Protein Location Alters Function

Subcellular mislocalization of proteins constitute a serious clinical problem that results in diseases that range from metabolic disorders to cancer. Two distinct opportunities are afforded by addressing this clinical need: 1) understanding why protein mislocalization occurs, and 2) establishing therapeutic methodologies to address the consequences. Deliberately changing the subcellular localization of signal transducing proteins involved in disease is a novel approach for therapeutic intervention. Mislocalized proteins are evolving as an important new class of drug targets for treating many diseases, particularly cancer. Mislocalization of proteins such as tumor suppressors and cell cycle regulators result in aberrant functioning of these proteins, leading to disease.

Protein Switch: Change Localization to Alter Function

The main goal of this project is to use ligand inducible nuclear import signals and export signals as a bi-directional “on/off switch” for the controlled targeting of therapeutic proteins to subcellular compartments. Specifically, through the careful addition and manipulation of precise signaling sequences, in an inducible system, we will be able to control the delivery of therapeutically active gene products to a subcellular compartment, such as the nucleus or mitochondria. Such a system would be useful when a controlled response in a specific subcellular compartment is desired, or alternatively to “turn off” or to remove the therapeutic protein (for example in the case there prolonged high level exposure becomes toxic) from that compartment.