PMID- 23582324
OWN - NLM
STAT- MEDLINE
DCOM- 20130617
LR  - 20230209
IS  - 1097-4172 (Electronic)
IS  - 0092-8674 (Print)
IS  - 0092-8674 (Linking)
VI  - 153
IP  - 2
DP  - 2013 Apr 11
TI  - Exit from pluripotency is gated by intracellular redistribution of the bHLH 
      transcription factor Tfe3.
PG  - 335-47
LID - S0092-8674(13)00334-6 [pii]
LID - 10.1016/j.cell.2013.03.012 [doi]
AB  - Factors that sustain self-renewal of mouse embryonic stem cells (ESCs) are well 
      described. In contrast, the machinery regulating exit from pluripotency is ill 
      defined. In a large-scale small interfering RNA (siRNA) screen, we found that 
      knockdown of the tumor suppressors Folliculin (Flcn) and Tsc2 prevent ESC 
      commitment. Tsc2 lies upstream of mammalian target of rapamycin (mTOR), whereas 
      Flcn acts downstream and in parallel. Flcn with its interaction partners Fnip1 
      and Fnip2 drives differentiation by restricting nuclear localization and activity 
      of the bHLH transcription factor Tfe3. Conversely, enforced nuclear Tfe3 enables 
      ESCs to withstand differentiation conditions. Genome-wide location and functional 
      analyses showed that Tfe3 directly integrates into the pluripotency circuitry 
      through transcriptional regulation of Esrrb. These findings identify a 
      cell-intrinsic rheostat for destabilizing ground-state pluripotency to allow 
      lineage commitment. Congruently, stage-specific subcellular relocalization of 
      Tfe3 suggests that Flcn-Fnip1/2 contributes to developmental progression of the 
      pluripotent epiblast in vivo.
CI  - Copyright (c) 2013 Elsevier Inc. All rights reserved.
FAU - Betschinger, Joerg
AU  - Betschinger J
AD  - Wellcome Trust-Medical Research Council Stem Cell Institute, University of 
      Cambridge, Cambridge CB2 1QR, UK. jb579@cam.ac.uk
FAU - Nichols, Jennifer
AU  - Nichols J
FAU - Dietmann, Sabine
AU  - Dietmann S
FAU - Corrin, Philip D
AU  - Corrin PD
FAU - Paddison, Patrick J
AU  - Paddison PJ
FAU - Smith, Austin
AU  - Smith A
LA  - eng
SI  - GEO/GSE39815
GR  - 079249/WT_/Wellcome Trust/United Kingdom
GR  - G1001028/MRC_/Medical Research Council/United Kingdom
GR  - G1100526/MRC_/Medical Research Council/United Kingdom
GR  - MC_PC_12009/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cell
JT  - Cell
JID - 0413066
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors)
RN  - 0 (Carrier Proteins)
RN  - 0 (FNIP1 protein, mouse)
RN  - 0 (MAPO1 protein, mouse)
RN  - 136896-33-8 (Tcfe3 protein, mouse)
RN  - 2DI9HA706A (Estrone)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
CIN - Cell. 2013 Apr 11;153(2):281-3. PMID: 23582317
CIN - Nat Rev Mol Cell Biol. 2013 Jun;14(6):324. PMID: 23657495
MH  - Animals
MH  - Apoptosis Regulatory Proteins/metabolism
MH  - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/*metabolism
MH  - Carrier Proteins/metabolism
MH  - *Cell Differentiation
MH  - Embryonic Stem Cells/*cytology/metabolism
MH  - Estrone/genetics/metabolism
MH  - *Gene Regulatory Networks
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC3661979
EDAT- 2013/04/16 06:00
MHDA- 2013/06/19 06:00
PMCR- 2013/04/11
CRDT- 2013/04/16 06:00
PHST- 2012/08/03 00:00 [received]
PHST- 2013/01/14 00:00 [revised]
PHST- 2013/03/07 00:00 [accepted]
PHST- 2013/04/16 06:00 [entrez]
PHST- 2013/04/16 06:00 [pubmed]
PHST- 2013/06/19 06:00 [medline]
PHST- 2013/04/11 00:00 [pmc-release]
AID - S0092-8674(13)00334-6 [pii]
AID - 10.1016/j.cell.2013.03.012 [doi]
PST - ppublish
SO  - Cell. 2013 Apr 11;153(2):335-47. doi: 10.1016/j.cell.2013.03.012.