p53 has a direct apoptogenic role at the mitochondria.

Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll UM
Mol Cell. 2003 11 (3): 577-90

PMID: 12667443

p53 induces apoptosis by target gene regulation and transcription-independent signaling. However, a mechanism for the latter was unknown. We recently reported that a fraction of induced p53 translocates to the mitochondria of apoptosing tumor cells. Targeting p53 to mitochondria is sufficient to launch apoptosis. Here, we provide evidence that p53 translocation to the mitochondria occurs in vivo in irradiated thymocytes. Further, we show that the p53 protein can directly induce permeabilization of the outer mitochondrial membrane by forming complexes with the protective BclXL and Bcl2 proteins, resulting in cytochrome c release. p53 binds to BclXL via its DNA binding domain. We probe the significance of mitochondrial p53 and show that tumor-derived transactivation-deficient mutants of p53 concomitantly lose the ability to interact with BclXL and promote cytochrome c release. This opens the possibility that mutations might represent "double-hits" by abrogating the transcriptional and mitochondrial apoptotic activity of p53.

MeSH Terms (25)

Animals Apoptosis bcl-X Protein Cytochrome c Group DNA HeLa Cells Humans Immunoblotting In Situ Nick-End Labeling Mice Mice, Inbred C57BL Microsomes, Liver Mitochondria Models, Molecular Mutation Plasmids Protein Binding Protein Structure, Tertiary Proto-Oncogene Proteins c-bcl-2 Signal Transduction Structure-Activity Relationship Transcription, Genetic Transcriptional Activation Transfection Tumor Suppressor Protein p53

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