A Conserved MST-FOXO Signaling Pathway Mediates Oxidative-Stress Responses and Extends Life Span

We demonstrate that the protein kinase MST1 mediates oxidativestress-induced cell death in primary mammalian neurons by directly activating the FOXO transcription factors

Maria K. Lehtinen; Zengqiang Yuan; Peter R. Boag; Yue Yang; Judit Villén; Esther B.E. Becker; Sara DiBacco; Núria de la Iglesia; Steven Gygi; T. Keith Blackwell; Azad Bonni

2006

Scholarcy highlights

  • Oxidative stress impacts diverse biological processes, including cell survival and aging as well as the pathogenesis of many diseases ranging from diabetes to neurodegenerative disorders of the brain
  • We find that MST1 phosphorylates the FOXO transcription factors at a site that is conserved within the forkhead domain of these proteins from mammals to C. elegans
  • We found that exposure of granule neurons to hydrogen peroxide stimulated the increased autophosphorylation of MST1/2, suggesting that the mammalian Ste20-like kinases family of kinases is activated in neurons in response to oxidative stress
  • To determine the importance of oxidative-stress-induced endogenous MST1 in neurons, we employed a plasmidbased method of RNA interference
  • Our findings suggest that exposure of primary mammalian neurons to acute oxidative stress stimulates the activation of MST1 and its association with FOXO3, leading to the phosphorylation of FOXO3 at serine 207
  • It will be interesting to consider the potential role of FOXO proteins downstream of MST kinases in cell death induced by other stimuli in addition to oxidative stress, including the activation of tumor suppressors
  • The identification of the FOXO transcription factors as major and evolutionarily conserved targets of MST1 suggests that mammalian Ste20-like kinases kinases play important roles in diverse biological processes including cellular responses to oxidative stress and longevity

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