p53 has a direct apoptogenic role at the mitochondria.
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.
Mihara
Motohiro
M
Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.
Erster
Susan
S
Zaika
Alexander
A
Petrenko
Oleksi
O
Chittenden
Thomas
T
Pancoska
Petr
P
Moll
Ute M
UM
D000818:Animals; D017209:Apoptosis; D003574:Cytochrome c Group / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D003574:Cytochrome c Group; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D004247:DNA