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Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress

Yusuke S Hori1, Atsushi Kuno, Ryusuke Hosoda

  • 1Department of Pharmacology, School of Medicine, Sapporo Medical University, Sapporo, Japan.

Plos One
|September 17, 2013
PubMed

Insights

Forkhead O (FOXO) transcription factors are crucial for sirtuin-1

Area of Science:

  • Cellular Biology
  • Biochemistry
  • Molecular Biology

Background:

  • Excessive reactive oxygen species (ROS) contribute to disease and aging.
  • Sirtuin-1 (SIRT1) is an NAD+-dependent deacetylase that reduces ROS and promotes cell survival.
  • SIRT1 influences p53 and Forkhead O (FOXO) transcription factors involved in cell fate.

Purpose of the Study:

  • To determine the roles of p53 and FOXO transcription factors in SIRT1's protective functions against oxidative stress.

Main Methods:

  • Utilized SIRT1 inhibitors (nicotinamide, splitomicin) and activators (resveratrol, NAD+).
  • Employed SIRT1-siRNA, p53-knockdown, and p53-deficient cells.
  • Investigated FOXO1, FOXO3a, and FOXO4 involvement via siRNA knockdown.

Main Results:

  • SIRT1 inhibition exacerbated ROS and apoptosis; activation by resveratrol suppressed them.
  • Resveratrol's effects were mediated by both p53-dependent and independent pathways.
  • FOXO1, FOXO3a, and FOXO4 were essential for resveratrol-induced SOD2 upregulation, ROS reduction, and anti-apoptosis.

Conclusions:

  • FOXO1, FOXO3a, and FOXO4 are indispensable for SIRT1-mediated cell survival under oxidative stress.
  • While p53 deacetylation plays a role, FOXOs are the primary mediators of SIRT1's protective effects via SOD2.

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