Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway

Science. 2002 Mar 29;295(5564):2450-2. doi: 10.1126/science.1069004. Epub 2002 Mar 7.

Abstract

Genetic determinants of longevity include the forkhead-related transcription factor DAF-16 in the worm Caenorhabditis elegans and the p66shc locus in mice. We demonstrate that p66shc regulates intracellular oxidant levels in mammalian cells and that hydrogen peroxide can negatively regulate forkhead activity. In p66shc-/- cells, the activity of the mammalian forkhead homolog FKHRL1 is increased and redox-dependent forkhead inactivation is reduced. In addition, expression of FKHRL1 results in an increase in both hydrogen peroxide scavenging and oxidative stress resistance. These results demonstrate an important functional relation between three distinct elements linked to aging: forkhead proteins, p66shc, and intracellular oxidants.

MeSH terms

  • Acetylcysteine / pharmacology
  • Adaptor Proteins, Signal Transducing*
  • Adaptor Proteins, Vesicular Transport*
  • Animals
  • Azoles / pharmacology
  • Blood
  • Cells, Cultured
  • Culture Media
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Free Radical Scavengers / pharmacology
  • Humans
  • Hydrogen Peroxide / metabolism
  • Hydrogen Peroxide / pharmacology
  • Mice
  • Mutation
  • Organoselenium Compounds / pharmacology
  • Oxidation-Reduction
  • Oxidative Stress
  • PC12 Cells
  • Phosphorylation
  • Protein-Serine-Threonine Kinases*
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Reactive Oxygen Species / metabolism
  • Shc Signaling Adaptor Proteins
  • Signal Transduction*
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Azoles
  • Culture Media
  • DNA-Binding Proteins
  • FOXO1 protein, human
  • FOXO3 protein, human
  • FOXO3 protein, rat
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • FoxO3 protein, mouse
  • Free Radical Scavengers
  • Organoselenium Compounds
  • Proteins
  • Proto-Oncogene Proteins
  • Reactive Oxygen Species
  • SHC1 protein, human
  • Shc Signaling Adaptor Proteins
  • Shc1 protein, mouse
  • Shc1 protein, rat
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Transcription Factors
  • Foxo1 protein, rat
  • ebselen
  • Hydrogen Peroxide
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Acetylcysteine