Researchers discover biochemical link between two rare diseases

St. Jude Children's Research Hospital (ALSAC)
Thursday, 6 April 2000

Study concludes protein absent in one disease phosphorylates protein mutated in second disease

(Memphis, Tennessee, April 6, 2000) Ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS) are two rare diseases for which patients are extremely prone to cancer development, and exhibit significant abnormalities in response to irradiation. In a paper published April 6 in the journal Nature, a group of researchers at St. Jude Children's Research Hospital provide a biochemical link between the two diseases and illustrate an important step in the radiation process.

"My laboratory studies how cells respond to radiation and chemotherapy," said lead researcher Michael Kastan, MD, PhD, chairman of the department of hematology/oncology at St. Jude. "We study the molecular responses that dictate whether a cell lives, dies or mutates. Since the cells in patients with AT and NBS are abnormal in the radiation responses, whichever gene is mutated in these patients must play a role in these responses."

About 10 years ago Dr. Kastan conducted research demonstrating that the protein P53 is important for radiation response. Subsequently, he showed that if he removed cells from patients with AT and irradiated them, these cells did not induce P53 the way normal cells did, indicating that the gene missing in AT played a role in signaling to P53. This gene was cloned about five years ago by a group of researchers at the Tel Aviv University, who named it ATM (mutated ataxia-telangiectasia).

"We have shown that ATM is a kinase enzyme and it directly phosphorylates P53 in response to irradiation," Dr. Kastan said. "That told us that ionizing radiation activates ATM which phosphorylates P53. We wanted to identify other targets for the ATM kinase so we developed a technique to characterize the protein sequence that ATM recognizes. One that we identified was a protein called P95 or NBS1. This gene was mutated in the NBS disease."

In the Nature paper, the group identifies the site of phosphorylation and shows this particular phosphorylation event is necessary for appropriate inhibition of DNA synthesis after irradiation. "If this inhibition does not occur, then increased genetic damage would be expected," Dr. Kastan said. "These observations help explain the similarities in these two diseases. Also, it helps clarify better the molecular basis for how cells respond."

"If we understand why cells are sensitive to radiation we could potentially develop drugs that would make any tumor cell sensitive to radiation," he said. "In fact, one of the things we're trying to do is find drugs that inhibit the ATM kinase so that we can take the most resistant tumor cell and make it sensitive to radiation. We've already shown genetically we can do that, now we want to do it with a drug."

St. Jude was founded by the late entertainer Danny Thomas. The hospital is an internationally recognized biomedical research center dedicated to finding cures for catastrophic diseases of childhood. The Hospital's work is supported through funds raised by the American Lebanese Syrian Associated Charities (ALSAC). All St. Jude Children's Research Hospital patients are treated regardless of their ability to pay. ALSAC covers all costs of treatment beyond those reimbursed by third party insurers, and total costs for families who have no insurance.

For more information, or to contact St. Jude Children's Research Hospital (ALSAC), see their website at: www.stjude.org