Rb is a transcriptional repressor which plays an important role in the development of the retina, central nervous system and other tissues. In the retina, excessive or deficient Rb activity during development can lead to a hypo- or hyperproliferative retinal abnormality, respectively. Rb blocks the G1-to-S phase transition in the cell cycle and is itself inhibited by phosphorylation. Hypophosphorylated Rb is active and arrests cells in G1 phase, while hyperphosphorylated Rb is inactive and allows cells to progress into S phase. The Rb pathway, consisting of proteins that modulate the phosphorylation state of Rb, regulates cell cycle progression and is disrupted not only in retinoblastomas, but in virtually all tumors. Therefore, determining how Rb is inhibited by phosphorylation is important for understanding the processes regulating cell growth, as well as the pathologic processes which can deregulate growth. Previously, it was thought that Rb acted as a simple """"""""on-off switch"""""""", existing either in a hypophosphorylated (active) state or a hyperphosphorylated (inactive) state. However, we recently showed that regulation of Rb is actually more complex. Rb is progressively phosphorylated and inactivated by cyclin-dependent kinases (which are part of the Rb pathway) as cells move through G1 phase. This allows Rb to repress different genes at different points in the cell cycle, according to its phosphorylation state. This new model for progressive phosphorylation and inactivation of Rb may explain how the Rb pathway controls the orderly progression of the cell cycle in development and differentiation, and how deregulation of the Rb pathway can lead to apoptosis or uncontrolled cell proliferation. We propose a series of experiments to further examine this mechanism of Rb phosphorylation and inactivation. In vitro biochemical studies will be designed to yield further insight into the molecular mechanism by which specific phosphorylation events inactivate Rb. Such mechanistic studies have already begun to yield potentially important new molecular therapies that specifically target the Rb pathway. In addition, physiologic experiments in cultured cells will be performed to explore how progressive Rb phosphorylation orders the sequential expression of cell cycle gene and how this process relates to the tumor suppressor function of Rb.
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