image: This is Cheryl Walker, Ph.D., of University of Texas M. D. Anderson Cancer Center. view more
Credit: MD Anderson
HOUSTON - While studying one tumor-suppressing protein, Cheryl Walker's research team at The University of Texas MD Anderson Cancer Center came across a separate surprise. They found another protective protein known to work inside the cell nucleus moonlighting out in the cell's cytoplasm.
Following up on this unexpected observation, they discovered the cancer-blocking nuclear protein ATM has a second job controlling and killing damaged cells in the area between the nucleus and the cell membrane. Both functions stymie cancer by preventing reproduction of defective cells.
Their groundbreaking paper in the Proceedings of the National Academy of the Sciences has been chosen for the Cozzarelli Prize as the best paper in the Biological Science category published in the Proceedings during 2010. The prizes are given to the top paper in six categories out of more than 3,700 studies published by the journal each year.
"The Cozzarelli Prize is wonderful recognition of research that brought to light a brand new aspect of cell biology and marked a new direction for our lab," said Walker, a Ph.D. and professor in the Department of Molecular Carcinogenesis. The department is located at MD Anderson's Virginia Harris Cockrell Cancer Research Center, Science Park, near Smithville, Texas.
"Discovery of ATM's additional anti-tumor role is the type of basic science research that heightens our understanding of cancer and paves the way for improved prevention and treatment," said Raymond DuBois, M.D., Ph.D., MD Anderson provost and executive vice president. "The Cozzarelli Prize is a great honor for Cheryl, her lab and MD Anderson.
"The award also highlights the opportunities available for graduate students at MD Anderson," DuBois said. Co-first author Angela Alexander is a doctoral student in The University of Texas Graduate School of Biomedical Sciences, which is operated jointly by MD Anderson and The University of Texas Health Science Center at Houston (UTHealth).
"The initial discovery by postdoctoral fellow Shengli Cai, Ph.D., Angela's first authorship and excellent collaboration with scientists at other institutions all made this a great project," Walker said.
The team discovered that ATM (short for Ataxia-Telangiectasia Mutated) recognizes damage caused by reactive oxygen species (ROS) in the cytoplasm and tells the cell to stop growing or orders the cell to consume itself, a process called autophagy.
Reactive oxygen species are a byproduct of cellular metabolism. They react with other molecules, are toxic in large amounts and kept in check by antioxidants. When that balance is disrupted, elevated ROS levels damage proteins, lipids and DNA.
Elevated ROS has been linked to more than 150 diseases, including diabetes, cancer, neurodegenerative diseases and atherosclerosis.
In its previously known role, ATM notices DNA damage, orders the cell to repair the damage and halts cell division. If repair is not possible, ATM sets off apoptosis - programmed cell death. ATM is commonly mutated in cancer.
ATM sets off a molecular chain of events to kill ROS-damaged cells that includes the tumor-suppressor TSC2, the protein originally targeted by the researchers.
One possibility raised by this research, Walker said, is the ability to activate ATM without damaging DNA.
The annual Cozzarelli award acknowledges recently published papers that reflect scientific excellence and originality. The award was established in 2005 and named the Cozzarelli Prize in 2007 to honor late PNAS Editor-in-Chief Nicholas R. Cozzarelli. The 2010 awards will be presented at the PNAS Editorial Board Meeting, and awardees will be recognized at the awards ceremony, during the National Academy of Sciences Annual Meeting on May 1, 2011, in National Harbor, Maryland.
MD Anderson news release about the paper on Feb. 17, 2010: Researchers Discover Second Protective Role for Tumor-Suppressor.