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.

Public Health Relevance

Many diseases have defects in the biochemical mechanisms that regulate cell growth and division, so understanding how these processes work is vital to understanding human health and developing therapeutics. This project aims to develop a molecular picture of how the protein FoxM1, which stimulates cell proliferation, is regulated.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM127707-02
Application #
9878889
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Sledjeski, Darren D
Project Start
2019-02-21
Project End
2023-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Santa Cruz
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064