PUMA Couples the Nuclear and Cytoplasmic Proapoptotic Function of p53

Jerry E. Chipuk, Lisa Bouchier-Hayes, Tomomi Kuwana, Donald D. Newmeyer, Douglas R. Green

doi:10.1126/science.1114297

PUMA Couples the Nuclear and Cytoplasmic Proapoptotic Function of p53

DOI Web Site 被引用文献6件

Jerry E. Chipuk

Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA.
Lisa Bouchier-Hayes

Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA.
Tomomi Kuwana

Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA.
Donald D. Newmeyer

Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA.
Douglas R. Green

Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA.

抄録

<jats:p> The <jats:italic>Trp53</jats:italic> 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 <jats:italic>PUMA</jats:italic> , 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 <jats:italic>PUMA</jats:italic> expression. Thus, PUMA couples the nuclear and cytoplasmic proapoptotic functions of p53. </jats:p>