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APE1/Ref-1 regulates PTEN expression mediated by Egr-1.

Damiano Fantini1, Carlo Vascotto, Marta Deganuto

  • 1Department of Biomedical Sciences and Technologies, University of Udine, Udine, Italy.

Free Radical Research
|March 8, 2008
PubMed
Summary

The multifunctional protein APE1 (Apέλy endonuclease 1) regulates cellular responses to oxidative stress by modulating PTEN expression. Acetylation of APE1 is crucial for activating PTEN gene expression, influencing cell survival pathways.

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Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • APE1/Ref-1 is a multifunctional protein with DNA repair and transcriptional regulatory roles.
  • It is critical in cellular response to oxidative stress and regulates genes via transcription factors like Egr-1 and p53.
  • PTEN is a key phosphatase in the PI-3K/Akt pathway, controlling cell growth and survival.

Purpose of the Study:

  • To investigate the role of APE1 in regulating PTEN expression.
  • To determine if APE1's acetylation status affects PTEN gene activation.
  • To elucidate the mechanism by which APE1 controls PTEN expression in response to oxidative stress.

Main Methods:

  • HeLa cells were used to study transient alterations in APE1 levels.
  • Experiments involved modulating APE1 levels, assessing PTEN expression, and analyzing APE1 acetylation.
  • Ectopic expression of Egr-1 and treatment with H(2)O(2) and histone deacetylase inhibitors were employed.

Main Results:

  • Transient changes in APE1 levels modulated PTEN expression in HeLa cells.
  • Acetylatable APE1 was required for PTEN gene activation, with acetylation enhancing its binding to regulatory complexes.
  • Exposure to H(2)O(2) and histone deacetylase inhibitors increased APE1 acetylation and PTEN induction, an effect absent in APE1-downregulated cells.
  • APE1-dependent PTEN expression was shown to be mediated by Egr-1.

Conclusions:

  • APE1 plays a significant role in the inducible expression of PTEN.
  • The acetylation status of APE1 is critical for its function in regulating PTEN.
  • These findings provide new insights into APE1's multifaceted functions in cellular oxidative stress response.