PMID- 22904092
OWN - NLM
STAT- MEDLINE
DCOM- 20130114
LR  - 20211203
IS  - 1362-4962 (Electronic)
IS  - 0305-1048 (Print)
IS  - 0305-1048 (Linking)
VI  - 40
IP  - 19
DP  - 2012 Oct
TI  - Translation termination efficiency modulates ATF4 response by regulating ATF4 
      mRNA translation at 5' short ORFs.
PG  - 9557-70
LID - 10.1093/nar/gks762 [doi]
AB  - The activating transcription factor 4 (ATF4) promotes transcriptional 
      upregulation of specific target genes in response to cellular stress. ATF4 
      expression is regulated at the translational level by two short open reading 
      frames (uORFs) in its 5'-untranslated region (5'-UTR). Here, we describe a 
      mechanism regulating ATF4 expression in translation termination-deficient human 
      cells. Using microarray analysis of total RNA and polysome-associated mRNAs, we 
      show that depletion of the eucaryotic release factor 3a (eRF3a) induces 
      upregulation of ATF4 and of ATF4 target genes. We show that eRF3a depletion 
      modifies ATF4 translational control at regulatory uORFs increasing ATF4 ORF 
      translation. Finally, we show that the increase of REDD1 expression, one of the 
      upregulated targets of ATF4, is responsible for the mTOR pathway inhibition in 
      eRF3a-depleted cells. Our results shed light on the molecular mechanisms 
      connecting eRF3a depletion to mammalian target of rapamycin (mTOR) pathway 
      inhibition and give an example of ATF4 activation that bypasses the signal 
      transduction cascade leading to the phosphorylation of eIF2alpha. We propose that in 
      mammals, in which the 5'-UTR regulatory elements of ATF4 mRNA are strictly 
      conserved, variations in translation termination efficiency allow the modulation 
      of the ATF4 response.
FAU - Ait Ghezala, Hayet
AU  - Ait Ghezala H
AD  - UPMC Univ Paris 06, CNRS-FRE 3402, Biologie de l'ARN, 9 quai Saint Bernard, 75005 
      Paris, France.
FAU - Jolles, Beatrice
AU  - Jolles B
FAU - Salhi, Samia
AU  - Salhi S
FAU - Castrillo, Katia
AU  - Castrillo K
FAU - Carpentier, Wassila
AU  - Carpentier W
FAU - Cagnard, Nicolas
AU  - Cagnard N
FAU - Bruhat, Alain
AU  - Bruhat A
FAU - Fafournoux, Pierre
AU  - Fafournoux P
FAU - Jean-Jean, Olivier
AU  - Jean-Jean O
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120816
PL  - England
TA  - Nucleic Acids Res
JT  - Nucleic acids research
JID - 0411011
RN  - 0 (ATF4 protein, human)
RN  - 0 (DDIT4 protein, human)
RN  - 0 (Peptide Termination Factors)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
RN  - 0 (peptide-chain-release factor 3)
RN  - 145891-90-3 (Activating Transcription Factor 4)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Activating Transcription Factor 4/*genetics/metabolism
MH  - Cell Line, Tumor
MH  - *Gene Expression Regulation
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Oligonucleotide Array Sequence Analysis
MH  - *Open Reading Frames
MH  - *Peptide Chain Termination, Translational
MH  - Peptide Termination Factors/genetics/physiology
MH  - RNA Stability
MH  - RNA, Messenger/metabolism
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
MH  - Transcription Factors/metabolism
MH  - Transcriptome
PMC - PMC3479206
EDAT- 2012/08/21 06:00
MHDA- 2013/01/15 06:00
PMCR- 2012/08/13
CRDT- 2012/08/21 06:00
PHST- 2012/08/21 06:00 [entrez]
PHST- 2012/08/21 06:00 [pubmed]
PHST- 2013/01/15 06:00 [medline]
PHST- 2012/08/13 00:00 [pmc-release]
AID - gks762 [pii]
AID - 10.1093/nar/gks762 [doi]
PST - ppublish
SO  - Nucleic Acids Res. 2012 Oct;40(19):9557-70. doi: 10.1093/nar/gks762. Epub 2012 
      Aug 16.