Phongkitkarun K.Chusorn P.Kamkaew M.Jamnongsong S.Lam E.W.F.Promptmas C.Sampattavanich S.Mahidol University2025-08-152025-08-152025-07-15Journal of Cell Science Vol.138 No.14 (2025)https://repository.li.mahidol.ac.th/handle/123456789/111663Forkhead box protein M1 (FOXM1) is a transcription factor that is required for the G2/M transition and is frequently upregulated in cancers, promoting tumor progression and therapy resistance. However, its dynamic regulation throughout the cell cycle remains unclear. We developed a tunable FOXM1-dihydrofolate reductase (DHFR) sensor, FOXM1-D, in non-malignant MCF10A cells, enabling real-time monitoring and manipulation of FOXM1 levels. Using trimethoprim to stabilize FOXM1-D, we quantified its production, degradation and nuclear translocation during G1 and G2 phases. Overexpression of FOXM1-D accelerated cell division in G1 and S phases but did not affect G2-synchronized cells. Notably, 70-90% of FOXM1-D-overexpressing cells were arrested after the first division, whereas those with timely degradation could undergo a second division. Sustained FOXM1-D overexpression induced cell cycle arrest in daughter cells, highlighting the role of FOXM1 kinetics in determining cell fate. Sustained FOXM1-D upregulates p21 (also known as CDKN1A), triggering G1 arrest. Thus, targeting FOXM1 exploits its dual capacity to induce oncogene-induced senescence or suppress mitotic entry. Our study provides a basis for precision therapies that align interventions with FOXM1 kinetics to improve outcomes in FOXM1-driven tumors.Biochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1242/jcs.2637492-s2.0-1050127798061477913740586720