Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress

Nature. 2002 Sep 19;419(6904):316-21. doi: 10.1038/nature01036.

Abstract

Reactive oxygen species are required for cell proliferation but can also induce apoptosis. In proliferating cells this paradox is solved by the activation of protein kinase B (PKB; also known as c-Akt), which protects cells from apoptosis. By contrast, it is unknown how quiescent cells that lack PKB activity are protected against cell death induced by reactive oxygen species. Here we show that the PKB-regulated Forkhead transcription factor FOXO3a (also known as FKHR-L1) protects quiescent cells from oxidative stress by directly increasing their quantities of manganese superoxide dismutase (MnSOD) messenger RNA and protein. This increase in protection from reactive oxygen species antagonizes apoptosis caused by glucose deprivation. In quiescent cells that lack the protective mechanism of PKB-mediated signalling, an alternative mechanism is induced as a consequence of PKB inactivity. This mechanism entails the activation of Forkhead transcription factors, the transcriptional activation of MnSOD and the subsequent reduction of reactive oxygen species. Increased resistance to oxidative stress is associated with longevity. The model of Forkhead involvement in regulating longevity stems from genetic analysis in Caenorhabditis elegans, and we conclude that this model also extends to mammalian systems.

Publication types

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

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Apoptosis
  • Cell Survival
  • Chromatin / metabolism
  • Culture Media, Serum-Free
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation / drug effects
  • Enzyme Induction
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Glucose / metabolism
  • Humans
  • Insulin / pharmacology
  • JNK Mitogen-Activated Protein Kinases
  • Longevity / physiology
  • Mitogen-Activated Protein Kinases / metabolism
  • Models, Biological
  • Mutation / genetics
  • Oxidative Stress*
  • Promoter Regions, Genetic / genetics
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Superoxide Dismutase / biosynthesis*
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured

Substances

  • Antioxidants
  • Chromatin
  • Culture Media, Serum-Free
  • DNA-Binding Proteins
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Insulin
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Reactive Oxygen Species
  • Transcription Factors
  • Superoxide Dismutase
  • superoxide dismutase 2
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Glucose