Coregulators as rheostats of cellular signaling

While transcription factors (TFs) are the molecular determinants of transcription, they are required to interact with a whole other class of proteins, transcriptional coregulators, to exert their myriad effects. Transcriptional coregulators comprise a family of many related and unrelated proteins, which often do not harbor DNA binding domains themselves but function within coregulator-TF complexes. These complexes can be competitive or permissive resulting in enhanced or repressed target gene expression. The composition of a complex is dependent on tissue type and temporal availability of individual components, and can determine the specificity of the same given extracellular signal in different cellular contexts. A number of cancer types have been defined by coregulator dysfunction and of the coregulators described to date well over half are directly associated with some disease state. Owing to the central role of coregulator proteins in driver pathways in several hormone dependent cancers it has been proposed that development of coregulator targeting agents is one way to overcome the resistance seen when using the more traditional approach of targeting the steroid receptor. The rationale behind this is that the resistance pathways invoked by driver pathway blockade will still require many of the same coregulators of the original pathway. Despite this, molecular targeting of corepressor or coactivators functional domains remains a rather unexplored area with great potential for a wide range of disease states. Naturally a first step towards exploiting this potential is the characterization of the mechanism of action of individual coregulator proteins. Our research aims to address this need.