PUMA Protein Coordinates The Cell-suicide Activities Of p53 In The Nucleus And Cytoplasm
- Date:
- September 9, 2005
- Source:
- St. Jude Children's Research Hospital
- Summary:
- 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.
- Share:
MEMPHIS, TENN. (Sept. 8, 2005) -- The discovery of how the activitiesof the protein p53 initiate signals that trigger cell suicide offerscritical insights for developing new anti-cancer drugs, according toinvestigators from St. Jude Children's Research Hospital. A report onthis work appears in the September 9 issue of Science.
The new study showed that the protein PUMA frees p53 from the gripof a third protein, Bcl-xL, so p53 can activate the series of signalsthat triggers programmed cell suicide, or apoptosis. Apoptosis is themechanism by which abnormal cells are eliminated from the body beforethey can cause disease, including cancer. For example, if the cellsuffers a non-repairable injury to its genetic material, the p53 genebecomes active and produces the p53 protein, which accumulates both inthe nucleus and cytoplasm of the damaged cell. The accumulation of p53in the cytoplasm and nucleus each contribute to apoptosis, but untilthis finding, scientists did not know these contributions were linked.
The study's finding solves the long-standing puzzle of why p53activity occurs in both the nucleus and cytoplasm during apoptosis,according to Jerry E. Chipuk, Ph.D., now a post-doctoral fellow in theDepartment of Immunology at St. Jude Children's Research Hospital.Chipuk is the first author of the Science article. This work wascompleted, before his appointment at St. Jude, with colleagues at theLa Jolla Institute for Allergy and Immunology and the University ofIowa.
The researchers propose the following scenario for the role ofPUMA in apoptosis: First, p53 inside the nucleus regulates theexpression (activity) of several genes linked to apoptosis, includingPUMA. The PUMA protein is then produced in the cytoplasm, where otherp53 proteins are bound to Bcl-xL. Finally, PUMA binds to the p53/Bcl-xLpair, causing p53 to break free. After p53 is liberated, it triggers aseries of signals on the cell's mitochondria-tiny membrane-boundcapsules of enzymes that produce the energy-rich molecules required forcellular activities. The membranes covering mitochondria becomepunctured, allowing certain molecules to leak out and engage theprocess of apoptosis.
The binding of PUMA to the p53/Bcl-xL pair creates what Chipukdescribes as the "tripartite nexus" (three-part connection) thatorchestrates the complex web of signals leading to apoptosis.
"Our scenario consolidates a lot of evidence from our group and otherresearchers to explain how p53, Bcl-xL, and PUMA work together totrigger apoptosis," said Douglas Green, Ph.D., chair of the ImmunologyDepartment at St. Jude and senior author of the paper. Green previouslyled the Division of Cellular Immunology at the La Jolla Institute ofAllergy and Immunology (San Diego, CA). A leader in the field ofapoptosis, he will integrate immune system research into the ongoingefforts of St. Jude to improve diagnosis and treatment of childhoodcatastrophic diseases.
"The concept of the tripartite nexus also gives us insight into how todevelop novel drugs to save certain cells," Green said. "For example,if we could block the formation of the nexus in children receivingradiation or chemotherapy for cancer, we might be able to saveotherwise healthy cells from the side effects of these treatments. Or,we might be able to encourage the formation of the tripartite nexus incells that pose a threat to the body."
Green's team studied the interaction of p53, Bcl-xL and PUMA inlaboratory models of cells. The researchers combined a p53/Bcl-xL pairwith the cytosol (liquid part) of cells that had been exposed toultraviolet (UV) radiation. UV radiation damages genes and normallywould cause the tripartite nexus to assemble in order to triggerapoptosis.
Cytosol from normal cells containing the PUMA gene disrupted theBcl-xL/p53 complex; but cytosol from cells lacking this gene did notdisrupt the complex. This strongly suggested that PUMA is needed tofree p53 from Bcl-xL.
In addition, the researchers showed that when an excessiveamount of p53 was present, PUMA was no longer required to release p53from Bcl-xL. This occurred, for example, when there was not enoughBcl-xL to bind all of the p53 that was produced by multiple damagingevents to the cell's genetic material. In this scenario, even in theabsence of PUMA, enough free p53 was available to cause the membranesof mitochondria to be punctured and apoptosis to occur.
The team also showed that in the absence of the p53 gene, PUMA itselfcould not trigger the puncturing of mitochondria and subsequentapoptosis.
Other authors of the paper include Lisa Bouchier-Hayes and Donald D.Newmeyer (La Jolla Institute for Allergy and Immunology) and TomomiKuwana (La Jolla Institute for Allergy and Immunology; currently at theUniversity of Iowa, Department of Pathology, Iowa City, IA). This workwas supported in part by the National Institutes of Health and anIndividual National Research Service Award to Jerry E. Chipuk.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized forits pioneering work in finding cures and saving children with cancerand other catastrophic diseases. Founded by late entertainer DannyThomas and based in Memphis, Tenn., St. Jude freely shares itsdiscoveries with scientific and medical communities around the world.No family ever pays for treatments not covered by insurance, andfamilies without insurance are never asked to pay. St. Jude isfinancially supported by ALSAC, its fund-raising organization. For moreinformation, please visit www.stjude.org.
Story Source:
Materials provided by St. Jude Children's Research Hospital. Note: Content may be edited for style and length.
Cite This Page: