Environmental Factor, December 2007, National Institute of Environmental Health Sciences
Michael Kastan Gives Falk Memorial Lecture
By Robin Arnette
In Rodbell Auditorium on November 8, Michael B. Kastan, M.D., Ph.D., became the twenty-third scientist to give the NIEHS Hans L. Falk Memorial Lecture, an annual seminar that features a researcher who has made significant contributions to environmental health sciences research. With his talk titled "DNA Damage Response Mechanisms: Implications for Human Disease," Kastan joined other notable investigators who have received this honor, such as Nobel Laureates Harold E. Varmus, M.D., J. Michael Bishop, M.D., and Sydney Brenner, M.D. NIEHS Acting Deputy Director William Suk, Ph.D., hosted the event.
Kastan is the director of the Cancer Center at St. Jude Children's Research Hospital, but he is best known for his work on the tumor suppressor protein p53. His peer-reviewed journal articles on the involvement of p53 in cellular responses to DNA damage are among the most cited scientific publications of the 1990s. He said that much of that work was funded by NIEHS, and he thanked the institute for that early support. "Dr. Suk put out an RFA [Request for Application] in 1991 that allowed us to ask the question, 'What controls the progression of the cell cycle in mammalian cells when they've been exposed to DNA damaging agents,'" Kastan said. "I'm deeply grateful."
The crux of that research was based on three pieces of evidence. Kastan and colleagues discovered that after a cell was exposed to ionizing radiation, p53 levels increased. In addition, GADD45, a protein implicated in growth arrest and programmed cell death, was identified as a downstream target of p53. Lastly, they saw that cells taken from patients with the cancer-prone disorder ataxia telangiactasia (AT) failed to induce p53 following ionizing radiation. Kastan said, "We had no idea what gene was missing in these patients, but we knew whatever it was, it signaled the p53."
Kastan proposed that these data indicated a signal transduction pathway was involved in the response to damage. After publication of the findings, Kastan said thousands of labs around the world studied downstream targets of p53. However, he was more interested in the upstream signaling pathway and knew that the AT gene was involved. After another lab cloned the AT-mutated (ATM) gene in 1995, Kastan finally had the missing piece to the DNA damage signaling puzzle and spent the next decade tracing its molecular steps.
Kastan's concern for cancer patients, though, led him to search for clinical ramifications resulting from studies of DNA damage signaling pathways. Kastan knew that AT patients were more prone to cancers since the mutations in their ATM gene resulted in an inability to activate a critical damage signaling pathway. He postulated that if loss of these pathways could increase cancer development, then perhaps activating such stress response pathways with drugs or other approaches could help prevent cancer or help cells deal with DNA damage. Kastan's lab recently discovered that chloroquine, a commonly used anti-malarial drug, could activate both ATM and p53 at low levels without inducing any DNA damage. He and his colleagues have subsequently discovered that low-dose, intermittent chloroquine treatment could significantly reduce tumor development in mouse models of Burkitt lymphoma and in mice lacking the ATM gene. They are currently working on strategies to optimize this approach as a potential way to reduce cancer development in certain high-risk patient populations.
Kastan ended his seminar by reminding the audience that each human cell experiences up to 10,000 damage events a day, and although the body has repair and other cellular mechanisms to deal with them, biomedical research provides another potential level of intervention. "We've learned enough about these cellular responses that we can begin to intervene for both better treatment of disease and prevention," Kastan said.