Uncontrolled cell proliferation, due to disruption of cell cycle control, is characteristic of many human cancers. In normal cells, cell cycle progression is mediated by different cyclin-cdk complexes, which become activated at different phases of the cell cycle. p27-Kip1 is a key regulator of G1 progression, in that it binds and inhibits cyclin E-cdk2 and facilitates the binding and nuclear import of cyclin D-cdk complexes. p27 is often deregulated in human cancers, either through accelerated protein proteolysis, through sequestration in active cyclin D-cdk complexes, or through its mislocalization to the cytoplasm away from its nuclear targets. Understanding the mechanism by which p27 gets deregulated in cancers is the focus of this project. I will be investigating whether p90-RSK1, a serine/threonine kinase that is activated by both the MAPK pathway and by the PI3K pathway, is involved in altering p27's protein function, stability, and localization. The cause of p27 alterations is not entirely known; the studies proposed in this project may give further insight into the regulation of p27 in the cell.
| Larrea, Michelle D; Wander, Seth A; Slingerland, Joyce M (2009) p27 as Jekyll and Hyde: regulation of cell cycle and cell motility. Cell Cycle 8:3455-61 |
| Larrea, Michelle D; Hong, Feng; Wander, Seth A et al. (2009) RSK1 drives p27Kip1 phosphorylation at T198 to promote RhoA inhibition and increase cell motility. Proc Natl Acad Sci U S A 106:9268-73 |
| Larrea, Michelle D; Liang, Jiyong; Da Silva, Thiago et al. (2008) Phosphorylation of p27Kip1 regulates assembly and activation of cyclin D1-Cdk4. Mol Cell Biol 28:6462-72 |
| Hong, Feng; Larrea, Michelle D; Doughty, Cheryl et al. (2008) mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation. Mol Cell 30:701-11 |
