MEMPHIS, TENN. (October 31, 2003) -- A team of scientists led by investigators at St. Jude Children's Research Hospital has demonstrated that the p53 gene, long considered to be a central conductor of the process by which abnormal cells self-destruct, actually relies on the PUMA gene to trigger that activity. The researchers showed that PUMA is the key gene in this process, despite the large number of genes regulated by p53 that were thought to be involved in cell suicide. Cell suicide, or apoptosis, is a natural way for the body to rid itself of cells that have sustained damage, before they become useless or even cancerous.
Specifically, the St. Jude study showed that PUMA accounts for nearly all of the apoptosis that is attributed to p53 in blood-forming cells and in cells of the central nervous system when they are exposed to radiation. PUMA also accounts for p53-dependent cell death in response to abnormal growth caused by oncogenes (cancer-causing genes).
"Our findings establish PUMA as the principal mediator of cell death in response to signals that drive damaged or weakened cells to commit suicide rather than pose a threat to the body," said Gerard P. Zambetti, PhD, an associate member of the St. Jude department of Biochemistry. "This discovery provides a detailed look at how the body tries to rid itself of cells that are unhealthy, and how cancer cells might disrupt this vital housekeeping mechanism during tumor development," he said.
Zambetti led the PUMA study, whose results are reported in the October issue of Cancer Cell. The finding is also important because p53 is mutated in about half of all cancers, and thus cannot activate PUMA.
"Even if p53 is normal, a cancer cell could still inactivate PUMA, and this would sever the biochemical pathway that leads to apoptosis," Zambetti said. The St. Jude team is currently studying the impact of the loss of PUMA on tumor development.
"Theoretically, the use of novel drugs that could bypass inactive p53 to directly stimulate the PUMA gene might form the basis of a new therapy to kill tumors," Zambetti said. "Although it would be a real challenge to activate PUMA only in cancer cells, our discovery does show how vital PUMA is to a cell's ability to self-destruct, rather than become cancerous." Zambetti's colleague explained further.
"Conversely, blocking PUMA might give normal cells injured by cancer treatments a chance to recover instead of undergoing apoptosis," said John L. Cleveland, PhD, a co-author and member of the St. Jude department of Biochemistry. "Cancer chemotherapy is limited by toxic effects that kill blood-producing cells and in some cases brain cells. In the future, it might be possible to block PUMA to protect these normal cells from dying, while allowing doctors to treat patients with higher doses of anti-cancer drugs," he said.
The St. Jude team demonstrated a central role for PUMA under several conditions that normally activate apoptosis, both in cells grown in the lab as well as in experimental mice. Specifically, the researchers demonstrated that p53 triggers apoptosis in white blood cells called thymocytes following irradiation; but cells that lacked PUMA did not undergo apoptosis. Similar results were also reported by a second team, led by Andreas Strasser of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, who recently published their findings in the journal Science.
In addition, St. Jude researchers showed that irradiation caused apoptosis in various parts of the developing nervous system of mice when PUMA was present. But no apoptosis occurred in the developing nervous system of mice that lacked the PUMA gene. "We were able to show for the first time in an intact animal that PUMA is absolutely essential for apoptosis that causes significant damage in the developing nervous system following irradiation," said Peter J. McKinnon, PhD, a coauthor and associate member of the St. Jude department of Genetics. "This is important because it proved that what we saw in test tube experiments actually reflects what happens in animals-and presumably in humans."
In addition, the St. Jude investigators showed that the well-recognized oncogene c-Myc fails to turn cells cancerous in the presence of PUMA. Instead, the cells undergo apoptosis.
"The c-Myc gene is a classic cancer promoter," Cleveland said. "Our discovery that this notorious oncogene kills normal cells by activating PUMA is very significant. If we could activate PUMA in cancers that overexpress c-Myc they would then self-destruct." The investigators also showed that PUMA is critical to apoptosis pathways that do not rely on p53, thus making PUMA an even more widespread mediator of cell death than previously believed. This suggests that the study's findings could have relevance to diseases other than cancer, such as stroke and neurodegenerative diseases, according to Zambetti. "The demonstration of PUMA's key role in apoptosis promises to open up exciting and fruitful new areas of research in the molecular study of cancer and other catastrophic diseases," Zambetti said.
Other authors of the paper include John R. Jeffers, Youngsoo Lee, Chunying Yang, JinLing Wang, Jennifer Brennan, and Kirsteen H. MacLean (St. Jude); Evan Parganas and James Ihle (Howard Hughes Medical Institute at St. Jude); and Jiawen Han and Thomas Chittenden (ImmunoGen Inc., Cambridge Mass.).
The work was supported by grants from the National Cancer Institute, a National Institutes of Health Cancer Center CORE Grant and by ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization. For more information, please visit http://www.stjude.org.
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