Programmed Cell Death

We are studying the mechanisms by which the Bcl-2 family of proteins regulates selective programmed cell death (apoptosis) of cancer cells. We are particularly interested in determining the molecular mechanisms by which Bcl-2 family proteins either inhibit or accelerate apoptosis.  The Bcl-2 family proteins that we study include those that initiate cell execution (Bax and Bak), as well as those that inhibit (Bcl-2, Bcl-XL, Mcl-1) or promote (Bim, Bid, Bad) the process.  By understanding the mechanisms involved we identify and validate potential therapeutic targets and identify small molecules that can be used to manipulate the cell death pathway in cells and animal models.  Our recent data indicate an unexpected role for the membrane binding domains of these proteins in regulating how Bcl-2 family proteins interact with each other to control cell fate. Because the proteins regulate cell death by direct physical interactions we have developed new techniques to measure protein-protein interactions in live cells.  We believe that by studying protein to protein interactions where they take place-in the membranes of live cells-we will be able to identify more effective therapies.  When combined with targeted therapies the newly FDA approved and in trial drugs that modulate the activities of Bcl-2 family proteins promise to greatly improve selective cancer cell killing.  Moreover, the new drugs that we are developing that acutely prevent programmed cell death have great promise in improving cell based therapies and cell based manufacturing.