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Nuclear/cytoplasmic shuttling of the transcription factor FoxO1 is regulated by neurotrophic factors

Lixia Gan1, Wenhua Zheng, Jean-Guy Chabot

  • 1Douglas Hospital Research Center, Department of Psychiatry, McGill University, Montreal, Québec, Canada.

Journal of Neurochemistry
|June 7, 2005
PubMed

Insights

Neurotrophic factors like IGF-1 and NGF regulate the movement of the FoxO1 (Forkhead box protein 1) transcription factor in neurons. This process is mediated by the PI3K/Akt pathway, impacting neuronal function.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Signaling

Background:

  • The role of FoxO1 (Forkhead box protein 1) in the central nervous system is largely unexplored.
  • FoxO1 is a key regulator of metabolism, cell cycle, and survival in peripheral tissues, targeted by insulin and growth factor signaling.

Purpose of the Study:

  • To investigate the impact of neurotrophic factors on the nuclear-cytoplasmic shuttling of FoxO1 in neuronal cells.
  • To elucidate the signaling pathways involved in neurotrophic factor-mediated FoxO1 regulation.

Main Methods:

  • Utilized PC12 cells and primary neuronal cultures (hippocampal and cortical).
  • Employed FoxO1-green fluorescent protein (GFP) fusion proteins and a PI3K/Akt inhibitor (LY294002).
  • Investigated phosphorylation sites and created triple alanine mutant FoxO1.

Main Results:

  • Insulin-like growth factor-1 (IGF-1) and nerve growth factor (NGF) induced FoxO1 nuclear exclusion in PC12 cells.
  • Neurotrophin-3 (NT-3), NT-4, and brain-derived neurotrophic factor (BDNF) had weaker or no effect.
  • FoxO1 phosphorylation at Thr24 and Ser256 was observed, and a triple mutant FoxO1 exhibited complete nuclear localization despite neurotrophic factor treatment.
  • Inhibition of PI3K/Akt pathway blocked FoxO1 translocation.

Conclusions:

  • Neurotrophic factors modulate FoxO1 nuclear/cytoplasmic localization in neuronal cells.
  • The PI3K/Akt pathway is crucial for mediating neurotrophic factor-induced FoxO1 shuttling.
  • Phosphorylation of specific Akt/PKB sites on FoxO1 is a key mechanism in this regulation.

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