTOR signaling, nucleophosmin-mediated nuclear export of ribosome subunits, protein synthesis levels, and cell growth. [Cancer Res 2007;67(4):1609–17]

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