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Calcineurin-mediated dephosphorylation stabilizes E2F1 protein by suppressing binding of the FBXW7 ubiquitin ligase

Yuki Sato1, Makoto Habara1, Shunsuke Hanaki1

  • 1Department of Veterinary Biochemistry, Yamaguchi University, Yamaguchi 753-8511, Japan.

Proceedings of the National Academy of Sciences of the United States of America
|October 3, 2024
PubMed

Insights

The ubiquitin ligase SCFFBXW7 targets E2F1 for degradation, a process inhibited by calcineurin. This pathway regulates cell proliferation and cancer development, offering potential therapeutic targets.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • E2F1 is a key cell cycle regulator and transcription factor.
  • E2F1 overexpression is linked to cancer progression.
  • Targeting E2F1 degradation may offer novel cancer therapies.

Purpose of the Study:

  • To identify the ubiquitin ligase responsible for E2F1 degradation.
  • To elucidate the regulatory mechanisms controlling E2F1 stability.
  • To explore the therapeutic potential of modulating E2F1 levels in cancer.

Main Methods:

  • Comprehensive analysis to identify SCFFBXW7 as the E2F1 ubiquitin ligase.
  • Investigated the role of E2F1 phosphorylation at serine-403 in FBXW7 binding.
  • Assessed the impact of calcineurin activity on E2F1 stability.
  • Utilized calcium channel blockers, ionomycin, and FK506 in cellular and in vivo models.

Main Results:

  • SCFFBXW7 was identified as the ubiquitin ligase for E2F1.
  • Phosphorylation of E2F1 at serine-403 promotes its degradation via FBXW7.
  • Calcineurin dephosphorylates E2F1 at serine-403, stabilizing the protein.
  • Calcium modulation and calcineurin inhibition affect E2F1 levels and target gene expression.
  • FK506 treatment inhibited tumor growth in mice by downregulating E2F1.

Conclusions:

  • The balance between FBXW7-mediated degradation and calcineurin-mediated stabilization of E2F1 is crucial for cell proliferation and cancer.
  • Dysregulation of this balance contributes to carcinogenesis.
  • Targeting the FBXW7-calcineurin-E2F1 axis presents a promising therapeutic strategy for cancer treatment.
Keywords:
E2F1FBXW7calciumdephosphorylationprotein stability

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