Dr. Benjamin Tsang finds a new dimension to the most frequently mutated gene in human cancer

May 1, 2006

Scientists today know more about p53 than perhaps any other gene. It was first identified in 1979, and in 1993 it was named “Molecule of the Year” by the international journal Science. p53’s job is to prevent normal cells from becoming cancerous and it is so good at this job that many cancers cannot develop unless they get rid of p53. In fact, more than half of all human cancers have lost or damaged their p53 genes.

Now, with thousands of scientists around the world studying p53, Dr. Benjamin Tsang, a Senior Scientist at the Ottawa Hospital Research Institute (OHRI), has found a new dimension to this important cancer biology gene. Dr. Tsang is also a Professor in two departments at the University of Ottawa: Cellular and Molecular Medicine, and Obstetrics and Gynecology.

Dr. Tsang’s finding relates to p53’s role in cell death. When a cell’s DNA becomes damaged (for example, by UV rays from the sun), p53 “decides” whether the damage can be fixed, or whether it is so severe that the cell should kill itself. The decision is incredibly important because if a cell with serious DNA damage is allowed to continue dividing, it could eventually become a cancer cell.

p53 induces cell suicide in two ways. The most well-studied way involves p53 binding to cell death genes in the nucleus and causing the cell to “transcribe” more of these genes into active cell death proteins. In the last few years, scientists have begun to recognize that p53 can induce cell death in other ways, but the mechanism has not been clear. Recent evidence has suggested that p53 might accumulate in an entirely different cellular compartment (the mitochondria), and interact directly with cell death proteins there.

Dr. Tsang’s new paper, published in the March 15th edition of Cancer Research, shows that in some ovarian cancer cells, this is indeed the case. Even more importantly, the research suggests that this process may control response to chemotherapy. Dr. Tsang’s group showed that p53 accumulates in the mitochondria of human ovarian cancer cells that are sensitive to chemotherapy, but not in cells that are resistant. They also show that in the sensitive cells, p53 directly induces mitochondria to release a cell death promoting factor called Smac. Their work represents the first demonstration of a role for Smac in chemosensitivity, and the first demonstration of the differential regulation of p53 accumulation in the mitochondria. This work could eventually lead to new ways to make cancer cells more sensitive to chemotherapy. It could also possibly lead to tests to determine whether or not chemotherapy is likely to be effective in individual cancers.

This work was done with Xiaokui Yang, Michael Fraser, and Dr. Ajoy Basak (all of the OHRI) and Ute Moll of the State University of New York. Funding is from the Canadian Institutes of Health Research and the National Cancer Institute of Canada.

In the last year, Dr. Tsang was awarded the Dr. J. David Grimes Research Career Achievement Award, and he became the President of the Canadian Fertility and Andrology Society. He is also an Honorary Professor at the Chinese Academy of Sciences, at Jinan University in China, and at Nanjing Medical University, also in China. He has led several international research collaborations (see Ottawa Sun story). For more information, see Dr. Tsang’s scientific profile.