ATM, a protein that reacts to DNA damage by ordering repairs or the suicide of the defective cell, plays a similar, previously unknown role in response to oxidative damage outside of the nucleus, researchers report this week in the online version of the Proceedings of the National Academy of Sciences.
"This tumor-suppressor that works in the nucleus to prevent replication of defective cells also has a second life out in the cytoplasm, which was totally unexpected," said senior author Cheryl Walker, Ph.D., professor in The University of Texas M. D. Anderson Cancer Center Department of Carcinogenesis.
"ATM recognizes damage caused by reactive oxygen species (ROS) and tells the cell to stop growing by suppressing the protein-synthesizing pathway mTORC1 or orders the cell to consume itself, a process called autophagy," Walker said. This pathway parallels the protein's role of damage recognition and response in the nucleus.
Reactive oxygen species are a byproduct of cellular metabolism and in small amounts play a role in cell signaling. Their ability to react with other molecules makes them toxic, and they are kept in check by antioxidant enzymes. When that natural balance is disrupted, elevated levels of these volatile molecules damage proteins, lipids and DNA, Walker said.
The authors note that elevated ROS has been linked to more than 150 diseases, including diabetes, cancer, neurodegenerative diseases and atherosclerosis.
In its previously known role, ATM (short for Ataxia-Telangiectasia Mutated) senses DNA damage, orders the cell to repair the damage and halts cell division pending repair via the tumor suppressor p53. If repair is not possible, ATM sets off apoptosis - programmed cell death. ATM is commonly mutated in cancer.
The added protective role discovered by the researchers also points to a potential way to activate the tumor-suppressor without damaging DNA.
Walker's lab was studying another tumor-suppressing protein called TSC2 that is active in the cellular cytoplasm and found that ATM appeared to be associated with TSC2 activation.
In a series of experiments, the research team uncovered the molecular pathway that begins with ROS activation of ATM which then:
Activates the tumor suppressor LKB1, which in turn phosphorylates and activates the AMP kinase (AMPK), a key player in energy sensing and growth factor signaling.
AMPK switches on the tumor-suppressor TSC2 (tuberous sclerosis complex 2).
TSC2 then suppresses the kinase mTOR (mammalian Target of Rapamycin), which shuts down the mTORC1 signaling pathway, an important regulator of protein creation and cell growth.
Because TORC1 suppresses autophagy, when TORC1 is suppressed by TSC2, autophagy is free to occur.
During autophagy, membranes form around organelles in the cytoplasm, which are subsequently digested. Autophagy plays a normal role in cell growth and stability, and is a natural cellular defense mechanism, providing nutrients for a starving cell, for example.
Autophagy also is thought to be a second form of programmed cell death, because it can eventually kill the cell, cannibalizing it and leaving it shot full of cavities. Whether autophagy is activated as a survival mechanism in response to ROS or as an ATM-driven programmed cell death remains to be explored, the authors noted.
Even so, the study links oxidative stress to a key metabolic pathway activated by ATM that integrates damage response pathways with energy signaling, protein synthesis and cell survival.
The study was funded by a variety of grants from the National Institutes of Health, M. D. Anderson Cancer Center, the Children's Hospital Boston Mental Retardation and Developmental Disabilities Research Center and the Sowell-Huggins Fellowship from The University of Texas Graduate School of Biomedical Sciences (GSBS) to co-first author and graduate student Angela Alexander. The GSBS is a joint enterprise of M. D. Anderson and The University of Texas Health Science Center at Houston.
Co-authors with Walker and Alexander are: co-first authors Sheng-Li Cai, Ph.D., Jinhee Kim PhD., and Adrian Nanez, Ph.D., postdoctoral fellows in the Walker lab at the time these studies were performed, Jianjun Shen, Ph.D., and Donna Kusewitt, Ph.D., DVM, all of M. D. Anderson's Department of Carcinogenesis in Smithville, TX; Gordon Mills, M.D., Ph.D., of M. D. Anderson's Department of Systems Biology; Mustafa Sahin, M.D., Ph.D.,of the Department of Neurology at Children's Hospital , Harvard Medical School; Kristeen MacLean and Michael B. Kastan, M.D., Ph.D., of the Department of Oncology at St. Jude Children's Research Hospital in Memphis, Tenn.; Ken Inoki, M.D., Ph.D., of the Life Sciences Institute at the University of Michigan; Kun-Liang Guan, Ph.D., of the Moores Cancer Center at the University of California at San Diego; and Maria Person, Ph.D., of the College of Pharmacy at The University of Texas at Austin.
About M. D. Anderson
The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For six of the past eight years, including 2009, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.
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