PMID- 25793896
OWN - NLM
STAT- MEDLINE
DCOM- 20151207
LR  - 20191210
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 3
DP  - 2015
TI  - Multi-functional regulation of 4E-BP gene expression by the Ccr4-Not complex.
PG  - e0113902
LID - 10.1371/journal.pone.0113902 [doi]
LID - e0113902
AB  - The mechanistic target of rapamycin (mTOR) signaling pathway is highly conserved 
      from yeast to humans. It senses various environmental cues to regulate cellular 
      growth and homeostasis. Deregulation of the pathway has been implicated in many 
      pathological conditions including cancer. Phosphorylation cascades through the 
      pathway have been extensively studied but not much is known about the regulation 
      of gene expression of the pathway components. Here, we report that the mRNA level 
      of eukaryotic translation initiation factor (eIF) subunit 4E-binding protein 
      (4E-BP) gene, one of the key mTOR signaling components, is regulated by the 
      highly conserved Ccr4-Not complex. RNAi knockdown of Not1, a putative scaffold 
      protein of this protein complex, increases the mRNA level of 4E-BP in Drosophila 
      Kc cells. Examination of the gene expression mechanism using reporter swap 
      constructs reveals that Not1 depletion increases reporter mRNAs with the 3'UTR of 
      4E-BP gene, but decreases the ones with the 4E-BP promoter region, suggesting 
      that Ccr4-Not complex regulates both degradation and transcription of 4E-BP mRNA. 
      These results indicate that the Ccr4-Not complex controls expression of a single 
      gene at multiple levels and adjusts the magnitude of the total effect. Thus, our 
      study reveals a novel regulatory mechanism of a key component of the mTOR 
      signaling pathway at the level of gene expression.
FAU - Okada, Hirokazu
AU  - Okada H
AD  - Institute of Molecular Systems Biology, Swiss Federal Institute of Technology 
      (ETH) Zurich, Wolfgang Pauli Str. 16, 8093, Zurich, Switzerland.
FAU - Schittenhelm, Ralf B
AU  - Schittenhelm RB
AD  - Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, 
      Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton 
      Campus, Wellington Road, Clayton, Victoria, 3800, Australia.
FAU - Straessle, Anna
AU  - Straessle A
AD  - Institute of Molecular Systems Biology, Swiss Federal Institute of Technology 
      (ETH) Zurich, Wolfgang Pauli Str. 16, 8093, Zurich, Switzerland.
FAU - Hafen, Ernst
AU  - Hafen E
AD  - Institute of Molecular Systems Biology, Swiss Federal Institute of Technology 
      (ETH) Zurich, Wolfgang Pauli Str. 16, 8093, Zurich, Switzerland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150320
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (3' Untranslated Regions)
RN  - 0 (Carrier Proteins)
RN  - 0 (Drosophila Proteins)
RN  - 0 (Insulin)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (NOT1 protein, Drosophila)
RN  - 0 (Peptide Initiation Factors)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (Thor protein, Drosophila)
RN  - EC 3.1.- (CCR4 protein, Drosophila)
RN  - EC 3.1.- (Ribonucleases)
SB  - IM
MH  - 3' Untranslated Regions/genetics
MH  - Animals
MH  - Carrier Proteins/*metabolism
MH  - Cell Line
MH  - Cell Size/drug effects
MH  - Drosophila Proteins/*genetics/*metabolism
MH  - Drosophila melanogaster/cytology/*genetics
MH  - *Gene Expression Regulation
MH  - Insulin/pharmacology
MH  - Intracellular Signaling Peptides and Proteins/*genetics/metabolism
MH  - Peptide Initiation Factors/*genetics/metabolism
MH  - Phosphorylation
MH  - Promoter Regions, Genetic/genetics
MH  - Protein Biosynthesis
MH  - RNA Stability/genetics
MH  - RNA, Messenger/genetics/metabolism
MH  - RNA-Binding Proteins
MH  - Ribonucleases/*metabolism
MH  - Transcription, Genetic
PMC - PMC4368434
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/03/21 06:00
MHDA- 2015/12/15 06:00
PMCR- 2015/03/20
CRDT- 2015/03/21 06:00
PHST- 2014/07/11 00:00 [received]
PHST- 2014/11/01 00:00 [accepted]
PHST- 2015/03/21 06:00 [entrez]
PHST- 2015/03/21 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
PHST- 2015/03/20 00:00 [pmc-release]
AID - PONE-D-14-31106 [pii]
AID - 10.1371/journal.pone.0113902 [doi]
PST - epublish
SO  - PLoS One. 2015 Mar 20;10(3):e0113902. doi: 10.1371/journal.pone.0113902. 
      eCollection 2015.