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The function of FOXO1 in the late phases of the cell cycle is suppressed by PLK1-mediated phosphorylation

Chengfu Yuan1, Lei Wang2, Liang Zhou1

  • 1Department of Human and Molecular Genetics; VCU Institute of Molecular Genetics; VCU Massey Cancer Center; Virginia Commonwealth University School of Medicine; Richmond, VA USA.

Cell Cycle (Georgetown, Tex.)
|January 11, 2014
PubMed

Insights

Polo-like kinase 1 (PLK1) phosphorylates forkhead box protein O1 (FOXO1), inhibiting its activity and promoting cell cycle progression. This interaction, crucial for cell division, reveals how PLK1 regulates FOXO1 to ensure cell survival and timely cell cycle progression.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Polo-like kinase 1 (PLK1) is vital for cell division, with its depletion impacting cell viability and apoptosis.
  • The precise mechanisms underlying PLK1's functions, particularly its transcriptional regulation, are not fully understood.

Purpose of the Study:

  • To identify novel substrates of PLK1 and elucidate their role in cell cycle regulation.
  • To investigate the interaction between PLK1 and forkhead box protein O1 (FOXO1) and its impact on cellular processes.

Main Methods:

  • Co-immunoprecipitation to detect PLK1-FOXO1 interaction.
  • Western blotting and in vitro kinase assays to confirm phosphorylation.
  • Immunofluorescence staining and subcellular fractionation to assess FOXO1 localization.
  • Cell viability assays and cell cycle analysis.

Main Results:

  • Forkhead box protein O1 (FOXO1) is identified as a novel physiological substrate of PLK1.
  • PLK1 phosphorylates FOXO1, primarily during the G2/M phase, impairing its transcriptional activity independently of Akt.
  • PLK1-induced FOXO1 phosphorylation leads to nuclear exclusion of FOXO1.
  • This phosphorylation abrogates FOXO1's pro-apoptotic function and its ability to inhibit cell cycle progression at G2/M.

Conclusions:

  • PLK1 negatively regulates FOXO1's function by promoting its nuclear exclusion and inhibiting its transcriptional activity.
  • PLK1-mediated phosphorylation of FOXO1 is a key mechanism for overcoming FOXO1-dependent cell growth inhibition and promoting cell survival.
  • This study reveals a novel regulatory pathway for FOXO1 during late cell cycle phases and sheds light on PLK1's role in cell cycle control and apoptosis.
Keywords:
FOXO1PLK1apoptosiscell divisionnuclear-cytoplasmic shuttlingphosphorylationregulationtranscription factor

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