title: The DNA-binding domain mediates both nuclear and cytosolic functions of p53.
abstract: Under conditions of genotoxic stress, human p53 activates the apoptotic effectors BAX or BAK to result in mitochondrial outer-membrane permeabilization and apoptosis. Antiapoptotic BCL-2 family member BCL-xL opposes this activity by sequestering cytosolic p53 via association with its DNA-binding domain, an interaction enhanced by p53 tetramerization. Here we characterized the BCL-xL-p53 complex by NMR spectroscopy and modulated it through mutagenesis to determine the relative contributions of BCL-xL's interactions with p53 or other BCL-2 family proteins to the BCL-xL-dependent inhibition of UV irradiation-induced apoptosis. Under our experimental conditions, one-third of the antiapoptotic activity of BCL-xL was mediated by p53 sequestration and the remaining two-thirds through sequestration of proapoptotic BCL-2 family members. Our studies define the contributions of cytosolic p53 to UV irradiation-induced apoptosis and provide opportunities to explore its contributions to other p53-dependent apoptotic signaling pathways.
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Ariele Viacava
authors.initials: AV
authors.lastname: Follis
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Fabien
authors.initials: F
authors.lastname: Llambi
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ou
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Baran
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.affiliation: 1] Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Kriwacki
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D016296:Mutagenesis; D019906:Nuclear Magnetic Resonance, Biomolecular; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D014466:Ultraviolet Rays; D051020:bcl-X Protein / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology
chemical_list: C494811:BCL2L1 protein, human; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein