PMID- 14612424
OWN - NLM
STAT- MEDLINE
DCOM- 20031216
LR  - 20220410
IS  - 0270-7306 (Print)
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Linking)
VI  - 23
IP  - 23
DP  - 2003 Dec
TI  - 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.
PG  - 8862-77
AB  - 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.
FAU - Hannan, Katherine M
AU  - Hannan KM
AD  - Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, East 
      Melbourne, Victoria 3002, USA.
FAU - Brandenburger, Yves
AU  - Brandenburger Y
FAU - Jenkins, Anna
AU  - Jenkins A
FAU - Sharkey, Kerith
AU  - Sharkey K
FAU - Cavanaugh, Alice
AU  - Cavanaugh A
FAU - Rothblum, Lawrence
AU  - Rothblum L
FAU - Moss, Tom
AU  - Moss T
FAU - Poortinga, Gretchen
AU  - Poortinga G
FAU - McArthur, Grant A
AU  - McArthur GA
FAU - Pearson, Richard B
AU  - Pearson RB
FAU - Hannan, Ross D
AU  - Hannan RD
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (DNA, Ribosomal)
RN  - 0 (Pol1 Transcription Initiation Complex Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Rrn3 protein, mouse)
RN  - 0 (transcription factor UBF)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Cell Division
MH  - DNA, Ribosomal/*genetics
MH  - Enzyme Activation
MH  - Mice
MH  - NIH 3T3 Cells
MH  - Phosphorylation
MH  - Pol1 Transcription Initiation Complex Proteins/chemistry/*metabolism
MH  - Protein Kinases/*metabolism
MH  - Protein Structure, Tertiary
MH  - Recombinant Proteins/chemistry/metabolism
MH  - Ribosomal Protein S6 Kinases/*metabolism
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transcription, Genetic
PMC - PMC262650
EDAT- 2003/11/13 05:00
MHDA- 2003/12/17 05:00
PMCR- 2003/12/01
CRDT- 2003/11/13 05:00
PHST- 2003/11/13 05:00 [pubmed]
PHST- 2003/12/17 05:00 [medline]
PHST- 2003/11/13 05:00 [entrez]
PHST- 2003/12/01 00:00 [pmc-release]
AID - 0071 [pii]
AID - 10.1128/MCB.23.23.8862-8877.2003 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2003 Dec;23(23):8862-77. doi: 10.1128/MCB.23.23.8862-8877.2003.