 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Jul 22, 2012 |
| Title |
CP003: Modulation of glutamine metabolism by the PI3K-PKB/c-akt-FOXO network regulates autophagy |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
|
| Summary |
The PI3K-PKB/c-akt-FOXO signalling network provides a major intracellular hub for regulation of cell proliferation, survival and stress resistance1. Here we report a novel function for FOXO transcription factors in regulating autophagy through modulation of intracellular glutamine levels. To identify novel transcriptional targets of this module we performed an unbiased microarray analysis after conditional activation of the key components PI3K, PKB, FOXO3 and FOXO4. Utilising this global pathway approach we identified glutamine synthetase (GS) as being transcriptionally regulated by PI3K-PKB-FOXO signalling. FOXO-mediated increase in GS expression specifically induced glutamine production independently of cell type, and this was evolutionary conserved. FOXO activation resulted in mTOR inhibition by preventing the translocation of mTOR to lysosomal membranes, which was dependent on GS activity. Increased GS activity resulted in increased autophagosome turnover as measured by LC3 lipidation, p62 degradation, and confocal imaging of LC3, p62, WIPI-1, ULK2 and Atg12. Inhibition of FOXO3-mediated autophagy resulted in increased apoptosis, suggesting that the induction of autophagy by FOXO3-mediated upregulation of GS is important for cellular survival. These findings reveal a novel signalling network that can directly modulate autophagy through regulation of glutamine metabolism.
|
| |
|
| Overall design |
conditional activation of foxo3 and foxo4 were followed in a timeseries. Each timepoint consists of 4 independent replicates, labeled with either cy3 or cy5 and put on array against time0 as reference.
|
| |
|
| Contributor(s) |
van der Vos KE, Eliasson P, Proikas-Cezanne T, Vervoort S, van Boxtel R, Putker M, van Zutphen IJ, Mauthe M, Zellmer S, Pals C, Verhagen L, Braat K, Dansen TB, Holstege FC, Gebhardt R, Burgering BM, Coffer PJ, Groot Koerkamp MJ |
| Citation(s) |
22820375 |
| Submission date |
Feb 10, 2012 |
| Last update date |
Sep 09, 2013 |
| Contact name |
Marian Groot Koerkamp |
| Organization name |
Princess Maxima Center for Pediatric Oncology
|
| Department |
Research
|
| Lab |
Drostlab
|
| Street address |
Heidelberglaan 25
|
| City |
Utrecht |
| State/province |
Utrecht |
| ZIP/Postal code |
3584 CS |
| Country |
Netherlands |
| |
|
| Platforms (1) |
|
| Samples (16)
|
|
| This SubSeries is part of SuperSeries: |
| GSE35705 |
Modulation of glutamine metabolism by the PI3K-PKB/c-akt-FOXO network regulates autophagy |
|
| Relations |
| BioProject |
PRJNA155671 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE35703_RAW.tar |
32.4 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
|
|
|
|
 |
Less...
More...