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Science 9 September 2005:
Vol. 309. no. 5741, pp. 1732 - 1735
DOI: 10.1126/science.1114297
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Reports

PUMA Couples the Nuclear and Cytoplasmic Proapoptotic Function of p53

Jerry E. Chipuk,1* Lisa Bouchier-Hayes,1 Tomomi Kuwana,1,2 Donald D. Newmeyer,1 Douglas R. Green1*{dagger}

The Trp53 tumor suppressor gene product (p53) functions in the nucleus to regulate proapoptotic genes, whereas cytoplasmic p53 directly activates proapoptotic Bcl-2 proteins to permeabilize mitochondria and initiate apoptosis. Here, we demonstrate that a tripartite nexus between Bcl-xL, cytoplasmic p53, and PUMA coordinates these distinct p53 functions. After genotoxic stress, Bcl-xL sequestered cytoplasmic p53. Nuclear p53 caused expression of PUMA, which then displaced p53 from Bcl-xL, allowing p53 to induce mitochondrial permeabilization. Mutant Bcl-xL that bound p53, but not PUMA, rendered cells resistant to p53-induced apoptosis irrespective of PUMA expression. Thus, PUMA couples the nuclear and cytoplasmic proapoptotic functions of p53.

1 Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA.
2 University of Iowa, Carver College of Medicine, Department of Pathology, Iowa City, IA 52242, USA.

* Present address: Department of Immunology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA.

{dagger} To whom correspondence should be addressed. E-mail: dgreen5240{at}aol.com

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