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.
Highlights
Cell cycle regulation and oncogenesis are inextricably linked through their use of common signaling pathways
We sought to detect the expression of Forkhead box M1 (FOXM1), cell division cycle 25A (CDC25A), CDK1 and CDK2 during cell cycle progression in the U2OS cell model
It is well known that FOXM1 participates in the G1/S and G2/ M cell cycle transition phases, as well as in the assembly of the mitotic spindle [41]
Summary
Cell cycle regulation and oncogenesis are inextricably linked through their use of common signaling pathways. The transcriptional activation of FOXM1 requires an LXL motif for binding of CDK/cyclin complexes, for efficient phosphorylation of FOXM1B Thr residue 596 that is essential for the recruitment of co-transactivator p300/CBP [7]. FOXM1 promotes G1/S transition through its relief of p21Cip and p27Kip inhibition [10] and its regulation of JNK1 [11]. It has been implicated, not directly shown, to mediate the transcriptional regulation of the dual phosphatase gene cell division cycle 25A (CDC25A) [6,10,12]
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