Proteins do not typically emerge from ribosomes ready to function. In fact, most proteins require precise signals to direct where, when, and how well to perform multiple functions. In my lab we study the structural and biophysical basis for how the glucocorticoid receptor (GR) responds to cellular signals. GR is a steroid activated transcription factor that is expressed in every tissue of the body. In each of these tissues GR performs a distinct function by binding different regions of the genome to affect regulation of gene programs. We are interested in understanding how signals change the conformation of GR to direct binding to specific genomic sites and expression of key genes. We have learned that once bound, the DNA sequence has a profound impact on GR structure and function, and we are pursuing how this influences recruitment of the correct complement of transcription factors to faithfully regulate genes.

We study GR in particular because its central role in the treatment of childhood acute lymphoblastic leukemia (ALL). ALL is the most common childhood cancer and is highly treatable, with 90% of patients cured by standard chemotherapy. For the remaining 10%, the prognosis is grim. Surprisingly, treatment response is best predicted by whether ALL cells die when treated ex vivo with a single component of chemotherapy – glucocorticoids, suggesting a central role for GR in ALL treatment efficacy. Since both sensitive and resistant patients have normal levels of wild type GR, it is our hypothesis that important signaling pathways have been disrupted in resistant patients that affect the ability of GR to efficiently kill ALL cells.

The long-term goals of my lab are to develop a deep understanding of how GR is fine-tuned by signals so that we can rationally develop compounds that will potently and specifically drive the genes that kill leukemias. Our immediate goals are to identify: all signals that have an impact on glucocorticoid induced cell death; GR regulated genes that induce cell death; and GR binding sites associated with these genes. In addition, we are elucidating how both drugs and DNA sequence change the structure of GR at these crucial genes.