Scientists Find New Clues About Fatal Childhood Disease, Ataxia Telangiectasia

September 10, 1998

Finding May Explain Tumor Development

For the first time, scientists have shown conclusively how the protein that is missing or altered in the fatal childhood disease ataxia telangiectasia* (A-T) acts as a key regulator of cell division after DNA damage. The finding helps researchers understand how cells in A-T patients form tumors and may lead to new understanding of other neurological and immune disorders.

The new research shows that the protein, called ATM for A-T, mutated, is a type of enzyme called a protein kinase that reacts to DNA damage by chemically modifying and triggering accumulation of a molecular "brake," or tumor suppressor, called p53. This tumor suppressor is defective in about half of all human cancers and is the master control switch for a process that normally prevents cells from dividing. In A-T patients, the ATM protein is missing or defective. This delays the accumulation of p53, allowing cells to replicate without repair of their DNA and thereby increasing the risk of cancer. The new finding is separately reported by two groups of researchers in the September 11, 1998, issue of Science.1,2 Both studies were partially funded by the National Institutes of Health (NIH).

The ATM gene was isolated in 1995 in the laboratory of Yosef Shiloh, Ph.D., of Tel Aviv University in Israel, with collaboration from an international team of colleagues. Until now, however, researchers have been uncertain about precisely how the protein produced by this gene works.

"This is an important milestone in our attempts to understand ATM's functions. It is also a step forward in our move from molecular genetics to the cellular biology of A-T," says Dr. Shiloh, senior author of one of the new reports. Similar findings are reported by Michael B. Kastan, M.D., Ph.D., of St. Jude Children's Research Hospital in Memphis, and his colleagues. Now that scientists better understand how the ATM protein works, they can move toward the next stage of research -- designing new treatments for A-T and possibly for cancer and other disorders.

"These papers represent new insights into how this protein functions," says Dr. Kastan. "The findings not only allow us to get better insights into this devastating disease, but also help us understand other important cellular processes. In particular, we're hoping to use these insights to improve cancer therapy by making tumor cells more sensitive to radiation."

Researchers have long been interested in A-T because it affects many different systems in the body, including the nervous, immune, reproductive, and circulatory systems. Children with A-T, who possess two defective copies of the ATM gene, typically have extreme sensitivity to ionizing radiation, such as X-rays, and progressive degeneration in the brain's cerebellum, which leads to ataxia, or weakened muscular control. Other problems include a greatly increased risk of cancer, especially leukemia and lymphoma; an unusually high risk of diabetes and lung infections; and telangiectasia, or dilated blood vessels in the eyes and other parts of the face. People with A-T usually die of respiratory failure or cancer by their early twenties. Carriers of A-T, who possess a single defective copy of the ATM gene, escape most problems associated with the disease but may have a slightly increased risk of cancer, including breast cancer in women. Because A-T has so many different sympto! ! ms, researchers believe studying the ATM protein will provide insights into a variety of disorders.

"This comes as great news for families with A-T children who have been waiting for a treatment, because scientists will be able to screen for drugs that affect ATM's activity. Researchers will also have a much better tool for figuring out how the ATM protein, missing in kids with A-T, functions in healthy people. With this knowledge, it might be easier to design drugs that will help A-T patients and even slow down the progression of their disease," says Brad Margus, President of the A-T Children's Project in Boca Raton, Florida. Margus also stated his hope that, with a closer connection to p53 and cancer, the ATM protein will now receive more attention than ever in the science world.

"When my daughter, Becky, was diagnosed with A-T 15 years ago, we were told that she had a one in three statistical risk of getting cancer, although there was no scientific confirmation," says George Smith, President of the A-T Medical Research Foundation in Hidden Hills, California. "To me, the fact that we have now confirmed the linkage between A-T and cancer means we're closer to finding an eventual cure for this disease."

Researchers are now searching for proteins in addition to p53 that may be modified and controlled by ATM. ATM's interactions with these additional proteins might explain the neurological, immune, and other problems experienced by A-T patients. "It's a major leap to go from discovery of a defective gene to understanding how it affects cells," says Giovanna Spinella, M.D., of the National Institute of Neurological Disorders and Stroke (NINDS), which helped fund Dr. Shiloh's research. "This finding opens the door to studies of how the normal protein helps maintain the health of cells, including those of the nervous system."

Dr. Shiloh's research was supported by the NINDS, the A-T Children's Project, the A-T Medical Research Foundation, the A-T Appeal, and the Thomas Appeal (A-T Medical Research Trust). Dr. Kastan's work was supported by the National Cancer Institute (NCI) and the National Institute of Environmental Health Sciences (NIEHS). The NINDS, NCI, and NIEHS are part of the NIH, located in Bethesda, Maryland. The NINDS is the nation's leading supporter of research on the brain and nervous system and a lead agency for the Congressionally designated Decade of the Brain.

(1) Banin, S.; Moyal, L.; Shieh, S.-Y.; Taya, C.; Anderson, C.W.; Chessa, L.; Smorodinsky, N.I.; Prives, C.; Reiss, Y.; Shiloh, Y.; Ziv, Y. "Enhanced Phosphorylation of p53 by ATM in Response to DNA Damage." Science, Vol. 281, September 11, 1998, pp. 1674-1677.

(2) Canman, C.E.; Lim, D.-S.; Cimprich, K.A.; Taya, Y.; Tamai, K.; Sakaguchi, K.; Appella, E.A.; Kastan, M.B.; Siliciano, J.D. "Activation of the ATM Kinase by Ionizing Radiation and Phosphorylation of p53." Science, Vol. 281, September 11, 1998, pp. 1677-1679.

*Pronounced Ay-TACK-see-uh Teh-LAN-jick-TAY-sha.

NIH/National Institute of Neurological Disorders and Stroke

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