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PUMA protein coordinates the cell-suicide activities of p53 in the nucleus and cytoplasm


PUMA travels from the nucleus to the cytoplasm to free p53 from the grip of Bcl-xL, allowing p53 to trigger signaling on mitochondria that leads to cell death, according to St. Jude

The discovery of how the activities of the protein p53 initiate signals that trigger cell suicide offers critical insights for developing new anti-cancer drugs, according to investigators from St. Jude Children’s Research Hospital. A report on this work appears in the September 9 issue of Science.

The new study showed that the protein PUMA frees p53 from the grip of a third protein, Bcl-xL, so p53 can activate the series of signals that triggers programmed cell suicide, or apoptosis. Apoptosis is the mechanism by which abnormal cells are eliminated from the body before they can cause disease, including cancer. For example, if the cell suffers a non-repairable injury to its genetic material, the p53 gene becomes active and produces the p53 protein, which accumulates both in the nucleus and cytoplasm of the damaged cell. The accumulation of p53 in the cytoplasm and nucleus each contribute to apoptosis, but until this finding, scientists did not know these contributions were linked.

The study’s finding solves the long-standing puzzle of why p53 activity occurs in both the nucleus and cytoplasm during apoptosis, according to Jerry E. Chipuk, Ph.D., now a post-doctoral fellow in the Department of Immunology at St. Jude Children’s Research Hospital. Chipuk is the first author of the Science article. This work was completed, before his appointment at St. Jude, with colleagues at the La Jolla Institute for Allergy and Immunology and the University of Iowa.

The researchers propose the following scenario for the role of PUMA in apoptosis: First, p53 inside the nucleus regulates the expression (activity) of several genes linked to apoptosis, including PUMA. The PUMA protein is then produced in the cytoplasm, where other p53 proteins are bound to Bcl-xL. Finally, PUMA binds to the p53/Bcl-xL pair, causing p53 to break free. After p53 is liberated, it triggers a series of signals on the cell’s mitochondria-tiny membrane-bound capsules of enzymes that produce the energy-rich molecules required for cellular activities. The membranes covering mitochondria become punctured, allowing certain molecules to leak out and engage the process of apoptosis.

The binding of PUMA to the p53/Bcl-xL pair creates what Chipuk describes as the "tripartite nexus" (three-part connection) that orchestrates the complex web of signals leading to apoptosis.

"Our scenario consolidates a lot of evidence from our group and other researchers to explain how p53, Bcl-xL, and PUMA work together to trigger apoptosis," said Douglas Green, Ph.D., chair of the Immunology Department at St. Jude and senior author of the paper. Green previously led the Division of Cellular Immunology at the La Jolla Institute of Allergy and Immunology (San Diego, CA). A leader in the field of apoptosis, he will integrate immune system research into the ongoing efforts of St. Jude to improve diagnosis and treatment of childhood catastrophic diseases.

"The concept of the tripartite nexus also gives us insight into how to develop novel drugs to save certain cells," Green said. "For example, if we could block the formation of the nexus in children receiving radiation or chemotherapy for cancer, we might be able to save otherwise healthy cells from the side effects of these treatments. Or, we might be able to encourage the formation of the tripartite nexus in cells that pose a threat to the body."

Green’s team studied the interaction of p53, Bcl-xL and PUMA in laboratory models of cells. The researchers combined a p53/Bcl-xL pair with the cytosol (liquid part) of cells that had been exposed to ultraviolet (UV) radiation. UV radiation damages genes and normally would cause the tripartite nexus to assemble in order to trigger apoptosis.

Cytosol from normal cells containing the PUMA gene disrupted the Bcl-xL/p53 complex; but cytosol from cells lacking this gene did not disrupt the complex. This strongly suggested that PUMA is needed to free p53 from Bcl-xL.

In addition, the researchers showed that when an excessive amount of p53 was present, PUMA was no longer required to release p53 from Bcl-xL. This occurred, for example, when there was not enough Bcl-xL to bind all of the p53 that was produced by multiple damaging events to the cell’s genetic material. In this scenario, even in the absence of PUMA, enough free p53 was available to cause the membranes of mitochondria to be punctured and apoptosis to occur.

The team also showed that in the absence of the p53 gene, PUMA itself could not trigger the puncturing of mitochondria and subsequent apoptosis.

Other authors of the paper include Lisa Bouchier-Hayes and Donald D. Newmeyer (La Jolla Institute for Allergy and Immunology) and Tomomi Kuwana (La Jolla Institute for Allergy and Immunology; currently at the University of Iowa, Department of Pathology, Iowa City, IA). This work was supported in part by the National Institutes of Health and an Individual National Research Service Award to Jerry E. Chipuk.

Carrie Strehlau | EurekAlert!
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