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| mTOR-Dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF |
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| Author(s): Hannan KM, Brandenburger Y, Jenkins A, Sharkey K, Cavanaugh A, Rothblum L, Moss T, Poortinga G, McArthur GA, Pearson RB, Hannan RD |
| Source: MOLECULAR AND CELLULAR BIOLOGY Volume: 23 Issue: 23 Pages: 8862-8877 Published: DEC 2003 |
| Times Cited: 85 References: 67 |
| Abstract: Mammalian target of rapamycin (mTOR) is a key regulator of cell growth acting via two independent targets, ribosomal protein S6 kinase 1 (S6K1) and 4EBP1. While each is known to regulate translational efficiency, the mechanism by which they control cell growth remains unclear. In addition to increased initiation of translation, the accelerated synthesis and accumulation of ribosomes are fundamental for efficient cell growth and proliferation. Using the mTOR inhibitor rapamycin, we show that mTOR is required for the rapid and sustained serum-induced activation of 45S ribosomal gene transcription (rDNA transcription), a major rate-limiting step in ribosome biogenesis and cellular growth. Expression of a constitutively active, rapamycin-insensitive mutant of S6K1 stimulated rDNA transcription in the absence of serum and rescued rapamycin repression of rDNA transcription. Moreover, overexpression of a dominant-negative S6K1 mutant repressed transcription in exponentially growing NIH 3T3 cells. Rapamycin treatment led to a rapid dephosphorylation of the carboxy-terminal activation domain of the rDNA transcription factor, UBF, which significantly reduced its ability to associate with the basal rDNA transcription factor SL-1. Rapamycin-mediated repression of rDNA transcription was rescued by purified recombinant phosphorylated UBF and endogenous UBF from exponentially growing NIH 3T3 cells but not by hypophosphorylated UBF from cells treated with rapamycin or dephosphorylated recombinant UBF. Thus, mTOR plays a critical role in the regulation of ribosome biogenesis via a mechanism that requires S6K1 activation and phosphorylation of UBF. |
| Document Type: Article |
| Language: English |
| Reprint Address: Pearson, RB (reprint author), Peter MacCallum Canc Ctr, Trescowthick Res Labs, Melbourne, Vic 3002 Australia |
Addresses:
1. Peter MacCallum Canc Ctr, Trescowthick Res Labs, Melbourne, Vic 3002 Australia
2. Univ Laval, Dept Med Biol, Quebec City, PQ G1R 2J6 Canada
3. Univ Laval, Canc Res Ctr, Quebec City, PQ G1R 2J6 Canada
4. Weis Ctr Res, Danville, PA USA
5. Univ Melbourne, Dept Biochem & Mol Biol, Parkville, Vic 3010 Australia
6. Baker Heart Res Inst, Prahran, Vic 3181 Australia |
| Publisher: AMER SOC MICROBIOLOGY, 1752 N ST NW, WASHINGTON, DC 20036-2904 USA |
| Subject Category: Biochemistry & Molecular Biology; Cell Biology |
| IDS Number: 744FY |
| ISSN: 0270-7306 |
| DOI: 10.1128/MCB.23.23.8862-8877.2003 |
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