Grant: Operating Grant

There are many factors that determine both the effectiveness and toxicity (adverse side effects) of drugs. In the case of an anticancer drug, this is largely determined by how much of the drug is able to reach the tumour (desired target) versus how much drug is taken up by normal cells (side effect). The ABC efflux pumps are one class of proteins that control the amount of drug that accumulates in cells; these pumps can also influence how efficiently drugs penetrate tissues such as the brain or are eliminated from the body through urine and feces. Some ABC proteins have a second function which is to export naturally occurring molecules that regulate diverse functions in both normal and malignant cells. The intent of this research is to study the ABC efflux pump known as ABCC4. ABCC4 is involved in the effectiveness (and toxicity) of an important group of drugs that are used to treat many diseases including certain cancers (eg prostate) and HIV infections. ABCC4 also plays a unique role in determining the amounts of several 'signaling' molecules (eg prostaglandins and cyclic AMP) that transmit information from one cell to another. This type of cell-to-cell communication is critical for a wide variety of physiological processes including those controlling cell growth and the perception of pain. This project seeks to understand (i) how ABCC4 can pump so many different drugs and signaling molecules out of cells by determining how mutations introduced into ABCC4 affect its transport activity and specificity; and (ii) how the amount of ABCC4 present at the surface of the cell is regulated by investigating how ABCC4 interacts with other proteins in the cell, and by exploring how the activity of the gene that encodes ABCC4 is controlled. Knowledge of these properties of ABCC4 is essential if we are to fully understand the role(s) of this ABC efflux pump in normal and malignant cell growth as well as its role in determining drug safety and efficacy.