Project Summary The goal of this research project is to characterize the molecular mechanisms regulating FoxM1 in cell proliferation. The FoxM1 transcription factor increases gene expression to drive the cell cycle and division. FoxM1 expression and activity are high and necessary in many human cancer cells, and thus FoxM1 is an attractive therapeutic target. We propose and will test a novel structural model for FoxM1 regulation, in which activity is modulated by conformational switching of an intrinsically disordered transactivation domain (TAD). We will determine the structure of inactive FoxM1, in which the TAD is bound and sequestered by a negative regulatory domain (NRD). We will also test hypotheses for how Cyclin-dependent and Polo-like kinases phosphorylate FoxM1, releasing the TAD from the NRD and enhancing a helical structure that binds the transcription coactivator protein CBP. These studies will provide fundamental new insights into cell cycle control through multisite phosphorylation and inform future strategies for developing therapeutics that inhibit FoxM1 and its role in cell division.