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Molecular Targets For Cancer & Aging Therapeutics - Research Overview

My laboratory takes a multidisciplinary approach to study important integral membrane proteins involved in cancer and cancer treatment. Using the tools of biochemistry, cell and molecular biology, organic synthesis and bioanalytical chemistry, we are defining the molecular mechanisms of substrate recognition by these membrane-associated proteins, and are investigating the mechanisms of their activity, assembly, trafficking, and cellular localization. The two major research areas in my laboratory focus on 1) the yeast and human isoprenylcysteine carboxylmethyltransferases (Icmt) and 2) the human ATP binding cassette (ABC) transporters ABCG2 and P-glycoprotein. Our major successes are highlighted by the purification and functional reconstitution of yeast Icmt, the quantitative evaluation of Icmt substrate specificity, the evaluation of the oligomerization of ABCG2 and the further elucidation of ABCG2 substrate specificity. In addition to increasing our understanding of the molecular mechanisms of these integral membrane proteins, these studies have also led to the identification of inhibitors and the development of high-throughput screening methodologies. These studies provide a foundation for the future development of novel biochemical tools and chemotherapeutic agents.

ABC Transporters: Roles in Multidrug Resistance and Bioavailability

One of our research interests is in the field of multidrug resistance in human cancer. Although numerous cancers can be successfully treated with ablative surgery, radiotherapy or chemotherapy, many cancers are intrinsically resistant to anti-cancer drugs or become resistant through the course of treatment. This broad-based cellular resistance to anti-cancer drugs results, in large part, from expression of a 170 kDa multidrug transporter or P-glycoprotein, encoded by the multidrug resistance MDR1 gene in humans. Many different human cancers express the MDR1 gene at levels sufficient to confer multidrug resistance and it can be estimated that approximately 50% of human cancers will express the gene at some time during therapy.

Therefore, it has become apparent that multidrug resistance in a clinical setting is an obstacle that must be overcome to treat cancers effectively. It is of obvious importance to fully understand how the transporter functions in order to combat this phenomenon clinically. Taking biochemical, molecular genetic, and cell biological approaches using both mammalian and microbial cell systems, the majority of our efforts focus on the elucidation of the mechanism of action of human P-glycoprotein and a related drug transporter MXR1 that is involved in mitoxantrone resistance. Ultimately, a complete understanding of these proteins could lead to the development of new inhibitory agents that could greatly facilitate the treatment of a large number of human cancers.

These drug transporters are members of a large superfamily of membrane transporters called the ATP-Binding Cassette (ABC) family. Through work with P-glycoprotein and ABCG2, our interest in the field of transporters and their relation to cellular function and human disease has developed. In the future, we are also interested in identifying and studying other ABC transporters possibly linked to human diseases. We hope to gain further understanding of the basic mechanism of action of ABC transporters to elucidate their cellular functions both normally and in potential disease states. Human ABCG2 is 655 amino acids in length with six predicted transmembrane domains and one soluble nucleotide binding domain (NBD) and is believed to form a functional dimer.