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VprBP/DCAF1 Regulates the Degradation and Nonproteolytic Activation of the Cell Cycle Transcription Factor FoxM1

Xianxi Wang1, Anthony Arceci1,2, Kelly Bird3

  • 1Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Molecular and Cellular Biology
|April 19, 2017
PubMed

Insights

The cullin 4-based E3 ubiquitin ligase CRL4VprBP regulates the oncogenic transcription factor FoxM1. VprBP activates FoxM1 independently of ubiquitylation, suggesting a novel nonproteolytic mechanism in cancer.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • The transcription factor FoxM1 is crucial for cell cycle progression and is frequently activated in human cancers, contributing to chromosome instability.
  • Aberrant FoxM1 activity is linked to tumorigenesis and malignancy.
  • Understanding FoxM1 regulation is vital for cancer therapy development.

Purpose of the Study:

  • To characterize the CRL4VprBP E3 ubiquitin ligase complex and its role in regulating FoxM1.
  • To investigate the paradoxical dual role of VprBP as both a regulator of FoxM1 degradation and a potent activator.
  • To elucidate the mechanism of FoxM1 activation by VprBP, particularly its independence from ubiquitylation.

Main Methods:

  • Characterization of the CRL4VprBP E3 ubiquitin ligase complex.
  • Assessment of FoxM1 ubiquitylation and degradation.
  • Analysis of VprBP's effect on FoxM1 target gene expression and mitotic entry.
  • Investigation of VprBP-CRL4 binding dynamics during mitosis.
  • Examination of VprBP protein levels in ovarian cancer patient tumors.

Main Results:

  • CRL4VprBP mediates FoxM1 ubiquitylation and degradation.
  • VprBP acts as a potent activator of FoxM1, enhancing its target gene expression and promoting mitotic entry.
  • VprBP activation of FoxM1 is independent of its ligase activity and ubiquitylation, suggesting a nonproteolytic mechanism.
  • VprBP binding to CRL4 is reduced during mitosis, correlating with ligase-independent activation.
  • VprBP protein levels are elevated in high-grade serous ovarian tumors with amplified FoxM1 signatures.

Conclusions:

  • VprBP controls both the abundance and activity of FoxM1 through distinct mechanisms.
  • VprBP repurposes E3 ligase substrate receptors for nonproteolytic functions, independent of the ubiquitin-proteasome system.
  • This study reveals a novel regulatory axis for FoxM1 with potential implications for ovarian cancer therapy.
Keywords:
FoxM1cell cyclecullin ring ligasetranscriptional regulationubiquitination

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