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

J Neurochem. 2005 Jun;93(5):1209-19. doi: 10.1111/j.1471-4159.2005.03108.x.

Abstract

FoxO1, a member of the FoxO subfamily of forkhead transcription factors, is an important target for insulin and growth factor signaling in the regulation of metabolism, cell cycle and proliferation, and survival in peripheral tissues. However, its role in the central nervous system is mostly unknown. In this study, we examined the effect of neurotrophic factors on nuclear/cytoplasmic shuttling of FoxO1. We showed that insulin-like growth factor-1 (IGF-1) and nerve growth factor (NGF) potently induced the nuclear exclusion of FoxO1-green fluorescent protein (GFP) while neurotrophin (NT)-3 and NT-4 were much weaker and brain-derived neurotrophic factor (BDNF) failed to induce FoxO1 translocation in PC12 cells. FoxO1 translocation was inhibited by LY294002, a well-established PI3K/Akt kinase inhibitor. Moreover, FoxO1 was phosphorylated at Thr24 and Ser256 residues by the above neurotrophic factors, with the exception of BDNF. Triple mutant FoxO1, in which three Akt/PKB phosphorylation sites (Thr24, Ser256 and Ser319) were mutated to alanine, resulted in the complete nuclear targeting of the expressed FoxO1-GFP fusion protein in the presence of the above neurotrophic factors in both PC12 cells and cultured hippocampal and cortical neurons. Taken together, these findings demonstrate that neurotrophic factors are able to regulate nuclear/cytoplasmic shuttling of FoxO1 via the PI3K/Akt pathway in neuronal cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Biological Transport / physiology
  • Cell Nucleus / metabolism*
  • Cytoplasm / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation / drug effects
  • Forkhead Transcription Factors
  • Green Fluorescent Proteins
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Luminescent Agents
  • Nerve Growth Factor / pharmacology
  • Nerve Growth Factors / pharmacology
  • Nerve Growth Factors / physiology*
  • Nerve Tissue Proteins / metabolism*
  • PC12 Cells
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / pharmacology
  • Tissue Distribution

Substances

  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Luminescent Agents
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Green Fluorescent Proteins
  • Foxo1 protein, rat
  • Insulin-Like Growth Factor I
  • Nerve Growth Factor
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt