Novel interactions between FOXM1 and CDC25A regulate the cell cycle
Con Sullivan1, Youhong Liu, Jingjing Shen
1Maine Institute for Human Genetics and Health, Brewer, Maine, United States of America.
Abstract:
FOXM1 is a critical regulator of the G1/S and G2/M cell cycle transitions, as well as of the mitotic spindle assembly. Previous studies have suggested that FOXM1 regulates CDC25A gene transcription, but the mechanism remains unknown. Here, we provide evidence that FOXM1 directly regulates CDC25A gene transcription via direct promoter binding and indirect activation of E2F-dependent pathways. Prior literature reported that CDC25B and CDC25C activate CDK1/cyclinB complexes in order to enable phosphorylation of FOXM1. It was unknown if CDC25A functions in a similar manner. We report that FOXM1 transcriptional activity is synergistically enhanced when co-expressed with CDC25A. The increase is dependent upon CDK1 phosphorylation of FOXM1 at T600, T611 and T620 residues. We also report a novel protein interaction between FOXM1 and CDC25A via the C-terminus of FOXM1. We demonstrate that the phosphorylation of Thr 600 and Thr 611 residues of FOXM1 enhanced this interaction, and that the interaction is dependent upon CDC25A phosphatase activity. Our work provides novel insight into the underlying mechanisms by which FOXM1 controls the cell cycle through its association with CDC25A.
Insights
Forkhead box M1 (FOXM1) directly regulates CDC25A gene transcription and cell cycle progression. This study reveals FOXM1
Area of Science:
- Molecular Biology
- Cell Cycle Regulation
- Gene Transcription
Background:
- FOXM1 is a key regulator of cell cycle transitions and mitotic spindle assembly.
- The precise mechanism by which FOXM1 regulates CDC25A transcription was previously unknown.
- CDC25B and CDC25C were known to activate CDK1/cyclinB for FOXM1 phosphorylation.
Purpose of the Study:
- To elucidate the mechanism of FOXM1-mediated CDC25A gene transcription.
- To investigate the functional relationship between FOXM1 and CDC25A in cell cycle control.
- To determine if CDC25A activates FOXM1 phosphorylation similarly to CDC25B and CDC25C.
Main Methods:
- Promoter binding assays to assess direct FOXM1 regulation of CDC25A.
- Analysis of E2F-dependent pathways.
- Co-expression studies of FOXM1 and CDC25A.
- Site-directed mutagenesis to investigate FOXM1 phosphorylation sites (T600, T611, T620).
- Co-immunoprecipitation to detect protein interactions between FOXM1 and CDC25A.
Main Results:
- FOXM1 directly binds to the CDC25A promoter, regulating its transcription.
- FOXM1 transcriptional activity is synergistically enhanced by CDC25A co-expression, dependent on CDK1 phosphorylation of FOXM1 at T600, T611, and T620.
- A novel interaction between FOXM1 and CDC25A was identified, enhanced by FOXM1 phosphorylation and dependent on CDC25A phosphatase activity.
Conclusions:
- FOXM1 directly regulates CDC25A transcription through promoter binding and activation of E2F pathways.
- CDC25A enhances FOXM1 transcriptional activity via CDK1-mediated phosphorylation, establishing a positive feedback loop.
- A novel, phosphorylation-dependent interaction between FOXM1 and CDC25A provides new insights into cell cycle control mechanisms.
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