Molecular analysis of a dual action F box protein in cell cycle regulation

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Scientists refer to cells as being 'programmed' to divide, to die or to differentiate. This describes the elaborate, and seemingly automatic, changes that take place in the way that a cell behaves under different circumstances. For example, cells grow when provided with the right nutrients, die if irrevocably damage, or differentiate into distinctly different types of cells when in the appropriate niche environment. Cells are sensitive to the signals that dictate changes to their programmes and thus to their behaviour at a particular time in their growth cycles. Often, to execute one programme means that others are disabled. These time-sensitive switches allow coordinated and absolute decisiveness to cells' fate. These switches are comprised of a family of proteins called SCF ligases, which directly control the cell's growth machinery. Understanding the how cells make their decisions and regulate cell fate is a matter of fundamental interest, and this proposal outlines experiments designed to understand the activity of SCF proteins, and how they achieve this. In particular we will focus on a component of this SCF called Fbxo7. It differentially regulates at least three different proteins that affect cellular proliferation, death, and differentiation. In other words, it is a master regulator. We want to understand how Fbxo7 is capable of varying its activity towards the proteins it binds, and ultimately how it controls cell fate. We will use a variety of methods to understand the protein's function, to solve its structure, and find other proteins that it regulates. By doing experiments to broaden our understanding of the proteins at the intersection of different cell programmes we hope to be able to affect and ultimately direct these programmes in clinically relevant settings.