FoxM1 is degraded at mitotic exit in a Cdh1-dependent manner
Jamila Laoukili1, Monica Alvarez-Fernandez, Marie Stahl
1Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.
Abstract:
The Forkhead transcription factor FoxM1 is required for the timely expression of many mitotic regulators, such as Cyclin B, Plk1, Aurora B and Cdc25B.(1-3) For this, FoxM1 is specifically activated in G(2) phase through Cyclin A/cdk2-dependent phosphorylation.(4-6) However, it is currently unclear how FoxM1 activity is removed as cells complete mitosis, and need to shut down expression of the mitotic regulators that are transcriptional targets of FoxM1. Here, we demonstrate that FoxM1 is actively degraded during exit from mitosis by the APC/C. We find that FoxM1 degradation requires Cdh1, a known co-factor for APC/C that is responsible for degradation of many mitotic regulators from anaphase until early G(1). FoxM1 binds to Cdh1, and FoxM1 degradation involves both D- and KEN-boxes present in the N-terminal part of FoxM1. Based on these data we propose that Cdh1-dependent degradation of FoxM1 is required to shut down transcriptional activation of mitotic regulators during exit from mitosis.
Insights
The study reveals that the transcription factor FoxM1 is degraded by the APC/C complex, requiring Cdh1. This degradation is essential for shutting down mitotic gene expression as cells exit mitosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- The transcription factor FoxM1 (Forkhead box M1) regulates key mitotic regulators, including Cyclin B, Plk1, Aurora B, and Cdc25B.
- FoxM1 is activated during the G2 phase via phosphorylation by Cyclin A/cdk2, but its inactivation mechanism at mitosis completion is unknown.
Purpose of the Study:
- To investigate the mechanism of FoxM1 inactivation upon completion of mitosis.
- To determine how the expression of FoxM1's transcriptional targets is shut down during mitotic exit.
Main Methods:
- Investigated FoxM1 degradation during mitotic exit.
- Utilized co-immunoprecipitation to assess FoxM1-Cdh1 binding.
- Analyzed the role of D- and KEN-boxes in FoxM1 degradation.
Main Results:
- Demonstrated that FoxM1 undergoes active degradation by the Anaphase-Promoting Complex/Cyclosome (APC/C) during mitotic exit.
- Identified Cdh1 as a crucial co-factor for APC/C-mediated FoxM1 degradation.
- Confirmed that FoxM1 degradation is dependent on D- and KEN-boxes within its N-terminal region.
Conclusions:
- Proposed that Cdh1-dependent degradation of FoxM1 by the APC/C is a critical process for silencing the transcription of mitotic regulators.
- This mechanism ensures the proper shutdown of cell cycle progression and facilitates the transition from mitosis to the G1 phase.
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