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Mol Cell Biol. 2017 Jun 15;37(13). pii: e00609-16. doi: 10.1128/MCB.00609-16. Print 2017 Jul 1.

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

Author information

1
Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
2
Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
3
Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
4
Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
5
Division of Gynecologic Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
6
Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA emanuele@email.unc.edu.

Abstract

The oncogenic transcription factor FoxM1 plays a vital role in cell cycle progression, is activated in numerous human malignancies, and is linked to chromosome instability. We characterize here a cullin 4-based E3 ubiquitin ligase and its substrate receptor, VprBP/DCAF1 (CRL4VprBP), which we show regulate FoxM1 ubiquitylation and degradation. Paradoxically, we also found that the substrate receptor VprBP is a potent FoxM1 activator. VprBP depletion reduces expression of FoxM1 target genes and impairs mitotic entry, whereas ectopic VprBP expression strongly activates a FoxM1 transcriptional reporter. VprBP binding to CRL4 is reduced during mitosis, and our data suggest that VprBP activation of FoxM1 is ligase independent. This implies a nonproteolytic activation mechanism that is reminiscent of, yet distinct from, the ubiquitin-dependent transactivation of the oncoprotein Myc by other E3s. Significantly, VprBP protein levels were upregulated in high-grade serous ovarian patient tumors, where the FoxM1 signature is amplified. These data suggest that FoxM1 abundance and activity are controlled by VprBP and highlight the functional repurposing of E3 ligase substrate receptors independent of the ubiquitin system.

KEYWORDS:

FoxM1; cell cycle; cullin ring ligase; transcriptional regulation; ubiquitination

PMID:
28416635
PMCID:
PMC5472828
DOI:
10.1128/MCB.00609-16
[Indexed for MEDLINE]
Free PMC Article

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