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.
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.