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Mol. Cell. Biol. doi:10.1128/MCB.02136-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

TSC1/TSC2 Control Serum-Dependent Translation in a TOP-Dependent and -Independent Manner

UCSF Cancer Research Institute., University of California, San Francisco, CA, USA; Agilent Technologies Inc., Santa Clara, CA, USA

^* To whom correspondence should be addressed. Email: dstokoe{at}cc.ucsf.edu.

	Abstract

The Tuberous Sclerosis Complex (TSC) proteins, TSC1/TSC2 regulate protein translation by inhibiting the Serine/Threonine kinase mTORC1 (mammalian Target Of Rapamycin Complex 1). However, how TSC1/TSC2 controls overall protein synthesis and the translation of specific mRNAs in response to different mitogenic and nutritional stimuli is largely unknown. Here we show that serum withdrawal inhibits mTORC1 signaling, causes disassembly of translation initiation complexes, and causes mRNA redistribution from polysomes to subpolysomes in wild type mouse embryo fibroblasts (WT MEFs). By contrast, these responses are defective in Tsc1^-/- or Tsc2^-/- MEFs. Microarray analysis of polysome- and subpolysome-associated mRNAs uncovered specific mRNAs that are translationally regulated by serum, 90% of which are TSC1/TSC2-dependent. Surprisingly, the mTORC1 inhibitor, rapamycin, abolished mTORC1 activity, but only affected 40% of the serum-regulated mRNAs. Serum-dependent signaling through mTORC1, and polysome redistribution of global and individual mRNAs, were restored upon re-expression of TSC1 and TSC2. Serum-responsive mRNAs that are sensitive to inhibition by rapamycin are highly enriched for terminal oligopyrimidine (TOP) and for very short 5' and 3' UTRs. These data demonstrate that TSC1/TSC2 complex regulates protein translation through mainly mTORC1-dependent mechanisms, and implicates a discrete profile of deregulated mRNA translation in tuberous sclerosis pathology.

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