I started working in the p53 field during my postdoctoral research because p53 is such a critical protector against cancer in mammalian cells.

In the event of a cellular emergency such as DNA damage, the tumor suppressor protein p53 triggers apoptosis, or programmed cell death—the tidy demolition of a damaged cell. This greatly helps to prevent the uncontrolled growth of mutated cells, the hallmark of cancer. As a transcription factor in the cell's nucleus, p53 is known to activate other genes that are involved in apoptosis. But p53 has long been suspected of also having a more direct role in the cell's demise. My group at Stony Brook University found this link which places p53 at the heart of the action—the cell's energy-producing organelles, the mitochondria. It turns out that mitochondria are also central in triggering a cell's destruction because they store many apoptotic activators. Gene activation by p53 ultimately results in the perforation of mitochondrial membranes with leakage of apoptotic proteins, activation of specific enzymes and, finally, the shredding of proteins and DNA. Exactly how the mitochondrial membranes are perforated is not known, but the family of Bcl-2 proteins is intimately involved. Our research has found that within one hour after cellular damage, p53 directly goes to mitochondria and binds to two minders of mitochondria, Bcl-xL and Bcl-2. This prevents Bcl-xL and Bcl-2 from protecting mitochondria against leakage and so causes the release of apoptotic proteins, thus killing the cell. Interestingly, cancer-derived p53 mutants that lost the ability to bind DNA and stimulate transcription also seem unable to bind to Bcl-xL. So, by blocking both routes to cell death, one mutation may mean double trouble. We are now at work on ways to exploit this new pathway for more effective cancer treatment.