title: PUMA couples the nuclear and cytoplasmic proapoptotic function of p53.
abstract: 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.
authors.affiliation: Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Jerry E
authors.initials: JE
authors.lastname: Chipuk
authors.forename: Lisa
authors.initials: L
authors.lastname: Bouchier-Hayes
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kuwana
authors.forename: Donald D
authors.initials: DD
authors.lastname: Newmeyer
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism*; D004249:DNA Damage; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D010539:Permeability; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D014466:Ultraviolet Rays; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein