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.
Katherine M. Hannan,Yves Brandenburger,Anna Jenkins,Kerith Sharkey,Alice H. Cavanaugh,Lawrence I. Rothblum,Tom Moss,Gretchen Poortinga,Grant A. McArthur,Richard B. Pearson,Richard B. Pearson,Ross D. Hannan,Ross D. Hannan +12 more
TLDR
It is shown 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.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.read more
Citations
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Journal ArticleDOI
TOR signaling in growth and metabolism.
TL;DR: The physiological consequences of mammalianTORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.
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Upstream and downstream of mTOR
Nissim Hay,Nahum Sonenberg +1 more
TL;DR: Both the upstream components of the signaling pathway(s) that activates mammalian TOR (mTOR) and the downstream targets that affect protein synthesis are described.
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mTOR: from growth signal integration to cancer, diabetes and ageing
TL;DR: Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.
Journal ArticleDOI
Growing roles for the mTOR pathway
TL;DR: Recent work identifying two structurally and functionally distinct mTOR-containing multiprotein complexes and TSC1/2, rheb, and AMPK as upstream regulators of mTOR is beginning to reveal how mTOR can sense diverse signals and produce a myriad of responses.
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mTOR at the nexus of nutrition, growth, ageing and disease
Grace Y. Liu,David M. Sabatini +1 more
TL;DR: This Review highlights recent advances in the understanding of the complex regulation of the mTOR pathway and discusses its function in the context of physiology, human disease and pharmacological intervention.
References
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Journal ArticleDOI
TOR, a Central Controller of Cell Growth
Tobias Schmelzle,Michael N. Hall +1 more
TL;DR: Findings reveal that the target of rapamycin TOR controls an unusually abundant and diverse set of readouts all of which are important for cell growth, suggesting that this conserved kinase is such a central regulator.
Journal ArticleDOI
Regulation of translation initiation by FRAP/mTOR
Journal ArticleDOI
Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E
TL;DR: Data show that mTOR signals downstream to at least two independent targets, S6K1 and 4EBP1/eIF4E, that function in translational control to regulate mammalian cell size.
Journal ArticleDOI
Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k
Harold B.J. Jefferies,Stefano Fumagalli,Patrick B. Dennis,Christoph Reinhard,Richard B. Pearson,George Thomas +5 more
TL;DR: It is demonstrated that an intact polypyrimidine tract is required for rapamycin to elicit an inhibitory effect on the translation of mRNAs encoding ribosomal proteins and elongation factors.
Journal ArticleDOI
Drosophila S6 kinase: a regulator of cell size.
TL;DR: Drosophila deficient in the S6 kinase gene (dS6K) exhibited an extreme delay in development and a severe reduction in body size, and these flies had smaller cells rather than fewer cells.