Researchers discover PUMA protein suicide role
activity occurs in both the nucleus and cytoplasm during apoptosis.
The discovery could form a basis in the development of new
anti-cancer therapies that target protein p53's activities.
Apoptosis is the mechanism in which abnormal cells are eliminated from the body before they can cause disease. Normally, 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.
According to investigators from St. Jude Children's Research Hospital, 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.
The researchers theorised that p53 inside the nucleus regulates the 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. PUMA then 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.
In addition, the binding of PUMA to the p53/Bcl-xL pair creates 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, chair of the Immunology Department at St. Jude and senior author of the paper.
"The concept of the tripartite nexus also gives us insight into how to develop novel drugs to save certain cells," Green added
If a method could be found to block the formation of the nexus in children receiving radiation or chemotherapy for cancer health cells might be saved from the side effects of these treatments. Or the encouragement of the formation of the tripartite nexus in cells that pose a threat to the body could be achieved.
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.
A report on this work appears in the September 9 issue of Science.
