PMID- 18070882
OWN - NLM
STAT- MEDLINE
DCOM- 20080331
LR  - 20231105
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 6
DP  - 2008 Feb 8
TI  - Rapid turnover of the mTOR complex 1 (mTORC1) repressor REDD1 and activation of 
      mTORC1 signaling following inhibition of protein synthesis.
PG  - 3465-3475
LID - S0021-9258(20)69811-8 [pii]
LID - 10.1074/jbc.M706643200 [doi]
AB  - mTORC1 is a complex of proteins that includes the mammalian target of rapamycin 
      (mTOR) and several regulatory proteins. It is activated by a variety of hormones 
      (e.g. insulin) and nutrients (e.g. amino acids) that act to stimulate cell growth 
      and proliferation and repressed by hormones (e.g. glucocorticoids) that act to 
      reduce cell growth. Curiously, mTORC1 signaling is reported to be rapidly (e.g. 
      within 1-2 h) activated by inhibitors of protein synthesis that act on either 
      mRNA translation elongation or gene transcription. However, the basis for the 
      mTORC1 activation has not been satisfactorily delineated. In the present study, 
      mTORC1 signaling was found to be activated in response to inhibition of either 
      the initiation or elongation phases of mRNA translation. Changes in mTORC1 
      signaling were inversely proportional to alterations in the expression of the 
      mTORC1 repressor, REDD1, but not the expression of TRB3 or TSC2. Moreover the 
      cycloheximide-induced increase in mTORC1 signaling was significantly attenuated 
      in cells lacking REDD1, showing that REDD1 plays an integral role in the 
      response. Finally, the half-life of REDD1 was estimated to be 5 min or less. 
      Overall, the results are consistent with a model in which inhibition of protein 
      synthesis leads to a loss of REDD1 protein because of its rapid degradation, and 
      in part reduced REDD1 expression subsequently leads to de-repression of mTORC1 
      activity.
FAU - Kimball, Scot R
AU  - Kimball SR
AD  - Department of Cellular and Molecular Physiology, Pennsylvania State University 
      College of Medicine, Hershey, Pennsylvania 17033 and the. Electronic address: 
      skimball@psu.edu.
FAU - Do, A N Dang
AU  - Do AND
AD  - Department of Cellular and Molecular Physiology, Pennsylvania State University 
      College of Medicine, Hershey, Pennsylvania 17033 and the.
FAU - Kutzler, Lydia
AU  - Kutzler L
AD  - Department of Cellular and Molecular Physiology, Pennsylvania State University 
      College of Medicine, Hershey, Pennsylvania 17033 and the.
FAU - Cavener, Douglas R
AU  - Cavener DR
AD  - Department of Biology, The Pennsylvania State University, University Park, 
      Pennsylvania 16802.
FAU - Jefferson, Leonard S
AU  - Jefferson LS
AD  - Department of Cellular and Molecular Physiology, Pennsylvania State University 
      College of Medicine, Hershey, Pennsylvania 17033 and the.
LA  - eng
GR  - R01 DK013499/DK/NIDDK NIH HHS/United States
GR  - R01 DK013499-38/DK/NIDDK NIH HHS/United States
GR  - R01 DK013499-39/DK/NIDDK NIH HHS/United States
GR  - DK-13499/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20071210
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Ddit4 protein, mouse)
RN  - 0 (Neuropeptides)
RN  - 0 (Phosphoproteins)
RN  - 0 (Protein Synthesis Inhibitors)
RN  - 0 (RNA, Messenger)
RN  - 0 (Ras Homolog Enriched in Brain Protein)
RN  - 0 (Rheb protein, mouse)
RN  - 0 (TRB3 protein, mouse)
RN  - 0 (Transcription Factors)
RN  - 0 (Tsc2 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (proline-rich Akt substrate, 40 kDa protein, mouse)
RN  - 98600C0908 (Cycloheximide)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (Monomeric GTP-Binding Proteins)
SB  - IM
MH  - Animals
MH  - Cell Cycle Proteins/metabolism
MH  - Cycloheximide/pharmacology
MH  - *Gene Expression Regulation
MH  - Mice
MH  - Mice, Transgenic
MH  - Models, Biological
MH  - Monomeric GTP-Binding Proteins/metabolism/*physiology
MH  - Neuropeptides/metabolism/*physiology
MH  - Phosphoproteins/metabolism/*physiology
MH  - Protein Biosynthesis
MH  - Protein Kinases/metabolism/*physiology
MH  - Protein Synthesis Inhibitors/pharmacology
MH  - RNA, Messenger/metabolism
MH  - Ras Homolog Enriched in Brain Protein
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/*physiology
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins
PMC - PMC2654224
MID - NIHMS89144
EDAT- 2007/12/12 09:00
MHDA- 2008/04/01 09:00
PMCR- 2009/03/11
CRDT- 2007/12/12 09:00
PHST- 2007/12/12 09:00 [pubmed]
PHST- 2008/04/01 09:00 [medline]
PHST- 2007/12/12 09:00 [entrez]
PHST- 2009/03/11 00:00 [pmc-release]
AID - S0021-9258(20)69811-8 [pii]
AID - 10.1074/jbc.M706643200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 Feb 8;283(6):3465-3475. doi: 10.1074/jbc.M706643200. Epub 2007 
      Dec 10.