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- Title
The DNA-binding domain mediates both nuclear and cytosolic functions of p53.
- Authors
Follis, Ariele Viacava; Llambi, Fabien; Ou, Li; Baran, Katherine; Green, Douglas R; Kriwacki, Richard W
- 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.
- Subjects
P53 protein; CYTOSOL; APOPTOSIS; DNA-binding proteins; IRRADIATION
- Publication
Nature Structural & Molecular Biology, 2014, Vol 21, Issue 6, p535
- ISSN
1545-9993
- Publication type
Article
- DOI
10.1038/nsmb.2829