Document Detail

Translational control of entrainment and synchrony of the suprachiasmatic circadian clock by mTOR/4E-BP1 signaling.
MedLine Citation:
PMID:  23972597     Owner:  NLM     Status:  MEDLINE    
Protein synthesis is critical for circadian clock function, but little is known of how translational regulation controls the master pacemaker in mammals, the suprachiasmatic nucleus (SCN). Here we demonstrate that the pivotal translational repressor, the eukaryotic translational initiation factor 4E binding protein 1 (4E-BP1), is rhythmically regulated via the mechanistic target of rapamycin (mTOR) signaling in the SCN and preferentially represses vasoactive intestinal peptide (Vip) mRNA translation. Knockout (KO) of Eif4ebp1 (gene encoding 4E-BP1) leads to upregulation of VIP and higher amplitude of molecular rhythms in the SCN. Consequently, the 4E-BP1 null mice exhibit accelerated re-entrainment to a shifted light/dark cycle and are more resistant to the rhythm-disruptive effects of constant light. Conversely, in Mtor(+/-) mice VIP expression is decreased and susceptibility to the effects of constant light is increased. These results reveal a key role for mTOR/4E-BP1-mediated translational control in regulating entrainment and synchrony of the master clock.
Ruifeng Cao; Barry Robinson; Haiyan Xu; Christos Gkogkas; Arkady Khoutorsky; Tommy Alain; Akiko Yanagiya; Tatiana Nevarko; Andrew C Liu; Shimon Amir; Nahum Sonenberg
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Neuron     Volume:  79     ISSN:  1097-4199     ISO Abbreviation:  Neuron     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-08-26     Completed Date:  2013-11-04     Revised Date:  2014-02-24    
Medline Journal Info:
Nlm Unique ID:  8809320     Medline TA:  Neuron     Country:  United States    
Other Details:
Languages:  eng     Pagination:  712-24     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Elsevier Inc. All rights reserved.
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MeSH Terms
Anthraquinones / pharmacology
Butadienes / pharmacology
Carrier Proteins / physiology*
Cell Line, Tumor
Circadian Rhythm / physiology*
Enzyme Inhibitors / pharmacology
Gene Expression Regulation / drug effects,  physiology*
Indoles / pharmacology
Mice, Inbred C57BL
Mice, Knockout
Nitriles / pharmacology
Period Circadian Proteins / genetics,  metabolism
Phosphoproteins / deficiency,  physiology*
Phosphorylation / drug effects,  genetics
Purines / pharmacology
RNA, Messenger / metabolism
RNA, Small Interfering / genetics,  metabolism
Signal Transduction / drug effects,  genetics,  physiology*
Sirolimus / pharmacology
Suprachiasmatic Nucleus / metabolism*
TOR Serine-Threonine Kinases / antagonists & inhibitors,  physiology*
Vasoactive Intestinal Peptide / genetics,  metabolism
Grant Support
MOP 13625//Canadian Institutes of Health Research; MOP114994//Canadian Institutes of Health Research; R01 GM066157/GM/NIGMS NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/1,5-bis((2-(methylamino)ethyl)amino)-4,8-dihydroxyanthracene-9,10-dione; 0/Anthraquinones; 0/Butadienes; 0/Carrier Proteins; 0/Eif4ebp1 protein, mouse; 0/Enzyme Inhibitors; 0/Indoles; 0/Nitriles; 0/PP242; 0/Per1 protein, mouse; 0/Per2 protein, mouse; 0/Period Circadian Proteins; 0/Phosphoproteins; 0/Purines; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/U 0126; 37221-79-7/Vasoactive Intestinal Peptide; EC Serine-Threonine Kinases; EC protein, mouse; W36ZG6FT64/Sirolimus

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