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Modulation of glutamine metabolism by the PI(3)K-PKB-FOXO network regulates autophagy

van der Vos, K. E., Eliasson, P., Proikas-Cezanne, T., Vervoort, S. J., van Boxtel, R., Putker, M., van Zutphen, I. J., Mauthe, M., Zellmer, S., Pals, C., Verhagen, L. P., Groot Koerkamp, M. J. A., Braat, A. K., Dansen, T. B., Holstege, F. C., Gebhardt, R., Burgering, B. M. & Coffer, P. J., 14-Aug-2012, In : Nature Cell Biology. 14, 8, p. 829-837 9 p.

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  • Modulation of glutamine metabolism by the PI(3)K–PKB–FOXO network regulates autophagy

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DOI

  • Kristan E van der Vos
  • Pernilla Eliasson
  • Tassula Proikas-Cezanne
  • Stephin J Vervoort
  • Ruben van Boxtel
  • Marrit Putker
  • Iris J van Zutphen
  • Mario Mauthe
  • Sebastian Zellmer
  • Cornelieke Pals
  • Liesbeth P Verhagen
  • Marian J A Groot Koerkamp
  • A Koen Braat
  • Tobias B Dansen
  • Frank C Holstege
  • Rolf Gebhardt
  • Boudewijn M Burgering
  • Paul J Coffer

The PI(3)K-PKB-FOXO signalling network provides a major intracellular hub for the regulation of cell proliferation, survival and stress resistance. Here we report an unexpected role for FOXO transcription factors in regulating autophagy by modulating intracellular glutamine levels. To identify transcriptional targets of this network, we performed global transcriptional analyses after conditional activation of the key components PI(3)K, PKB/Akt, FOXO3 and FOXO4. Using this pathway approach, we identified glutamine synthetase as being transcriptionally regulated by PI(3)K-PKB-FOXO signalling. Conditional activation of FOXO also led to an increased level of glutamine production. FOXO activation resulted in mTOR inhibition by preventing the translocation of mTOR to lysosomal membranes in a glutamine-synthetase-dependent manner. This resulted in an increased level of autophagy as measured by LC3 lipidation, p62 degradation and fluorescent imaging of multiple autophagosomal markers. Inhibition of FOXO3-mediated autophagy increased the level of apoptosis, suggesting that the induction of autophagy by FOXO3-mediated glutamine synthetase expression is important for cellular survival. These findings reveal a growth-factor-responsive network that can directly modulate autophagy through the regulation of glutamine metabolism.

Original languageEnglish
Pages (from-to)829-837
Number of pages9
JournalNature Cell Biology
Volume14
Issue number8
Publication statusPublished - 14-Aug-2012

    Keywords

  • 3-Phosphoinositide-Dependent Protein Kinases, Animals, Autophagy, Base Sequence, Blotting, Western, Cell Proliferation, Forkhead Box Protein O3, Forkhead Transcription Factors/genetics, Gene Expression Regulation, Glutamate Synthase/genetics, Glutamine/metabolism, Humans, Mice, Microarray Analysis, Molecular Sequence Data, Phosphatidylinositol 3-Kinases/genetics, Polymerase Chain Reaction, Protein-Serine-Threonine Kinases/genetics, Rats, Sequence Alignment, Signal Transduction

ID: 72812519