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Regulation of FoxO activity by CBP/p300-mediated acetylation

Lars P van der Heide1, Marten P Smidt

  • 1Rudolf Magnus Institute of Neuroscience, UMC Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.

Trends in Biochemical Sciences
|February 5, 2005
PubMed

Insights

Acetylation of Forkhead box, class O (FoxO) transcription factors by CBP/p300 inhibits their DNA binding. This acetylation shifts FoxO function from cell protection to promoting cell death.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Transcription Regulation

Background:

  • Insulin signaling inhibits Forkhead box, class O (FoxO) transcription factors via phosphorylation.
  • Acetylation by CREB-binding protein (CBP) and p300 represents a novel regulatory pathway for FoxO factors.
  • The precise functional outcomes of FoxO acetylation remain incompletely understood.

Purpose of the Study:

  • To investigate the role of CBP/p300-mediated acetylation in regulating FoxO transcription factor activity.
  • To elucidate the mechanism by which acetylation affects FoxO binding to target DNA.
  • To determine how acetylation influences the cellular functions governed by FoxO.

Main Methods:

  • Investigated the interaction between FoxO factors and CBP/p300.
  • Assessed the impact of acetylation on FoxO binding to DNA.
  • Evaluated changes in FoxO-mediated transcriptional activity and cellular outcomes.

Main Results:

  • Binding of CBP/p300 to FoxO factors is crucial for FoxO-mediated transcription.
  • CBP/p300 function as cofactors by destabilizing histone-DNA interactions.
  • Acetylation of FoxO factors by CBP/p300 disrupts their interaction with target DNA, attenuating transcriptional activity.
  • Acetylation redirects FoxO function from cell-cycle arrest and oxidative stress resistance towards promoting cell death.

Conclusions:

  • Acetylation by CBP/p300 acts as a critical switch in FoxO factor function.
  • This post-translational modification reconfigures FoxO from a protective role to one that promotes cell death.
  • Understanding this acetylation-dependent regulation is key to deciphering FoxO's diverse cellular roles.

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