Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons

Science. 2008 Mar 21;319(5870):1665-8. doi: 10.1126/science.1152337.

Abstract

Activation of cyclin-dependent kinase 1 (Cdk1) has been linked to cell death of postmitotic neurons in brain development and disease. We found that Cdk1 phosphorylated the transcription factor FOXO1 at Ser249 in vitro and in vivo. The phosphorylation of FOXO1 at Ser249 disrupted FOXO1 binding with 14-3-3 proteins and thereby promoted the nuclear accumulation of FOXO1 and stimulated FOXO1-dependent transcription, leading to cell death in neurons. In proliferating cells, Cdk1 induced FOXO1 Ser249 phosphorylation at the G2/M phase of the cell cycle, resulting in FOXO1-dependent expression of the mitotic regulator Polo-like kinase (Plk). These findings define a conserved signaling link between Cdk1 and FOXO1 that may have a key role in diverse biological processes, including the degeneration of postmitotic neurons.

Publication types

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

MeSH terms

  • 14-3-3 Proteins / metabolism
  • Animals
  • Apoptosis
  • CDC2 Protein Kinase / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Cycle*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism*
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Rats
  • Serine / metabolism
  • Signal Transduction
  • Transcription, Genetic

Substances

  • 14-3-3 Proteins
  • Cell Cycle Proteins
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins
  • Foxo1 protein, rat
  • Serine
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1
  • CDC2 Protein Kinase