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Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation

Haojie Huang1, Kevin M Regan, Fang Wang

  • 1Department of Biochemistry, and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

Proceedings of the National Academy of Sciences of the United States of America
|January 26, 2005
PubMed

Insights

Skp2 ubiquitin ligase targets FOXO1 for degradation, promoting tumor growth. This Skp2-mediated proteolysis of FOXO1 is crucial in tumorigenesis, impacting cell proliferation and survival.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • Forkhead transcription factors (FOXO1, FOXO3a, FOXO4) are critical tumor suppressors.
  • Loss of FOXO function via degradation contributes to cancer development.

Purpose of the Study:

  • Identify the ubiquitin ligase responsible for FOXO ubiquitination.
  • Investigate the role of this regulation in tumorigenesis.

Main Methods:

  • Investigated the interaction between Skp2 and FOXO1.
  • Assessed Skp2-mediated ubiquitination and degradation of FOXO1.
  • Examined the effect of Skp2 on FOXO1 transactivation and cellular processes.
  • Analyzed FOXO1 expression in a mouse lymphoma model with Skp2 overexpression.

Main Results:

  • Skp2 directly interacts with, ubiquitinates, and degrades FOXO1.
  • Skp2-induced FOXO1 degradation is dependent on Akt-mediated phosphorylation at Ser-256.
  • Skp2 expression inhibits FOXO1 activity and its tumor-suppressive functions.
  • FOXO1 protein is lost in a mouse lymphoma model with high Skp2 expression.

Conclusions:

  • Skp2-promoted proteolysis of FOXO1 is a significant mechanism in tumorigenesis.
  • Targeting the Skp2-FOXO1 axis may offer therapeutic strategies for cancer.

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