PMID- 25043031
OWN - NLM
STAT- MEDLINE
DCOM- 20141014
LR  - 20220223
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 513
IP  - 7518
DP  - 2014 Sep 18
TI  - Coordinated regulation of protein synthesis and degradation by mTORC1.
PG  - 440-3
LID - 10.1038/nature13492 [doi]
AB  - Eukaryotic cells coordinately control anabolic and catabolic processes to 
      maintain cell and tissue homeostasis. Mechanistic target of rapamycin complex 1 
      (mTORC1) promotes nutrient-consuming anabolic processes, such as protein 
      synthesis. Here we show that as well as increasing protein synthesis, mTORC1 
      activation in mouse and human cells also promotes an increased capacity for 
      protein degradation. Cells with activated mTORC1 exhibited elevated levels of 
      intact and active proteasomes through a global increase in the expression of 
      genes encoding proteasome subunits. The increase in proteasome gene expression, 
      cellular proteasome content, and rates of protein turnover downstream of mTORC1 
      were all dependent on induction of the transcription factor nuclear factor 
      erythroid-derived 2-related factor 1 (NRF1; also known as NFE2L1). Genetic 
      activation of mTORC1 through loss of the tuberous sclerosis complex tumour 
      suppressors, TSC1 or TSC2, or physiological activation of mTORC1 in response to 
      growth factors or feeding resulted in increased NRF1 expression in cells and 
      tissues. We find that this NRF1-dependent elevation in proteasome levels serves 
      to increase the intracellular pool of amino acids, which thereby influences rates 
      of new protein synthesis. Therefore, mTORC1 signalling increases the efficiency 
      of proteasome-mediated protein degradation for both quality control and as a 
      mechanism to supply substrate for sustained protein synthesis.
FAU - Zhang, Yinan
AU  - Zhang Y
AD  - Department of Genetics and Complex Diseases, Harvard School of Public Health, 
      Boston, Massachusetts 02115, USA.
FAU - Nicholatos, Justin
AU  - Nicholatos J
AD  - Department of Genetics and Complex Diseases, Harvard School of Public Health, 
      Boston, Massachusetts 02115, USA.
FAU - Dreier, John R
AU  - Dreier JR
AD  - Translational Medicine Division, Department of Medicine, Brigham and Women's 
      Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
FAU - Ricoult, Stephane J H
AU  - Ricoult SJ
AD  - Department of Genetics and Complex Diseases, Harvard School of Public Health, 
      Boston, Massachusetts 02115, USA.
FAU - Widenmaier, Scott B
AU  - Widenmaier SB
AD  - Department of Genetics and Complex Diseases, Harvard School of Public Health, 
      Boston, Massachusetts 02115, USA.
FAU - Hotamisligil, Gokhan S
AU  - Hotamisligil GS
AD  - Department of Genetics and Complex Diseases, Harvard School of Public Health, 
      Boston, Massachusetts 02115, USA.
FAU - Kwiatkowski, David J
AU  - Kwiatkowski DJ
AD  - Translational Medicine Division, Department of Medicine, Brigham and Women's 
      Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
FAU - Manning, Brendan D
AU  - Manning BD
AD  - Department of Genetics and Complex Diseases, Harvard School of Public Health, 
      Boston, Massachusetts 02115, USA.
LA  - eng
GR  - CA122617/CA/NCI NIH HHS/United States
GR  - CAPMC/CIHR/Canada
GR  - P01 CA120964/CA/NCI NIH HHS/United States
GR  - CA120964/CA/NCI NIH HHS/United States
GR  - R01 CA122617/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20140713
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Amino Acids)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Nuclear Respiratory Factor 1)
RN  - 0 (Proteins)
RN  - 0 (Sterol Regulatory Element Binding Protein 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
CIN - Nature. 2016 Jan 21;529(7586):E1-2. PMID: 26791731
CIN - Nature. 2016 Jan 21;529(7586):E2-3. PMID: 26791732
MH  - Amino Acids/metabolism
MH  - Animals
MH  - Humans
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Multiprotein Complexes/*metabolism
MH  - Nuclear Respiratory Factor 1/genetics/metabolism
MH  - Proteasome Endopeptidase Complex/genetics/metabolism
MH  - *Protein Biosynthesis
MH  - Proteins/chemistry/*metabolism
MH  - *Proteolysis
MH  - Signal Transduction
MH  - Sterol Regulatory Element Binding Protein 1/metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Transcription, Genetic
PMC - PMC4402229
MID - NIHMS676605
EDAT- 2014/07/22 06:00
MHDA- 2014/10/15 06:00
PMCR- 2015/04/19
CRDT- 2014/07/22 06:00
PHST- 2014/02/21 00:00 [received]
PHST- 2014/05/15 00:00 [accepted]
PHST- 2014/07/22 06:00 [entrez]
PHST- 2014/07/22 06:00 [pubmed]
PHST- 2014/10/15 06:00 [medline]
PHST- 2015/04/19 00:00 [pmc-release]
AID - nature13492 [pii]
AID - 10.1038/nature13492 [doi]
PST - ppublish
SO  - Nature. 2014 Sep 18;513(7518):440-3. doi: 10.1038/nature13492. Epub 2014 Jul 13.