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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.
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.
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.