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The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its

Dan Kawamori1, Hideaki Kaneto, Yoshihisa Nakatani

  • 1Department of Internal Medicine and Therapeutics (A8), Osaka University Graduate School of Medicine, Suita City, Japan.

The Journal of Biological Chemistry
|November 12, 2005
PubMed

Insights

Oxidative stress and JNK signaling disrupt pancreatic beta-cell function by affecting PDX-1. The study reveals Foxo1 acts as a key mediator in this process, influencing PDX-1 translocation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Endocrinology

Background:

  • Oxidative stress and c-Jun N-terminal kinase (JNK) pathway activation are known to cause pancreatic beta-cell dysfunction.
  • This dysfunction is linked to the nucleocytoplasmic translocation of the pancreatic transcription factor PDX-1.

Purpose of the Study:

  • To investigate the role of the forkhead transcription factor Foxo1/FKHR as a mediator between the JNK pathway and PDX-1.
  • To elucidate the mechanisms underlying PDX-1 translocation under oxidative stress.

Main Methods:

  • Utilized the pancreatic beta-cell line HIT-T15.
  • Manipulated JNK pathway activity (overexpression and suppression).
  • Assessed intracellular localization of Foxo1 and PDX-1.
  • Employed adenovirus-mediated gene transfer and small interfering RNA (siRNA) for Foxo1 manipulation.
  • Measured Akt activity and Foxo1 phosphorylation.

Main Results:

  • Oxidative stress induced nuclear localization of Foxo1 in HIT-T15 cells.
  • JNK pathway activation mimicked and mediated oxidative stress-induced Foxo1 nuclear translocation.
  • Akt activity decreased, leading to reduced Foxo1 phosphorylation under oxidative stress or JNK activation.
  • Foxo1 overexpression reduced nuclear PDX-1, while Foxo1 suppression maintained PDX-1 nuclear expression under oxidative stress.

Conclusions:

  • Foxo1 acts as a crucial mediator in the nucleocytoplasmic translocation of PDX-1.
  • The JNK pathway and oxidative stress influence PDX-1 translocation via Foxo1.
  • Findings provide insights into the molecular mechanisms of pancreatic beta-cell dysfunction.

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